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-,Title,Genes,Version,Released Date,Link,path
-0,ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MYH7 Version 2.0.0,MYH7,2.0.0,4/22/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN002?version=2.0.0,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
-1,ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1,MYH7,1.0.0,6/25/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN002?version=1.0.0,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-0,ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3.1.0,PTEN,3.1.0,3/14/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN003?version=3.1.0,ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
-1,ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3.0.0,PTEN,3.0.0,3/27/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN003?version=3.0.0,ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.0.0_version=3.0.0.csv
-2,ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2,PTEN,2.0.0,9/10/2019,https://cspec.genome.network/cspec/ui/svi/doc/GN003?version=2.0.0,ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-3,ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 1.0.0,PTEN,1.0.0,8/17/2018,https://cspec.genome.network/cspec/ui/svi/doc/GN003?version=1.0.0,ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion1.0.0_version=1.0.0.csv
-0,"ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH23, COCH, GJB2, KCNQ4, MYO6, MYO7A, SLC26A4, TECTA and USH2A Version 2","CDH23, COCH, GJB2, KCNQ4, MYO6, MYO7A, SLC26A4, TECTA, USH2A",2.0.0,3/30/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN005?version=2.0.0,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
-1,ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1,"TECTA, KCNQ4, SLC26A4, MYO7A, USH2A, MYO6, GJB2, COCH, CDH23",1.0.0,8/15/2018,https://cspec.genome.network/cspec/ui/svi/doc/GN005?version=1.0.0,ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-0,ClinGen Phenylketonuria Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PAH Version 2.0.0,PAH,2.0.0,7/16/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN006?version=2.0.0,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
-1,ClinGen PAH Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1,PAH,1.0.0,3/2/2018,https://cspec.genome.network/cspec/ui/svi/doc/GN006?version=1.0.0,ClinGenPAHExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-0,ClinGen CDH1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 3.1,CDH1,3.1.0,3/29/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN007?version=3.1.0,ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
-1,ClinGen CDH1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 3,CDH1,3.0.0,9/21/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN007?version=3.0.0,ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3_version=3.0.0.csv
-2,ClinGen CDH1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2,CDH1,2.0.0,9/6/2019,https://cspec.genome.network/cspec/ui/svi/doc/GN007?version=2.0.0,ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-3,ClinGen CDH1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH1 Version 1.0.0,CDH1,1.0.0,9/19/2018,https://cspec.genome.network/cspec/ui/svi/doc/GN007?version=1.0.0,ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH1Version1.0.0_version=1.0.0.csv
-0,ClinGen Myeloid Malignancy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2,RUNX1,2.0.0,9/15/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN008?version=2.0.0,ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-1,ClinGen Myeloid Malignancy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1,RUNX1,1.0.0,7/10/2019,https://cspec.genome.network/cspec/ui/svi/doc/GN008?version=1.0.0,ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-0,ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.3.0,TP53,2.3.0,2/7/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN009?version=2.3.0,ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
-1,ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.2.0,TP53,2.2.0,9/30/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN009?version=2.2.0,ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.2.0_version=2.2.0.csv
-2,ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.1.0,TP53,2.1.0,9/13/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN009?version=2.1.0,ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.1.0_version=2.1.0.csv
-3,ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 2.0.0,TP53,2.0.0,7/30/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN009?version=2.0.0,ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.0.0_version=2.0.0.csv
-4,ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 1.4.0,TP53,1.4.0,7/5/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN009?version=1.4.0,ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version1.4.0_version=1.4.0.csv
-5,ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 1.3.0,TP53,1.3.0,3/8/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN009?version=1.3.0,ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version1.3.0_version=1.3.0.csv
-6,ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.2,TP53,1.2.0,8/6/2019,https://cspec.genome.network/cspec/ui/svi/doc/GN009?version=1.2.0,ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.2_version=1.2.0.csv
-7,ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 1.0.0,TP53,1.0.0,8/6/2019,https://cspec.genome.network/cspec/ui/svi/doc/GN009?version=1.0.0,ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version1.0.0_version=1.0.0.csv
-0,ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2,GAA,2.0.0,6/2/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN010?version=2.0.0,ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-0,ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2.1,"ITGA2B, ITGB3",2.1.0,11/1/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN011?version=2.1.0,ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2.1_version=2.1.0.csv
-1,ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2.0,"ITGA2B, ITGB3",2.0.0,9/4/2020,https://cspec.genome.network/cspec/ui/svi/doc/GN011?version=2.0.0,ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2.0_version=2.0.0.csv
-2,ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ITGA2B Version 1.0.0,"ITGA2B, ITGB3",1.0.0,6/12/2020,https://cspec.genome.network/cspec/ui/svi/doc/GN011?version=1.0.0,ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforITGA2BVersion1.0.0_version=1.0.0.csv
-0,ClinGen Malignant Hyperthermia Susceptibility Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RYR1 Version 2,RYR1,2.0.0,3/1/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN012?version=2.0.0,ClinGenMalignantHyperthermiaSusceptibilityExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRYR1Version2_version=2.0.0.csv
-1,ClinGen Malignant Hyperthermia Susceptibility Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1,RYR1,1.0.0,11/9/2020,https://cspec.genome.network/cspec/ui/svi/doc/GN012?version=1.0.0,ClinGenMalignantHyperthermiaSusceptibilityExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-0,ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2,LDLR,1.2.0,11/9/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN013?version=1.2.0,ClinGenFamilialHypercholesterolemiaExpertPanelSpecificationstotheACMGAMPVariantClassificationGuidelinesVersion1.2_version=1.2.0.csv
-0,ClinGen Mitochondrial Disease Nuclear and Mitochondrial Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1_ntDNA,"SLC19A3, PDHA1, POLG, ETHE1",1.0.0,4/30/2020,https://cspec.genome.network/cspec/ui/svi/doc/GN014?version=1.0.0,ClinGenMitochondrialDiseaseNuclearandMitochondrialExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_ntDNA_version=1.0.0.csv
-0,ClinGen Mitochondrial Disease Nuclear and Mitochondrial Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1_mtDNA,,1.0.0,4/30/2020,https://cspec.genome.network/cspec/ui/svi/doc/GN015?version=1.0.0,ClinGenMitochondrialDiseaseNuclearandMitochondrialExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_mtDNA_version=1.0.0.csv
-0,ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HNF1A Version 2.1.0,HNF1A,2.1.0,8/11/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN017?version=2.1.0,ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF1AVersion2.1.0_version=2.1.0.csv
-1,ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HNF1A Version 2.0.0,HNF1A,2.0.0,1/11/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN017?version=2.0.0,ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF1AVersion2.0.0_version=2.0.0.csv
-2,ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.2,HNF1A,1.2.0,6/5/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN017?version=1.2.0,ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.2_version=1.2.0.csv
-3,ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1,HNF1A,1.1.0,6/5/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN017?version=1.1.0,ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1_version=1.1.0.csv
-4,ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HNF1A Version 1.0.0,HNF1A,1.0.0,6/4/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN017?version=1.0.0,ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF1AVersion1.0.0_version=1.0.0.csv
-0,ClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1.0,"AKT3, MTOR, PIK3CA, PIK3R2",1.1.0,8/19/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN018?version=1.1.0,ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
-1,ClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1,"AKT3, MTOR, PIK3CA, PIK3R2",1.0.0,5/15/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN018?version=1.0.0,ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-0,ClinGen Glaucoma Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MYOC Version 2.0.0,MYOC,2.0.0,12/12/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN019?version=2.0.0,ClinGenGlaucomaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYOCVersion2.0.0_version=2.0.0.csv
-1,ClinGen Glaucoma Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1,MYOC,1.1.0,11/19/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN019?version=1.1.0,ClinGenGlaucomaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1_version=1.1.0.csv
-2,ClinGen Glaucoma Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1,MYOC,1.0.0,10/12/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN019?version=1.0.0,ClinGenGlaucomaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-0,"ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ATM Version 1.3.0",ATM,1.3.0,3/27/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN020?version=1.3.0,"ClinGenHereditaryBreast,OvarianandPancreaticCancerExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforATMVersion1.3.0_version=1.3.0.csv"
-1,"ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ATM Version 1.2.0",ATM,1.2.0,11/28/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN020?version=1.2.0,"ClinGenHereditaryBreast,OvarianandPancreaticCancerExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforATMVersion1.2.0_version=1.2.0.csv"
-2,"ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ATM Version 1.1",ATM,1.1.0,2/25/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN020?version=1.1.0,"ClinGenHereditaryBreast,OvarianandPancreaticCancerExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforATMVersion1.1_version=1.1.0.csv"
-3,"ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ATM Version 1",ATM,1.0.0,1/19/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN020?version=1.0.0,"ClinGenHereditaryBreast,OvarianandPancreaticCancerExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforATMVersion1_version=1.0.0.csv"
-0,ClinGen ACADVL Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1,ACADVL,1.0.0,11/9/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN021?version=1.0.0,ClinGenACADVLExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-0,ClinGen FBN1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1,FBN1,1.0.0,1/5/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN022?version=1.0.0,ClinGenFBN1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-0,ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for OTOF and MYO15A Version 1,"MYO15A, OTOF",1.0.0,3/30/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN023?version=1.0.0,ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforOTOFandMYO15AVersion1_version=1.0.0.csv
-0,ClinGen DICER1 and miRNA-Processing Gene Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DICER1 Version 1.3.0,DICER1,1.3.0,1/30/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN024?version=1.3.0,ClinGenDICER1andmiRNA-ProcessingGeneExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDICER1Version1.3.0_version=1.3.0.csv
-1,ClinGen DICER1 and miRNA-Processing Gene Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DICER1 Version 1.2.0,DICER1,1.2.0,5/31/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN024?version=1.2.0,ClinGenDICER1andmiRNA-ProcessingGeneExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDICER1Version1.2.0_version=1.2.0.csv
-2,ClinGen DICER1 and miRNA-Processing Gene Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DICER1 Version 1.1.0,DICER1,1.1.0,9/21/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN024?version=1.1.0,ClinGenDICER1andmiRNA-ProcessingGeneExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDICER1Version1.1.0_version=1.1.0.csv
-3,ClinGen DICER1 and miRNA-Processing Gene Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DICER1 Version 1,DICER1,1.0.0,5/5/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN024?version=1.0.0,ClinGenDICER1andmiRNA-ProcessingGeneExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDICER1Version1_version=1.0.0.csv
-0,ClinGen Cerebral Creatine Deficiency Syndromes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GATM Version 2.0.0,GATM,2.0.0,12/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN025?version=2.0.0,ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGATMVersion2.0.0_version=2.0.0.csv
-1,ClinGen Cerebral Creatine Deficiency Syndromes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GATM Version 1.1.0,GATM,1.1.0,9/14/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN025?version=1.1.0,ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGATMVersion1.1.0_version=1.1.0.csv
-2,ClinGen Cerebral Creatine Deficiency Syndromes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GATM Version 1,GATM,1.0.0,3/21/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN025?version=1.0.0,ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGATMVersion1_version=1.0.0.csv
-0,ClinGen Cerebral Creatine Deficiency Syndromes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GAMT Version 2.0.0,GAMT,2.0.0,5/23/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN026?version=2.0.0,ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGAMTVersion2.0.0_version=2.0.0.csv
-1,ClinGen Cerebral Creatine Deficiency Syndromes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GAMT Version 1.1.0,GAMT,1.1.0,9/14/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN026?version=1.1.0,ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGAMTVersion1.1.0_version=1.1.0.csv
-2,ClinGen Cerebral Creatine Deficiency Syndromes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GAMT Version 1,GAMT,1.0.0,3/21/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN026?version=1.0.0,ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGAMTVersion1_version=1.0.0.csv
-0,ClinGen Cerebral Creatine Deficiency Syndromes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SLC6A8 Version 1.2.0,SLC6A8,1.2.0,4/10/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN027?version=1.2.0,ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSLC6A8Version1.2.0_version=1.2.0.csv
-1,ClinGen Cerebral Creatine Deficiency Syndromes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SLC6A8 Version 1.1.0,SLC6A8,1.1.0,9/14/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN027?version=1.1.0,ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSLC6A8Version1.1.0_version=1.1.0.csv
-2,ClinGen Cerebral Creatine Deficiency Syndromes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SLC6A8 Version 1,SLC6A8,1.0.0,3/21/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN027?version=1.0.0,ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSLC6A8Version1_version=1.0.0.csv
-0,ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TCF4 Version 4.0.0,TCF4,4.0.0,2/28/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN032?version=4.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTCF4Version4.0.0_version=4.0.0.csv
-1,ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TCF4 Version 3.0.0,TCF4,3.0.0,5/9/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN032?version=3.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTCF4Version3.0.0_version=3.0.0.csv
-2,ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2,"CDKL5, FOXG1, MECP2, SLC9A6, TCF4, UBE3A",2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-3,ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1,"CDKL5, FOXG1, MECP2, SLC9A6, TCF4, UBE3A",1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-0,ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SLC9A6 Version 3.0.0,SLC9A6,3.0.0,5/9/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN033?version=3.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSLC9A6Version3.0.0_version=3.0.0.csv
-1,ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2,"CDKL5, FOXG1, MECP2, SLC9A6, TCF4, UBE3A",2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-2,ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1,"CDKL5, FOXG1, MECP2, SLC9A6, TCF4, UBE3A",1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-0,ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDKL5 Version 4.1.0,CDKL5,4.1.0,3/31/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN034?version=4.1.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDKL5Version4.1.0_version=4.1.0.csv
-1,ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDKL5 Version 4.0.0,CDKL5,4.0.0,2/26/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN034?version=4.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDKL5Version4.0.0_version=4.0.0.csv
-2,ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDKL5 Version 3.0.0,CDKL5,3.0.0,5/9/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN034?version=3.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDKL5Version3.0.0_version=3.0.0.csv
-3,ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2,"CDKL5, FOXG1, MECP2, SLC9A6, TCF4, UBE3A",2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-4,ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1,"CDKL5, FOXG1, MECP2, SLC9A6, TCF4, UBE3A",1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-0,ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for FOXG1 Version 4.1.0,FOXG1,4.1.0,3/31/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN035?version=4.1.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforFOXG1Version4.1.0_version=4.1.0.csv
-1,ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for FOXG1 Version 4.0.0,FOXG1,4.0.0,2/26/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN035?version=4.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforFOXG1Version4.0.0_version=4.0.0.csv
-2,ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for FOXG1 Version 3.0.0,FOXG1,3.0.0,5/9/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN035?version=3.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforFOXG1Version3.0.0_version=3.0.0.csv
-3,ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2,"CDKL5, FOXG1, MECP2, SLC9A6, TCF4, UBE3A",2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-4,ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1,"CDKL5, FOXG1, MECP2, SLC9A6, TCF4, UBE3A",1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-0,ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MECP2 Version 4.1.0,MECP2,4.1.0,3/31/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN036?version=4.1.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMECP2Version4.1.0_version=4.1.0.csv
-1,ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MECP2 Version 3.0.0,MECP2,3.0.0,5/9/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN036?version=3.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMECP2Version3.0.0_version=3.0.0.csv
-2,ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2,"CDKL5, FOXG1, MECP2, SLC9A6, TCF4, UBE3A",2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-3,ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1,"CDKL5, FOXG1, MECP2, SLC9A6, TCF4, UBE3A",1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-0,ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for UBE3A Version 5.0.0,UBE3A,5.0.0,2/28/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN037?version=5.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforUBE3AVersion5.0.0_version=5.0.0.csv
-1,ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for UBE3A Version 4.0.0,UBE3A,4.0.0,5/9/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN037?version=4.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforUBE3AVersion4.0.0_version=4.0.0.csv
-2,ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for UBE3A Version 3.0.0,UBE3A,3.0.0,11/10/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN037?version=3.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforUBE3AVersion3.0.0_version=3.0.0.csv
-3,ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2,"CDKL5, FOXG1, MECP2, SLC9A6, TCF4, UBE3A",2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-4,ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1,"CDKL5, FOXG1, MECP2, SLC9A6, TCF4, UBE3A",1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-0,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SHOC2 Version 2.3.0,SHOC2,2.3.0,12/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN038?version=2.3.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSHOC2Version2.3.0_version=2.3.0.csv
-1,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SHOC2 Version 2.2.0,SHOC2,2.2.0,12/2/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN038?version=2.2.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSHOC2Version2.2.0_version=2.2.0.csv
-2,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SHOC2 Version 2.1.0,SHOC2,2.1.0,9/17/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN038?version=2.1.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSHOC2Version2.1.0_version=2.1.0.csv
-3,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SHOC2 Version 2.0.0,SHOC2,2.0.0,8/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN038?version=2.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSHOC2Version2.0.0_version=2.0.0.csv
-4,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1,"SHOC2, NRAS, RAF1, SOS1, SOS2, PTPN11, KRAS, MAP2K1, HRAS, RIT1, MAP2K2, BRAF",1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-0,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for NRAS Version 2.3.0,NRAS,2.3.0,12/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN039?version=2.3.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforNRASVersion2.3.0_version=2.3.0.csv
-1,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for NRAS Version 2.2.0,NRAS,2.2.0,12/2/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN039?version=2.2.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforNRASVersion2.2.0_version=2.2.0.csv
-2,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for NRAS Version 2.1.0,NRAS,2.1.0,9/17/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN039?version=2.1.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforNRASVersion2.1.0_version=2.1.0.csv
-3,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for NRAS Version 2.0.0,NRAS,2.0.0,8/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN039?version=2.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforNRASVersion2.0.0_version=2.0.0.csv
-4,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1,"SHOC2, NRAS, RAF1, SOS1, SOS2, PTPN11, KRAS, MAP2K1, HRAS, RIT1, MAP2K2, BRAF",1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-0,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RAF1 Version 2.3.0,RAF1,2.3.0,12/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN040?version=2.3.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRAF1Version2.3.0_version=2.3.0.csv
-1,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RAF1 Version 2.2.0,RAF1,2.2.0,12/2/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN040?version=2.2.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRAF1Version2.2.0_version=2.2.0.csv
-2,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RAF1 Version 2.1.0,RAF1,2.1.0,9/17/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN040?version=2.1.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRAF1Version2.1.0_version=2.1.0.csv
-3,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RAF1 Version 2.0.0,RAF1,2.0.0,8/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN040?version=2.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRAF1Version2.0.0_version=2.0.0.csv
-4,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1,"SHOC2, NRAS, RAF1, SOS1, SOS2, PTPN11, KRAS, MAP2K1, HRAS, RIT1, MAP2K2, BRAF",1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-0,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SOS1 Version 2.3.0,SOS1,2.3.0,12/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN041?version=2.3.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS1Version2.3.0_version=2.3.0.csv
-1,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SOS1 Version 2.2.0,SOS1,2.2.0,12/2/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN041?version=2.2.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS1Version2.2.0_version=2.2.0.csv
-2,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SOS1 Version 2.1.0,SOS1,2.1.0,9/17/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN041?version=2.1.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS1Version2.1.0_version=2.1.0.csv
-3,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SOS1 Version 2.0.0,SOS1,2.0.0,8/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN041?version=2.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS1Version2.0.0_version=2.0.0.csv
-4,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1,"SHOC2, NRAS, RAF1, SOS1, SOS2, PTPN11, KRAS, MAP2K1, HRAS, RIT1, MAP2K2, BRAF",1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-0,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SOS2 Version 2.3.0,SOS2,2.3.0,12/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN042?version=2.3.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS2Version2.3.0_version=2.3.0.csv
-1,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SOS2 Version 2.2.0,SOS2,2.2.0,12/2/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN042?version=2.2.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS2Version2.2.0_version=2.2.0.csv
-2,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SOS2 Version 2.1.0,SOS2,2.1.0,9/17/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN042?version=2.1.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS2Version2.1.0_version=2.1.0.csv
-3,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SOS2 Version 2.0.0,SOS2,2.0.0,8/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN042?version=2.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS2Version2.0.0_version=2.0.0.csv
-4,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1,"SHOC2, NRAS, RAF1, SOS1, SOS2, PTPN11, KRAS, MAP2K1, HRAS, RIT1, MAP2K2, BRAF",1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-0,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTPN11 Version 2.3.0,PTPN11,2.3.0,12/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN043?version=2.3.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTPN11Version2.3.0_version=2.3.0.csv
-1,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTPN11 Version 2.2.0,PTPN11,2.2.0,12/2/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN043?version=2.2.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTPN11Version2.2.0_version=2.2.0.csv
-2,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTPN11 Version 2.1.0,PTPN11,2.1.0,9/17/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN043?version=2.1.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTPN11Version2.1.0_version=2.1.0.csv
-3,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTPN11 Version 2.0.0,PTPN11,2.0.0,8/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN043?version=2.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTPN11Version2.0.0_version=2.0.0.csv
-4,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1,"SHOC2, NRAS, RAF1, SOS1, SOS2, PTPN11, KRAS, MAP2K1, HRAS, RIT1, MAP2K2, BRAF",1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-0,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KRAS Version 2.3.0,KRAS,2.3.0,12/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN044?version=2.3.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforKRASVersion2.3.0_version=2.3.0.csv
-1,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KRAS Version 2.2.0,KRAS,2.2.0,12/2/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN044?version=2.2.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforKRASVersion2.2.0_version=2.2.0.csv
-2,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KRAS Version 2.1.0,KRAS,2.1.0,9/17/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN044?version=2.1.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforKRASVersion2.1.0_version=2.1.0.csv
-3,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KRAS Version 2.0.0,KRAS,2.0.0,8/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN044?version=2.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforKRASVersion2.0.0_version=2.0.0.csv
-4,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1,"SHOC2, NRAS, RAF1, SOS1, SOS2, PTPN11, KRAS, MAP2K1, HRAS, RIT1, MAP2K2, BRAF",1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-0,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MAP2K1 Version 2.3.0,MAP2K1,2.3.0,12/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN045?version=2.3.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K1Version2.3.0_version=2.3.0.csv
-1,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MAP2K1 Version 2.2.0,MAP2K1,2.2.0,12/2/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN045?version=2.2.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K1Version2.2.0_version=2.2.0.csv
-2,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MAP2K1 Version 2.1.0,MAP2K1,2.1.0,9/17/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN045?version=2.1.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K1Version2.1.0_version=2.1.0.csv
-3,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MAP2K1 Version 2.0.0,MAP2K1,2.0.0,8/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN045?version=2.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K1Version2.0.0_version=2.0.0.csv
-4,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1,"SHOC2, NRAS, RAF1, SOS1, SOS2, PTPN11, KRAS, MAP2K1, HRAS, RIT1, MAP2K2, BRAF",1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-0,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HRAS Version 2.3.0,HRAS,2.3.0,12/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN046?version=2.3.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHRASVersion2.3.0_version=2.3.0.csv
-1,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HRAS Version 2.2.0,HRAS,2.2.0,12/2/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN046?version=2.2.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHRASVersion2.2.0_version=2.2.0.csv
-2,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HRAS Version 2.1.0,HRAS,2.1.0,9/17/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN046?version=2.1.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHRASVersion2.1.0_version=2.1.0.csv
-3,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HRAS Version 2.0.0,HRAS,2.0.0,8/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN046?version=2.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHRASVersion2.0.0_version=2.0.0.csv
-4,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1,"SHOC2, NRAS, RAF1, SOS1, SOS2, PTPN11, KRAS, MAP2K1, HRAS, RIT1, MAP2K2, BRAF",1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-0,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RIT1 Version 2.3.0,RIT1,2.3.0,12/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN047?version=2.3.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRIT1Version2.3.0_version=2.3.0.csv
-1,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RIT1 Version 2.2.0,RIT1,2.2.0,12/2/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN047?version=2.2.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRIT1Version2.2.0_version=2.2.0.csv
-2,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RIT1 Version 2.1.0,RIT1,2.1.0,9/17/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN047?version=2.1.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRIT1Version2.1.0_version=2.1.0.csv
-3,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RIT1 Version 2.0.0,RIT1,2.0.0,8/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN047?version=2.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRIT1Version2.0.0_version=2.0.0.csv
-4,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1,"SHOC2, NRAS, RAF1, SOS1, SOS2, PTPN11, KRAS, MAP2K1, HRAS, RIT1, MAP2K2, BRAF",1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-0,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MAP2K2 Version 2.3.0,MAP2K2,2.3.0,12/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN048?version=2.3.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K2Version2.3.0_version=2.3.0.csv
-1,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MAP2K2 Version 2.2.0,MAP2K2,2.2.0,12/2/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN048?version=2.2.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K2Version2.2.0_version=2.2.0.csv
-2,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MAP2K2 Version 2.1.0,MAP2K2,2.1.0,9/17/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN048?version=2.1.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K2Version2.1.0_version=2.1.0.csv
-3,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MAP2K2 Version 2.0.0,MAP2K2,2.0.0,8/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN048?version=2.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K2Version2.0.0_version=2.0.0.csv
-4,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1,"SHOC2, NRAS, RAF1, SOS1, SOS2, PTPN11, KRAS, MAP2K1, HRAS, RIT1, MAP2K2, BRAF",1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-0,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRAF Version 2.3.0,BRAF,2.3.0,12/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN049?version=2.3.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRAFVersion2.3.0_version=2.3.0.csv
-1,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRAF Version 2.2.0,BRAF,2.2.0,12/2/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN049?version=2.2.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRAFVersion2.2.0_version=2.2.0.csv
-2,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRAF Version 2.1.0,BRAF,2.1.0,9/17/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN049?version=2.1.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRAFVersion2.1.0_version=2.1.0.csv
-3,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRAF Version 2.0.0,BRAF,2.0.0,8/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN049?version=2.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRAFVersion2.0.0_version=2.0.0.csv
-4,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1,"SHOC2, NRAS, RAF1, SOS1, SOS2, PTPN11, KRAS, MAP2K1, HRAS, RIT1, MAP2K2, BRAF",1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-0,ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN1A Version 2.0.0,SCN1A,2.0.0,1/7/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN067?version=2.0.0,ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN1AVersion2.0.0_version=2.0.0.csv
-1,ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN1A Version 1.0.0,SCN1A,1.0.0,3/19/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN067?version=1.0.0,ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN1AVersion1.0.0_version=1.0.0.csv
-0,ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN2A Version 2.0.0,SCN2A,2.0.0,1/7/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN068?version=2.0.0,ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN2AVersion2.0.0_version=2.0.0.csv
-1,ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN2A Version 1.0.0,SCN2A,1.0.0,3/19/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN068?version=1.0.0,ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN2AVersion1.0.0_version=1.0.0.csv
-0,ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN3A Version 2.0.0,SCN3A,2.0.0,1/7/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN069?version=2.0.0,ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN3AVersion2.0.0_version=2.0.0.csv
-1,ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN3A Version 1.0.0,SCN3A,1.0.0,3/19/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN069?version=1.0.0,ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN3AVersion1.0.0_version=1.0.0.csv
-0,ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN8A Version 2.0.0,SCN8A,2.0.0,1/7/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN070?version=2.0.0,ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN8AVersion2.0.0_version=2.0.0.csv
-1,ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN8A Version 1.0.0,SCN8A,1.0.0,3/19/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN070?version=1.0.0,ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN8AVersion1.0.0_version=1.0.0.csv
-0,ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F8 Version 1.0.0,F8,1.0.0,10/5/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN071?version=1.0.0,ClinGenCoagulationFactorDeficiencyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforF8Version1.0.0_version=1.0.0.csv
-0,ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN1B Version 2.0.0,SCN1B,2.0.0,1/7/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN076?version=2.0.0,ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN1BVersion2.0.0_version=2.0.0.csv
-1,ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN1B Version 1.0.0,SCN1B,1.0.0,3/19/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN076?version=1.0.0,ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN1BVersion1.0.0_version=1.0.0.csv
-0,"ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PALB2 Version 1.1.0",PALB2,1.1.0,11/28/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN077?version=1.1.0,"ClinGenHereditaryBreast,OvarianandPancreaticCancerExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPALB2Version1.1.0_version=1.1.0.csv"
-1,"ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PALB2 Version 1.0.0",PALB2,1.0.0,3/17/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN077?version=1.0.0,"ClinGenHereditaryBreast,OvarianandPancreaticCancerExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPALB2Version1.0.0_version=1.0.0.csv"
-0,ClinGen VHL Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VHL Version 1.1.0,VHL,1.1.0,1/10/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN078?version=1.1.0,ClinGenVHLExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforVHLVersion1.1.0_version=1.1.0.csv
-1,ClinGen VHL Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VHL Version 1.0.0,VHL,1.0.0,2/29/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN078?version=1.0.0,ClinGenVHLExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforVHLVersion1.0.0_version=1.0.0.csv
-0,ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GP1BA Version 1.0.0,GP1BA,1.0.0,2/12/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN079?version=1.0.0,ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGP1BAVersion1.0.0_version=1.0.0.csv
-0,ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F9 Version 1.0.0,F9,1.0.0,10/5/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN080?version=1.0.0,ClinGenCoagulationFactorDeficiencyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforF9Version1.0.0_version=1.0.0.csv
-0,ClinGen von Willebrand Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VWF Version 1.0.0,VWF,1.0.0,7/9/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN081?version=1.0.0,ClinGenvonWillebrandDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforVWFVersion1.0.0_version=1.0.0.csv
-0,ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GP1BB Version 1.0.0,GP1BB,1.0.0,2/12/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN082?version=1.0.0,ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGP1BBVersion1.0.0_version=1.0.0.csv
-0,ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GP9 Version 1.0.0,GP9,1.0.0,2/11/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN083?version=1.0.0,ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGP9Version1.0.0_version=1.0.0.csv
-0,ClinGen Thrombosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPINC1 Version 1.1.0,SERPINC1,1.1.0,2/7/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN084?version=1.1.0,ClinGenThrombosisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSERPINC1Version1.1.0_version=1.1.0.csv
-1,ClinGen Thrombosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPINC1 Version 1.0.0,SERPINC1,1.0.0,7/17/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN084?version=1.0.0,ClinGenThrombosisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSERPINC1Version1.0.0_version=1.0.0.csv
-0,ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HNF4A Version 2.0.0,HNF4A,2.0.0,10/11/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN085?version=2.0.0,ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF4AVersion2.0.0_version=2.0.0.csv
-1,ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HNF4A Version 1.1.0,HNF4A,1.1.0,8/11/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN085?version=1.1.0,ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF4AVersion1.1.0_version=1.1.0.csv
-2,ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HNF4A Version 1.0.0,HNF4A,1.0.0,11/16/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN085?version=1.0.0,ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF4AVersion1.0.0_version=1.0.0.csv
-0,ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GCK Version 2.0.0,GCK,2.0.0,2/17/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN086?version=2.0.0,ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGCKVersion2.0.0_version=2.0.0.csv
-1,ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GCK Version 1.3.0,GCK,1.3.0,8/11/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN086?version=1.3.0,ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGCKVersion1.3.0_version=1.3.0.csv
-2,ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GCK Version 1.2.0,GCK,1.2.0,6/7/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN086?version=1.2.0,ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGCKVersion1.2.0_version=1.2.0.csv
-3,ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GCK Version 1.1.0,GCK,1.1.0,3/23/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN086?version=1.1.0,ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGCKVersion1.1.0_version=1.1.0.csv
-4,ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GCK Version 1.0.0,GCK,1.0.0,11/16/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN086?version=1.0.0,ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGCKVersion1.0.0_version=1.0.0.csv
-0,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MRAS Version 1.4.0,MRAS,1.4.0,12/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN087?version=1.4.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMRASVersion1.4.0_version=1.4.0.csv
-1,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MRAS Version 1.3.0,MRAS,1.3.0,12/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN087?version=1.3.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMRASVersion1.3.0_version=1.3.0.csv
-2,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MRAS Version 1.2.0,MRAS,1.2.0,12/2/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN087?version=1.2.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMRASVersion1.2.0_version=1.2.0.csv
-3,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MRAS Version 1.1.0,MRAS,1.1.0,9/17/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN087?version=1.1.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMRASVersion1.1.0_version=1.1.0.csv
-4,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MRAS Version 1.0.0,MRAS,1.0.0,8/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN087?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMRASVersion1.0.0_version=1.0.0.csv
-0,ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for APC Version 2.1.0,APC,2.1.0,11/24/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN089?version=2.1.0,ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforAPCVersion2.1.0_version=2.1.0.csv
-1,ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for APC Version 2.0.3,APC,2.0.3,7/24/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN089?version=2.0.3,ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforAPCVersion2.0.3_version=2.0.3.csv
-2,ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for APC Version 1.0.0,APC,1.0.0,1/10/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN089?version=1.0.0,ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforAPCVersion1.0.0_version=1.0.0.csv
-0,ClinGen von Willebrand Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VWF Version 1.0.0,VWF,1.0.0,7/9/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN090?version=1.0.0,ClinGenvonWillebrandDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforVWFVersion1.0.0_version=1.0.0.csv
-0,ClinGen Lysosomal Diseases Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for IDUA Version 1.0.0,IDUA,1.0.0,12/5/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN091?version=1.0.0,ClinGenLysosomalDiseasesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforIDUAVersion1.0.0_version=1.0.0.csv
-0,ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA1 Version 1.2.0,BRCA1,1.2.0,1/9/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN092?version=1.2.0,ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA1Version1.2.0_version=1.2.0.csv
-1,ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA1 Version 1.1.0,BRCA1,1.1.0,12/21/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN092?version=1.1.0,ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA1Version1.1.0_version=1.1.0.csv
-2,ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA1 Version 1.0.0,BRCA1,1.0.0,8/9/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN092?version=1.0.0,ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA1Version1.0.0_version=1.0.0.csv
-0,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for LZTR1 Version 1.3.0,LZTR1,1.3.0,12/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN094?version=1.3.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforLZTR1Version1.3.0_version=1.3.0.csv
-1,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for LZTR1 Version 1.2.0,LZTR1,1.2.0,12/2/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN094?version=1.2.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforLZTR1Version1.2.0_version=1.2.0.csv
-2,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for LZTR1 Version 1.1.0,LZTR1,1.1.0,9/17/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN094?version=1.1.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforLZTR1Version1.1.0_version=1.1.0.csv
-3,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for LZTR1 Version 1.0.0,LZTR1,1.0.0,8/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN094?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforLZTR1Version1.0.0_version=1.0.0.csv
-0,ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MYBPC3 Version 1.0.0,MYBPC3,1.0.0,4/22/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN095?version=1.0.0,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYBPC3Version1.0.0_version=1.0.0.csv
-0,ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA2 Version 1.2.0,BRCA2,1.2.0,1/9/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN097?version=1.2.0,ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA2Version1.2.0_version=1.2.0.csv
-1,ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA2 Version 1.1.0,BRCA2,1.1.0,12/21/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN097?version=1.1.0,ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA2Version1.1.0_version=1.1.0.csv
-2,ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA2 Version 1.0.0,BRCA2,1.0.0,8/9/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN097?version=1.0.0,ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA2Version1.0.0_version=1.0.0.csv
-0,ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TNNI3 Version 1.0.0,TNNI3,1.0.0,4/22/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN098?version=1.0.0,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTNNI3Version1.0.0_version=1.0.0.csv
-0,ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TNNT2 Version 1.0.0,TNNT2,1.0.0,4/22/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN099?version=1.0.0,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTNNT2Version1.0.0_version=1.0.0.csv
-0,ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TPM1 Version 1.0.0,TPM1,1.0.0,4/22/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN100?version=1.0.0,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTPM1Version1.0.0_version=1.0.0.csv
-0,ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ACTC1 Version 1.0.0,ACTC1,1.0.0,4/22/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN101?version=1.0.0,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforACTC1Version1.0.0_version=1.0.0.csv
-0,ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MYL2 Version 1.0.0,MYL2,1.0.0,4/22/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN102?version=1.0.0,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYL2Version1.0.0_version=1.0.0.csv
-0,ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MYL3 Version 1.0.0,MYL3,1.0.0,4/22/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN103?version=1.0.0,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYL3Version1.0.0_version=1.0.0.csv
-0,ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for FOXN1 Version 1.0.0,FOXN1,1.0.0,7/29/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN113?version=1.0.0,ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforFOXN1Version1.0.0_version=1.0.0.csv
-0,ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ADA Version 1.0.0,ADA,1.0.0,10/9/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN114?version=1.0.0,ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforADAVersion1.0.0_version=1.0.0.csv
-0,ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MLH1 Version 1.0.0,MLH1,1.0.0,8/9/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN115?version=1.0.0,ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMLH1Version1.0.0_version=1.0.0.csv
-0,ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DCLRE1C Version 1.0.0,DCLRE1C,1.0.0,10/9/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN116?version=1.0.0,ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDCLRE1CVersion1.0.0_version=1.0.0.csv
-0,ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for IL7R Version 1.0.0,IL7R,1.0.0,10/9/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN119?version=1.0.0,ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforIL7RVersion1.0.0_version=1.0.0.csv
-0,ClinGen Leber Congenital Amaurosis/early onset Retinal Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPE65 Version 1.0.0,RPE65,1.0.0,10/24/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN120?version=1.0.0,ClinGenLeberCongenitalAmaurosisearlyonsetRetinalDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRPE65Version1.0.0_version=1.0.0.csv
-0,ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for JAK3 Version 1.0.0,JAK3,1.0.0,10/9/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN121?version=1.0.0,ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforJAK3Version1.0.0_version=1.0.0.csv
-0,ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RAG1 Version 1.0.0,RAG1,1.0.0,10/9/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN123?version=1.0.0,ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRAG1Version1.0.0_version=1.0.0.csv
-0,ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RAG2 Version 1.0.0,RAG2,1.0.0,10/9/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN124?version=1.0.0,ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRAG2Version1.0.0_version=1.0.0.csv
-0,ClinGen Pulmonary Hypertension Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BMPR2 Version 1.1.0,BMPR2,1.1.0,4/6/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN125?version=1.1.0,ClinGenPulmonaryHypertensionExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBMPR2Version1.1.0_version=1.1.0.csv
-1,ClinGen Pulmonary Hypertension Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BMPR2 Version 1.0.0,BMPR2,1.0.0,3/1/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN125?version=1.0.0,ClinGenPulmonaryHypertensionExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBMPR2Version1.0.0_version=1.0.0.csv
-0,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RRAS2 Version 1.3.0,RRAS2,1.3.0,12/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN127?version=1.3.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRRAS2Version1.3.0_version=1.3.0.csv
-1,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RRAS2 Version 1.2.0,RRAS2,1.2.0,12/2/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN127?version=1.2.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRRAS2Version1.2.0_version=1.2.0.csv
-2,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RRAS2 Version 1.1.0,RRAS2,1.1.0,9/17/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN127?version=1.1.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRRAS2Version1.1.0_version=1.1.0.csv
-3,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RRAS2 Version 1.0.0,RRAS2,1.0.0,8/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN127?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRRAS2Version1.0.0_version=1.0.0.csv
-0,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PPP1CB Version 1.3.0,PPP1CB,1.3.0,12/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN128?version=1.3.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPPP1CBVersion1.3.0_version=1.3.0.csv
-1,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PPP1CB Version 1.2.0,PPP1CB,1.2.0,12/2/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN128?version=1.2.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPPP1CBVersion1.2.0_version=1.2.0.csv
-2,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PPP1CB Version 1.1.0,PPP1CB,1.1.0,9/17/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN128?version=1.1.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPPP1CBVersion1.1.0_version=1.1.0.csv
-3,ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PPP1CB Version 1.0.0,PPP1CB,1.0.0,8/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN128?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPPP1CBVersion1.0.0_version=1.0.0.csv
-0,ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for IL2RG Version 1.0.0,IL2RG,1.0.0,10/9/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN129?version=1.0.0,ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforIL2RGVersion1.0.0_version=1.0.0.csv
-0,ClinGen Hereditary Hemorrhagic Telangiectasia Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ACVRL1 Version 1.1.0,ACVRL1,1.1.0,3/20/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN135?version=1.1.0,ClinGenHereditaryHemorrhagicTelangiectasiaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforACVRL1Version1.1.0_version=1.1.0.csv
-1,ClinGen Hereditary Hemorrhagic Telangiectasia Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ACVRL1 Version 1.0.0,ACVRL1,1.0.0,3/5/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN135?version=1.0.0,ClinGenHereditaryHemorrhagicTelangiectasiaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforACVRL1Version1.0.0_version=1.0.0.csv
-0,ClinGen Hereditary Hemorrhagic Telangiectasia Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ENG Version 1.1.0,ENG,1.1.0,3/20/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN136?version=1.1.0,ClinGenHereditaryHemorrhagicTelangiectasiaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforENGVersion1.1.0_version=1.1.0.csv
-1,ClinGen Hereditary Hemorrhagic Telangiectasia Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ENG Version 1.0.0,ENG,1.0.0,3/5/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN136?version=1.0.0,ClinGenHereditaryHemorrhagicTelangiectasiaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforENGVersion1.0.0_version=1.0.0.csv
-0,ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MSH2 Version 1.0.0,MSH2,1.0.0,8/9/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN137?version=1.0.0,ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMSH2Version1.0.0_version=1.0.0.csv
-0,ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MSH6 Version 1.0.0,MSH6,1.0.0,8/9/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN138?version=1.0.0,ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMSH6Version1.0.0_version=1.0.0.csv
-0,ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PMS2 Version 1.0.0,PMS2,1.0.0,8/9/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN139?version=1.0.0,ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPMS2Version1.0.0_version=1.0.0.csv
-1,ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PMS2 Version 1.0.0,PMS2,1.0.0,8/9/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN139?version=1.0.0,ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPMS2Version1.0.0_version=1.0.0.csv
-0,ClinGen Congenital Myopathies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for NEB Version 1.0.0,NEB,1.0.0,8/7/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN146?version=1.0.0,ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforNEBVersion1.0.0_version=1.0.0.csv
-0,ClinGen Congenital Myopathies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ACTA1 Version 2.0.0,ACTA1,2.0.0,8/27/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN147?version=2.0.0,ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforACTA1Version2.0.0_version=2.0.0.csv
-1,ClinGen Congenital Myopathies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ACTA1 Version 1.0.0,ACTA1,1.0.0,8/7/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN147?version=1.0.0,ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforACTA1Version1.0.0_version=1.0.0.csv
-0,ClinGen Congenital Myopathies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DNM2 Version 1.0.0,DNM2,1.0.0,8/7/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN148?version=1.0.0,ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDNM2Version1.0.0_version=1.0.0.csv
-0,ClinGen Congenital Myopathies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MTM1 Version 1.0.0,MTM1,1.0.0,8/7/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN149?version=1.0.0,ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMTM1Version1.0.0_version=1.0.0.csv
-0,ClinGen Congenital Myopathies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RYR1 Version 2.0.0,RYR1,2.0.0,12/12/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN150?version=2.0.0,ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRYR1Version2.0.0_version=2.0.0.csv
-1,ClinGen Congenital Myopathies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RYR1 Version 1.0.0,RYR1,1.0.0,8/7/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN150?version=1.0.0,ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRYR1Version1.0.0_version=1.0.0.csv
-0,ClinGen Leber Congenital Amaurosis/early onset Retinal Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GUCY2D Version 1.0.0,GUCY2D,1.0.0,1/22/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN167?version=1.0.0,ClinGenLeberCongenitalAmaurosisearlyonsetRetinalDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGUCY2DVersion1.0.0_version=1.0.0.csv
-0,ClinGen Congenital Myopathies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ACTA1 Version 1.0.0,ACTA1,1.0.0,8/7/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN169?version=1.0.0,ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforACTA1Version1.0.0_version=1.0.0.csv
-0,ClinGen Congenital Myopathies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RYR1 Version 2.0.0,RYR1,2.0.0,12/12/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN179?version=2.0.0,ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRYR1Version2.0.0_version=2.0.0.csv
-1,ClinGen Congenital Myopathies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RYR1 Version 1.0.0,RYR1,1.0.0,8/7/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN179?version=1.0.0,ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRYR1Version1.0.0_version=1.0.0.csv
-0,ClinGen Limb Girdle Muscular Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DYSF Version 1.0.0,DYSF,1.0.0,1/7/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN180?version=1.0.0,ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDYSFVersion1.0.0_version=1.0.0.csv
-0,ClinGen Limb Girdle Muscular Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SGCB Version 1.0.0,SGCB,1.0.0,1/7/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN184?version=1.0.0,ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSGCBVersion1.0.0_version=1.0.0.csv
-0,ClinGen Limb Girdle Muscular Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SGCG Version 1.0.0,SGCG,1.0.0,1/7/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN185?version=1.0.0,ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSGCGVersion1.0.0_version=1.0.0.csv
-0,ClinGen Limb Girdle Muscular Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SGCD Version 1.0.0,SGCD,1.0.0,1/7/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN186?version=1.0.0,ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSGCDVersion1.0.0_version=1.0.0.csv
-0,ClinGen Limb Girdle Muscular Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CAPN3 Version 1.0.0,CAPN3,1.0.0,1/7/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN187?version=1.0.0,ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCAPN3Version1.0.0_version=1.0.0.csv
-0,ClinGen Limb Girdle Muscular Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ANO5 Version 1.0.0,ANO5,1.0.0,1/7/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN188?version=1.0.0,ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforANO5Version1.0.0_version=1.0.0.csv
-0,ClinGen Limb Girdle Muscular Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SGCA Version 1.0.0,SGCA,1.0.0,1/7/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN189?version=1.0.0,ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSGCAVersion1.0.0_version=1.0.0.csv
diff --git a/VCI/parsing_csr_criteria/cspec_version_guide_processed.csv b/VCI/parsing_csr_criteria/cspec_version_guide_processed.csv
deleted file mode 100644
index 3bfde5375503b34111c1f0e360d53c6d08a02e14..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/cspec_version_guide_processed.csv
+++ /dev/null
@@ -1,474 +0,0 @@
-Title,Genes,Version,Released Date,Link,path
-Cardiomyopathy,MYH7,2.0.0,4/22/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN002?version=2.0.0,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
-Cardiomyopathy,MYH7,1.0.0,6/25/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN002?version=1.0.0,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-PTEN,PTEN,3.1.0,3/14/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN003?version=3.1.0,ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
-PTEN,PTEN,3.0.0,3/27/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN003?version=3.0.0,ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.0.0_version=3.0.0.csv
-PTEN,PTEN,2.0.0,9/10/2019,https://cspec.genome.network/cspec/ui/svi/doc/GN003?version=2.0.0,ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-PTEN,PTEN,1.0.0,8/17/2018,https://cspec.genome.network/cspec/ui/svi/doc/GN003?version=1.0.0,ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion1.0.0_version=1.0.0.csv
-Hearing Loss,CDH23,2.0.0,3/30/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN005?version=2.0.0,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
-Hearing Loss,COCH,2.0.0,3/30/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN005?version=2.0.0,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
-Hearing Loss,GJB2,2.0.0,3/30/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN005?version=2.0.0,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
-Hearing Loss,KCNQ4,2.0.0,3/30/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN005?version=2.0.0,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
-Hearing Loss,MYO6,2.0.0,3/30/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN005?version=2.0.0,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
-Hearing Loss,MYO7A,2.0.0,3/30/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN005?version=2.0.0,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
-Hearing Loss,SLC26A4,2.0.0,3/30/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN005?version=2.0.0,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
-Hearing Loss,TECTA,2.0.0,3/30/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN005?version=2.0.0,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
-Hearing Loss,USH2A,2.0.0,3/30/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN005?version=2.0.0,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
-Hearing Loss,TECTA,1.0.0,8/15/2018,https://cspec.genome.network/cspec/ui/svi/doc/GN005?version=1.0.0,ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Hearing Loss,KCNQ4,1.0.0,8/15/2018,https://cspec.genome.network/cspec/ui/svi/doc/GN005?version=1.0.0,ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Hearing Loss,SLC26A4,1.0.0,8/15/2018,https://cspec.genome.network/cspec/ui/svi/doc/GN005?version=1.0.0,ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Hearing Loss,MYO7A,1.0.0,8/15/2018,https://cspec.genome.network/cspec/ui/svi/doc/GN005?version=1.0.0,ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Hearing Loss,USH2A,1.0.0,8/15/2018,https://cspec.genome.network/cspec/ui/svi/doc/GN005?version=1.0.0,ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Hearing Loss,MYO6,1.0.0,8/15/2018,https://cspec.genome.network/cspec/ui/svi/doc/GN005?version=1.0.0,ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Hearing Loss,GJB2,1.0.0,8/15/2018,https://cspec.genome.network/cspec/ui/svi/doc/GN005?version=1.0.0,ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Hearing Loss,COCH,1.0.0,8/15/2018,https://cspec.genome.network/cspec/ui/svi/doc/GN005?version=1.0.0,ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Hearing Loss,CDH23,1.0.0,8/15/2018,https://cspec.genome.network/cspec/ui/svi/doc/GN005?version=1.0.0,ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Phenylketonuria,PAH,2.0.0,7/16/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN006?version=2.0.0,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
-PAH,PAH,1.0.0,3/2/2018,https://cspec.genome.network/cspec/ui/svi/doc/GN006?version=1.0.0,ClinGenPAHExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-CDH1,CDH1,3.1.0,3/29/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN007?version=3.1.0,ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
-CDH1,CDH1,3.0.0,9/21/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN007?version=3.0.0,ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3_version=3.0.0.csv
-CDH1,CDH1,2.0.0,9/6/2019,https://cspec.genome.network/cspec/ui/svi/doc/GN007?version=2.0.0,ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-CDH1,CDH1,1.0.0,9/19/2018,https://cspec.genome.network/cspec/ui/svi/doc/GN007?version=1.0.0,ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH1Version1.0.0_version=1.0.0.csv
-Myeloid Malignancy,RUNX1,2.0.0,9/15/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN008?version=2.0.0,ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Myeloid Malignancy,RUNX1,1.0.0,7/10/2019,https://cspec.genome.network/cspec/ui/svi/doc/GN008?version=1.0.0,ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-TP53,TP53,2.3.0,2/7/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN009?version=2.3.0,ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
-TP53,TP53,2.2.0,9/30/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN009?version=2.2.0,ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.2.0_version=2.2.0.csv
-TP53,TP53,2.1.0,9/13/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN009?version=2.1.0,ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.1.0_version=2.1.0.csv
-TP53,TP53,2.0.0,7/30/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN009?version=2.0.0,ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.0.0_version=2.0.0.csv
-TP53,TP53,1.4.0,7/5/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN009?version=1.4.0,ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version1.4.0_version=1.4.0.csv
-TP53,TP53,1.3.0,3/8/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN009?version=1.3.0,ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version1.3.0_version=1.3.0.csv
-TP53,TP53,1.2.0,8/6/2019,https://cspec.genome.network/cspec/ui/svi/doc/GN009?version=1.2.0,ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.2_version=1.2.0.csv
-TP53,TP53,1.0.0,8/6/2019,https://cspec.genome.network/cspec/ui/svi/doc/GN009?version=1.0.0,ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version1.0.0_version=1.0.0.csv
-Lysosomal Storage Disorders Variant Curation,GAA,2.0.0,6/2/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN010?version=2.0.0,ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Platelet Disorders,ITGA2B,2.1.0,11/1/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN011?version=2.1.0,ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2.1_version=2.1.0.csv
-Platelet Disorders,ITGB3,2.1.0,11/1/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN011?version=2.1.0,ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2.1_version=2.1.0.csv
-Platelet Disorders,ITGA2B,2.0.0,9/4/2020,https://cspec.genome.network/cspec/ui/svi/doc/GN011?version=2.0.0,ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2.0_version=2.0.0.csv
-Platelet Disorders,ITGB3,2.0.0,9/4/2020,https://cspec.genome.network/cspec/ui/svi/doc/GN011?version=2.0.0,ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2.0_version=2.0.0.csv
-Platelet Disorders,ITGA2B,1.0.0,6/12/2020,https://cspec.genome.network/cspec/ui/svi/doc/GN011?version=1.0.0,ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforITGA2BVersion1.0.0_version=1.0.0.csv
-Platelet Disorders,ITGB3,1.0.0,6/12/2020,https://cspec.genome.network/cspec/ui/svi/doc/GN011?version=1.0.0,ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforITGA2BVersion1.0.0_version=1.0.0.csv
-Malignant Hyperthermia Susceptibility,RYR1,2.0.0,3/1/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN012?version=2.0.0,ClinGenMalignantHyperthermiaSusceptibilityExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRYR1Version2_version=2.0.0.csv
-Malignant Hyperthermia Susceptibility,RYR1,1.0.0,11/9/2020,https://cspec.genome.network/cspec/ui/svi/doc/GN012?version=1.0.0,ClinGenMalignantHyperthermiaSusceptibilityExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Familial Hypercholesterolemia,LDLR,1.2.0,11/9/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN013?version=1.2.0,ClinGenFamilialHypercholesterolemiaExpertPanelSpecificationstotheACMGAMPVariantClassificationGuidelinesVersion1.2_version=1.2.0.csv
-Mitochondrial Disease Nuclear and Mitochondrial,SLC19A3,1.0.0,4/30/2020,https://cspec.genome.network/cspec/ui/svi/doc/GN014?version=1.0.0,ClinGenMitochondrialDiseaseNuclearandMitochondrialExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_ntDNA_version=1.0.0.csv
-Mitochondrial Disease Nuclear and Mitochondrial,PDHA1,1.0.0,4/30/2020,https://cspec.genome.network/cspec/ui/svi/doc/GN014?version=1.0.0,ClinGenMitochondrialDiseaseNuclearandMitochondrialExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_ntDNA_version=1.0.0.csv
-Mitochondrial Disease Nuclear and Mitochondrial,POLG,1.0.0,4/30/2020,https://cspec.genome.network/cspec/ui/svi/doc/GN014?version=1.0.0,ClinGenMitochondrialDiseaseNuclearandMitochondrialExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_ntDNA_version=1.0.0.csv
-Mitochondrial Disease Nuclear and Mitochondrial,ETHE1,1.0.0,4/30/2020,https://cspec.genome.network/cspec/ui/svi/doc/GN014?version=1.0.0,ClinGenMitochondrialDiseaseNuclearandMitochondrialExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_ntDNA_version=1.0.0.csv
-Mitochondrial Disease Nuclear and Mitochondrial,,1.0.0,4/30/2020,https://cspec.genome.network/cspec/ui/svi/doc/GN015?version=1.0.0,ClinGenMitochondrialDiseaseNuclearandMitochondrialExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_mtDNA_version=1.0.0.csv
-Monogenic Diabetes,HNF1A,2.1.0,8/11/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN017?version=2.1.0,ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF1AVersion2.1.0_version=2.1.0.csv
-Monogenic Diabetes,HNF1A,2.0.0,1/11/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN017?version=2.0.0,ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF1AVersion2.0.0_version=2.0.0.csv
-Monogenic Diabetes,HNF1A,1.2.0,6/5/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN017?version=1.2.0,ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.2_version=1.2.0.csv
-Monogenic Diabetes,HNF1A,1.1.0,6/5/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN017?version=1.1.0,ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1_version=1.1.0.csv
-Monogenic Diabetes,HNF1A,1.0.0,6/4/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN017?version=1.0.0,ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF1AVersion1.0.0_version=1.0.0.csv
-Brain Malformations,AKT3,1.1.0,8/19/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN018?version=1.1.0,ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
-Brain Malformations,MTOR,1.1.0,8/19/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN018?version=1.1.0,ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
-Brain Malformations,PIK3CA,1.1.0,8/19/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN018?version=1.1.0,ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
-Brain Malformations,PIK3R2,1.1.0,8/19/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN018?version=1.1.0,ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
-Brain Malformations,AKT3,1.0.0,5/15/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN018?version=1.0.0,ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Brain Malformations,MTOR,1.0.0,5/15/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN018?version=1.0.0,ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Brain Malformations,PIK3CA,1.0.0,5/15/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN018?version=1.0.0,ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Brain Malformations,PIK3R2,1.0.0,5/15/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN018?version=1.0.0,ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Glaucoma,MYOC,2.0.0,12/12/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN019?version=2.0.0,ClinGenGlaucomaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYOCVersion2.0.0_version=2.0.0.csv
-Glaucoma,MYOC,1.1.0,11/19/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN019?version=1.1.0,ClinGenGlaucomaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1_version=1.1.0.csv
-Glaucoma,MYOC,1.0.0,10/12/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN019?version=1.0.0,ClinGenGlaucomaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-"Hereditary Breast, Ovarian and Pancreatic Cancer",ATM,1.3.0,3/27/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN020?version=1.3.0,"ClinGenHereditaryBreast,OvarianandPancreaticCancerExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforATMVersion1.3.0_version=1.3.0.csv"
-"Hereditary Breast, Ovarian and Pancreatic Cancer",ATM,1.2.0,11/28/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN020?version=1.2.0,"ClinGenHereditaryBreast,OvarianandPancreaticCancerExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforATMVersion1.2.0_version=1.2.0.csv"
-"Hereditary Breast, Ovarian and Pancreatic Cancer",ATM,1.1.0,2/25/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN020?version=1.1.0,"ClinGenHereditaryBreast,OvarianandPancreaticCancerExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforATMVersion1.1_version=1.1.0.csv"
-"Hereditary Breast, Ovarian and Pancreatic Cancer",ATM,1.0.0,1/19/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN020?version=1.0.0,"ClinGenHereditaryBreast,OvarianandPancreaticCancerExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforATMVersion1_version=1.0.0.csv"
-ACADVL,ACADVL,1.0.0,11/9/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN021?version=1.0.0,ClinGenACADVLExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-FBN1,FBN1,1.0.0,1/5/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN022?version=1.0.0,ClinGenFBN1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Hearing Loss,MYO15A,1.0.0,3/30/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN023?version=1.0.0,ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforOTOFandMYO15AVersion1_version=1.0.0.csv
-Hearing Loss,OTOF,1.0.0,3/30/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN023?version=1.0.0,ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforOTOFandMYO15AVersion1_version=1.0.0.csv
-DICER1 and miRNA-Processing Gene,DICER1,1.3.0,1/30/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN024?version=1.3.0,ClinGenDICER1andmiRNA-ProcessingGeneExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDICER1Version1.3.0_version=1.3.0.csv
-DICER1 and miRNA-Processing Gene,DICER1,1.2.0,5/31/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN024?version=1.2.0,ClinGenDICER1andmiRNA-ProcessingGeneExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDICER1Version1.2.0_version=1.2.0.csv
-DICER1 and miRNA-Processing Gene,DICER1,1.1.0,9/21/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN024?version=1.1.0,ClinGenDICER1andmiRNA-ProcessingGeneExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDICER1Version1.1.0_version=1.1.0.csv
-DICER1 and miRNA-Processing Gene,DICER1,1.0.0,5/5/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN024?version=1.0.0,ClinGenDICER1andmiRNA-ProcessingGeneExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDICER1Version1_version=1.0.0.csv
-Cerebral Creatine Deficiency Syndromes,GATM,2.0.0,12/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN025?version=2.0.0,ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGATMVersion2.0.0_version=2.0.0.csv
-Cerebral Creatine Deficiency Syndromes,GATM,1.1.0,9/14/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN025?version=1.1.0,ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGATMVersion1.1.0_version=1.1.0.csv
-Cerebral Creatine Deficiency Syndromes,GATM,1.0.0,3/21/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN025?version=1.0.0,ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGATMVersion1_version=1.0.0.csv
-Cerebral Creatine Deficiency Syndromes,GAMT,2.0.0,5/23/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN026?version=2.0.0,ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGAMTVersion2.0.0_version=2.0.0.csv
-Cerebral Creatine Deficiency Syndromes,GAMT,1.1.0,9/14/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN026?version=1.1.0,ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGAMTVersion1.1.0_version=1.1.0.csv
-Cerebral Creatine Deficiency Syndromes,GAMT,1.0.0,3/21/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN026?version=1.0.0,ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGAMTVersion1_version=1.0.0.csv
-Cerebral Creatine Deficiency Syndromes,SLC6A8,1.2.0,4/10/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN027?version=1.2.0,ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSLC6A8Version1.2.0_version=1.2.0.csv
-Cerebral Creatine Deficiency Syndromes,SLC6A8,1.1.0,9/14/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN027?version=1.1.0,ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSLC6A8Version1.1.0_version=1.1.0.csv
-Cerebral Creatine Deficiency Syndromes,SLC6A8,1.0.0,3/21/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN027?version=1.0.0,ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSLC6A8Version1_version=1.0.0.csv
-Rett and Angelman-like Disorders,TCF4,4.0.0,2/28/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN032?version=4.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTCF4Version4.0.0_version=4.0.0.csv
-Rett and Angelman-like Disorders,TCF4,3.0.0,5/9/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN032?version=3.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTCF4Version3.0.0_version=3.0.0.csv
-Rett and Angelman-like Disorders,CDKL5,2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Rett and Angelman-like Disorders,FOXG1,2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Rett and Angelman-like Disorders,MECP2,2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Rett and Angelman-like Disorders,SLC9A6,2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Rett and Angelman-like Disorders,TCF4,2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Rett and Angelman-like Disorders,UBE3A,2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Rett and Angelman-like Disorders,CDKL5,1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Rett and Angelman-like Disorders,FOXG1,1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Rett and Angelman-like Disorders,MECP2,1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Rett and Angelman-like Disorders,SLC9A6,1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Rett and Angelman-like Disorders,TCF4,1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Rett and Angelman-like Disorders,UBE3A,1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Rett and Angelman-like Disorders,SLC9A6,3.0.0,5/9/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN033?version=3.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSLC9A6Version3.0.0_version=3.0.0.csv
-Rett and Angelman-like Disorders,CDKL5,2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Rett and Angelman-like Disorders,FOXG1,2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Rett and Angelman-like Disorders,MECP2,2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Rett and Angelman-like Disorders,SLC9A6,2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Rett and Angelman-like Disorders,TCF4,2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Rett and Angelman-like Disorders,UBE3A,2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Rett and Angelman-like Disorders,CDKL5,1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Rett and Angelman-like Disorders,FOXG1,1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Rett and Angelman-like Disorders,MECP2,1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Rett and Angelman-like Disorders,SLC9A6,1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Rett and Angelman-like Disorders,TCF4,1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Rett and Angelman-like Disorders,UBE3A,1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Rett and Angelman-like Disorders,CDKL5,4.1.0,3/31/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN034?version=4.1.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDKL5Version4.1.0_version=4.1.0.csv
-Rett and Angelman-like Disorders,CDKL5,4.0.0,2/26/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN034?version=4.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDKL5Version4.0.0_version=4.0.0.csv
-Rett and Angelman-like Disorders,CDKL5,3.0.0,5/9/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN034?version=3.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDKL5Version3.0.0_version=3.0.0.csv
-Rett and Angelman-like Disorders,CDKL5,2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Rett and Angelman-like Disorders,FOXG1,2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Rett and Angelman-like Disorders,MECP2,2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Rett and Angelman-like Disorders,SLC9A6,2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Rett and Angelman-like Disorders,TCF4,2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Rett and Angelman-like Disorders,UBE3A,2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Rett and Angelman-like Disorders,CDKL5,1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Rett and Angelman-like Disorders,FOXG1,1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Rett and Angelman-like Disorders,MECP2,1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Rett and Angelman-like Disorders,SLC9A6,1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Rett and Angelman-like Disorders,TCF4,1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Rett and Angelman-like Disorders,UBE3A,1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Rett and Angelman-like Disorders,FOXG1,4.1.0,3/31/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN035?version=4.1.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforFOXG1Version4.1.0_version=4.1.0.csv
-Rett and Angelman-like Disorders,FOXG1,4.0.0,2/26/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN035?version=4.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforFOXG1Version4.0.0_version=4.0.0.csv
-Rett and Angelman-like Disorders,FOXG1,3.0.0,5/9/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN035?version=3.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforFOXG1Version3.0.0_version=3.0.0.csv
-Rett and Angelman-like Disorders,CDKL5,2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Rett and Angelman-like Disorders,FOXG1,2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Rett and Angelman-like Disorders,MECP2,2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Rett and Angelman-like Disorders,SLC9A6,2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Rett and Angelman-like Disorders,TCF4,2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Rett and Angelman-like Disorders,UBE3A,2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Rett and Angelman-like Disorders,CDKL5,1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Rett and Angelman-like Disorders,FOXG1,1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Rett and Angelman-like Disorders,MECP2,1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Rett and Angelman-like Disorders,SLC9A6,1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Rett and Angelman-like Disorders,TCF4,1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Rett and Angelman-like Disorders,UBE3A,1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Rett and Angelman-like Disorders,MECP2,4.1.0,3/31/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN036?version=4.1.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMECP2Version4.1.0_version=4.1.0.csv
-Rett and Angelman-like Disorders,MECP2,3.0.0,5/9/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN036?version=3.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMECP2Version3.0.0_version=3.0.0.csv
-Rett and Angelman-like Disorders,CDKL5,2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Rett and Angelman-like Disorders,FOXG1,2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Rett and Angelman-like Disorders,MECP2,2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Rett and Angelman-like Disorders,SLC9A6,2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Rett and Angelman-like Disorders,TCF4,2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Rett and Angelman-like Disorders,UBE3A,2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Rett and Angelman-like Disorders,CDKL5,1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Rett and Angelman-like Disorders,FOXG1,1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Rett and Angelman-like Disorders,MECP2,1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Rett and Angelman-like Disorders,SLC9A6,1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Rett and Angelman-like Disorders,TCF4,1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Rett and Angelman-like Disorders,UBE3A,1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Rett and Angelman-like Disorders,UBE3A,5.0.0,2/28/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN037?version=5.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforUBE3AVersion5.0.0_version=5.0.0.csv
-Rett and Angelman-like Disorders,UBE3A,4.0.0,5/9/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN037?version=4.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforUBE3AVersion4.0.0_version=4.0.0.csv
-Rett and Angelman-like Disorders,UBE3A,3.0.0,11/10/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN037?version=3.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforUBE3AVersion3.0.0_version=3.0.0.csv
-Rett and Angelman-like Disorders,CDKL5,2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Rett and Angelman-like Disorders,FOXG1,2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Rett and Angelman-like Disorders,MECP2,2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Rett and Angelman-like Disorders,SLC9A6,2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Rett and Angelman-like Disorders,TCF4,2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Rett and Angelman-like Disorders,UBE3A,2.0.0,12/31/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=2.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
-Rett and Angelman-like Disorders,CDKL5,1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Rett and Angelman-like Disorders,FOXG1,1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Rett and Angelman-like Disorders,MECP2,1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Rett and Angelman-like Disorders,SLC9A6,1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Rett and Angelman-like Disorders,TCF4,1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Rett and Angelman-like Disorders,UBE3A,1.0.0,2/17/2021,https://cspec.genome.network/cspec/ui/svi/doc/GN016?version=1.0.0,ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,SHOC2,2.3.0,12/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN038?version=2.3.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSHOC2Version2.3.0_version=2.3.0.csv
-RASopathy,SHOC2,2.2.0,12/2/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN038?version=2.2.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSHOC2Version2.2.0_version=2.2.0.csv
-RASopathy,SHOC2,2.1.0,9/17/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN038?version=2.1.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSHOC2Version2.1.0_version=2.1.0.csv
-RASopathy,SHOC2,2.0.0,8/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN038?version=2.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSHOC2Version2.0.0_version=2.0.0.csv
-RASopathy,SHOC2,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,NRAS,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,RAF1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,SOS1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,SOS2,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,PTPN11,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,KRAS,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,MAP2K1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,HRAS,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,RIT1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,MAP2K2,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,BRAF,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,NRAS,2.3.0,12/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN039?version=2.3.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforNRASVersion2.3.0_version=2.3.0.csv
-RASopathy,NRAS,2.2.0,12/2/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN039?version=2.2.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforNRASVersion2.2.0_version=2.2.0.csv
-RASopathy,NRAS,2.1.0,9/17/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN039?version=2.1.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforNRASVersion2.1.0_version=2.1.0.csv
-RASopathy,NRAS,2.0.0,8/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN039?version=2.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforNRASVersion2.0.0_version=2.0.0.csv
-RASopathy,SHOC2,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,NRAS,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,RAF1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,SOS1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,SOS2,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,PTPN11,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,KRAS,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,MAP2K1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,HRAS,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,RIT1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,MAP2K2,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,BRAF,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,RAF1,2.3.0,12/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN040?version=2.3.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRAF1Version2.3.0_version=2.3.0.csv
-RASopathy,RAF1,2.2.0,12/2/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN040?version=2.2.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRAF1Version2.2.0_version=2.2.0.csv
-RASopathy,RAF1,2.1.0,9/17/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN040?version=2.1.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRAF1Version2.1.0_version=2.1.0.csv
-RASopathy,RAF1,2.0.0,8/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN040?version=2.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRAF1Version2.0.0_version=2.0.0.csv
-RASopathy,SHOC2,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,NRAS,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,RAF1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,SOS1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,SOS2,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,PTPN11,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,KRAS,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,MAP2K1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,HRAS,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,RIT1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,MAP2K2,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,BRAF,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,SOS1,2.3.0,12/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN041?version=2.3.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS1Version2.3.0_version=2.3.0.csv
-RASopathy,SOS1,2.2.0,12/2/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN041?version=2.2.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS1Version2.2.0_version=2.2.0.csv
-RASopathy,SOS1,2.1.0,9/17/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN041?version=2.1.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS1Version2.1.0_version=2.1.0.csv
-RASopathy,SOS1,2.0.0,8/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN041?version=2.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS1Version2.0.0_version=2.0.0.csv
-RASopathy,SHOC2,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,NRAS,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,RAF1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,SOS1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,SOS2,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,PTPN11,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,KRAS,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,MAP2K1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,HRAS,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,RIT1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,MAP2K2,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,BRAF,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,SOS2,2.3.0,12/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN042?version=2.3.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS2Version2.3.0_version=2.3.0.csv
-RASopathy,SOS2,2.2.0,12/2/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN042?version=2.2.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS2Version2.2.0_version=2.2.0.csv
-RASopathy,SOS2,2.1.0,9/17/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN042?version=2.1.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS2Version2.1.0_version=2.1.0.csv
-RASopathy,SOS2,2.0.0,8/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN042?version=2.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS2Version2.0.0_version=2.0.0.csv
-RASopathy,SHOC2,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,NRAS,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,RAF1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,SOS1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,SOS2,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,PTPN11,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,KRAS,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,MAP2K1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,HRAS,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,RIT1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,MAP2K2,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,BRAF,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,PTPN11,2.3.0,12/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN043?version=2.3.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTPN11Version2.3.0_version=2.3.0.csv
-RASopathy,PTPN11,2.2.0,12/2/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN043?version=2.2.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTPN11Version2.2.0_version=2.2.0.csv
-RASopathy,PTPN11,2.1.0,9/17/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN043?version=2.1.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTPN11Version2.1.0_version=2.1.0.csv
-RASopathy,PTPN11,2.0.0,8/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN043?version=2.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTPN11Version2.0.0_version=2.0.0.csv
-RASopathy,SHOC2,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,NRAS,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,RAF1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,SOS1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,SOS2,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,PTPN11,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,KRAS,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,MAP2K1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,HRAS,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,RIT1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,MAP2K2,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,BRAF,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,KRAS,2.3.0,12/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN044?version=2.3.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforKRASVersion2.3.0_version=2.3.0.csv
-RASopathy,KRAS,2.2.0,12/2/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN044?version=2.2.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforKRASVersion2.2.0_version=2.2.0.csv
-RASopathy,KRAS,2.1.0,9/17/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN044?version=2.1.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforKRASVersion2.1.0_version=2.1.0.csv
-RASopathy,KRAS,2.0.0,8/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN044?version=2.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforKRASVersion2.0.0_version=2.0.0.csv
-RASopathy,SHOC2,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,NRAS,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,RAF1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,SOS1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,SOS2,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,PTPN11,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,KRAS,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,MAP2K1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,HRAS,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,RIT1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,MAP2K2,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,BRAF,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,MAP2K1,2.3.0,12/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN045?version=2.3.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K1Version2.3.0_version=2.3.0.csv
-RASopathy,MAP2K1,2.2.0,12/2/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN045?version=2.2.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K1Version2.2.0_version=2.2.0.csv
-RASopathy,MAP2K1,2.1.0,9/17/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN045?version=2.1.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K1Version2.1.0_version=2.1.0.csv
-RASopathy,MAP2K1,2.0.0,8/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN045?version=2.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K1Version2.0.0_version=2.0.0.csv
-RASopathy,SHOC2,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,NRAS,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,RAF1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,SOS1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,SOS2,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,PTPN11,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,KRAS,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,MAP2K1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,HRAS,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,RIT1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,MAP2K2,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,BRAF,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,HRAS,2.3.0,12/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN046?version=2.3.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHRASVersion2.3.0_version=2.3.0.csv
-RASopathy,HRAS,2.2.0,12/2/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN046?version=2.2.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHRASVersion2.2.0_version=2.2.0.csv
-RASopathy,HRAS,2.1.0,9/17/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN046?version=2.1.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHRASVersion2.1.0_version=2.1.0.csv
-RASopathy,HRAS,2.0.0,8/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN046?version=2.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHRASVersion2.0.0_version=2.0.0.csv
-RASopathy,SHOC2,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,NRAS,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,RAF1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,SOS1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,SOS2,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,PTPN11,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,KRAS,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,MAP2K1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,HRAS,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,RIT1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,MAP2K2,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,BRAF,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,RIT1,2.3.0,12/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN047?version=2.3.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRIT1Version2.3.0_version=2.3.0.csv
-RASopathy,RIT1,2.2.0,12/2/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN047?version=2.2.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRIT1Version2.2.0_version=2.2.0.csv
-RASopathy,RIT1,2.1.0,9/17/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN047?version=2.1.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRIT1Version2.1.0_version=2.1.0.csv
-RASopathy,RIT1,2.0.0,8/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN047?version=2.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRIT1Version2.0.0_version=2.0.0.csv
-RASopathy,SHOC2,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,NRAS,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,RAF1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,SOS1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,SOS2,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,PTPN11,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,KRAS,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,MAP2K1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,HRAS,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,RIT1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,MAP2K2,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,BRAF,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,MAP2K2,2.3.0,12/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN048?version=2.3.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K2Version2.3.0_version=2.3.0.csv
-RASopathy,MAP2K2,2.2.0,12/2/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN048?version=2.2.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K2Version2.2.0_version=2.2.0.csv
-RASopathy,MAP2K2,2.1.0,9/17/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN048?version=2.1.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K2Version2.1.0_version=2.1.0.csv
-RASopathy,MAP2K2,2.0.0,8/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN048?version=2.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K2Version2.0.0_version=2.0.0.csv
-RASopathy,SHOC2,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,NRAS,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,RAF1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,SOS1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,SOS2,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,PTPN11,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,KRAS,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,MAP2K1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,HRAS,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,RIT1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,MAP2K2,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,BRAF,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,BRAF,2.3.0,12/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN049?version=2.3.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRAFVersion2.3.0_version=2.3.0.csv
-RASopathy,BRAF,2.2.0,12/2/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN049?version=2.2.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRAFVersion2.2.0_version=2.2.0.csv
-RASopathy,BRAF,2.1.0,9/17/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN049?version=2.1.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRAFVersion2.1.0_version=2.1.0.csv
-RASopathy,BRAF,2.0.0,8/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN049?version=2.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRAFVersion2.0.0_version=2.0.0.csv
-RASopathy,SHOC2,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,NRAS,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,RAF1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,SOS1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,SOS2,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,PTPN11,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,KRAS,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,MAP2K1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,HRAS,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,RIT1,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,MAP2K2,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-RASopathy,BRAF,1.0.0,7/18/2017,https://cspec.genome.network/cspec/ui/svi/doc/GN004?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
-Epilepsy Sodium Channel,SCN1A,2.0.0,1/7/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN067?version=2.0.0,ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN1AVersion2.0.0_version=2.0.0.csv
-Epilepsy Sodium Channel,SCN1A,1.0.0,3/19/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN067?version=1.0.0,ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN1AVersion1.0.0_version=1.0.0.csv
-Epilepsy Sodium Channel,SCN2A,2.0.0,1/7/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN068?version=2.0.0,ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN2AVersion2.0.0_version=2.0.0.csv
-Epilepsy Sodium Channel,SCN2A,1.0.0,3/19/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN068?version=1.0.0,ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN2AVersion1.0.0_version=1.0.0.csv
-Epilepsy Sodium Channel,SCN3A,2.0.0,1/7/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN069?version=2.0.0,ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN3AVersion2.0.0_version=2.0.0.csv
-Epilepsy Sodium Channel,SCN3A,1.0.0,3/19/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN069?version=1.0.0,ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN3AVersion1.0.0_version=1.0.0.csv
-Epilepsy Sodium Channel,SCN8A,2.0.0,1/7/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN070?version=2.0.0,ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN8AVersion2.0.0_version=2.0.0.csv
-Epilepsy Sodium Channel,SCN8A,1.0.0,3/19/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN070?version=1.0.0,ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN8AVersion1.0.0_version=1.0.0.csv
-Coagulation Factor Deficiency,F8,1.0.0,10/5/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN071?version=1.0.0,ClinGenCoagulationFactorDeficiencyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforF8Version1.0.0_version=1.0.0.csv
-Epilepsy Sodium Channel,SCN1B,2.0.0,1/7/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN076?version=2.0.0,ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN1BVersion2.0.0_version=2.0.0.csv
-Epilepsy Sodium Channel,SCN1B,1.0.0,3/19/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN076?version=1.0.0,ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN1BVersion1.0.0_version=1.0.0.csv
-"Hereditary Breast, Ovarian and Pancreatic Cancer",PALB2,1.1.0,11/28/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN077?version=1.1.0,"ClinGenHereditaryBreast,OvarianandPancreaticCancerExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPALB2Version1.1.0_version=1.1.0.csv"
-"Hereditary Breast, Ovarian and Pancreatic Cancer",PALB2,1.0.0,3/17/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN077?version=1.0.0,"ClinGenHereditaryBreast,OvarianandPancreaticCancerExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPALB2Version1.0.0_version=1.0.0.csv"
-VHL,VHL,1.1.0,1/10/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN078?version=1.1.0,ClinGenVHLExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforVHLVersion1.1.0_version=1.1.0.csv
-VHL,VHL,1.0.0,2/29/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN078?version=1.0.0,ClinGenVHLExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforVHLVersion1.0.0_version=1.0.0.csv
-Platelet Disorders,GP1BA,1.0.0,2/12/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN079?version=1.0.0,ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGP1BAVersion1.0.0_version=1.0.0.csv
-Coagulation Factor Deficiency,F9,1.0.0,10/5/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN080?version=1.0.0,ClinGenCoagulationFactorDeficiencyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforF9Version1.0.0_version=1.0.0.csv
-von Willebrand Disease,VWF,1.0.0,7/9/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN081?version=1.0.0,ClinGenvonWillebrandDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforVWFVersion1.0.0_version=1.0.0.csv
-Platelet Disorders,GP1BB,1.0.0,2/12/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN082?version=1.0.0,ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGP1BBVersion1.0.0_version=1.0.0.csv
-Platelet Disorders,GP9,1.0.0,2/11/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN083?version=1.0.0,ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGP9Version1.0.0_version=1.0.0.csv
-Thrombosis,SERPINC1,1.1.0,2/7/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN084?version=1.1.0,ClinGenThrombosisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSERPINC1Version1.1.0_version=1.1.0.csv
-Thrombosis,SERPINC1,1.0.0,7/17/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN084?version=1.0.0,ClinGenThrombosisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSERPINC1Version1.0.0_version=1.0.0.csv
-Monogenic Diabetes,HNF4A,2.0.0,10/11/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN085?version=2.0.0,ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF4AVersion2.0.0_version=2.0.0.csv
-Monogenic Diabetes,HNF4A,1.1.0,8/11/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN085?version=1.1.0,ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF4AVersion1.1.0_version=1.1.0.csv
-Monogenic Diabetes,HNF4A,1.0.0,11/16/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN085?version=1.0.0,ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF4AVersion1.0.0_version=1.0.0.csv
-Monogenic Diabetes,GCK,2.0.0,2/17/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN086?version=2.0.0,ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGCKVersion2.0.0_version=2.0.0.csv
-Monogenic Diabetes,GCK,1.3.0,8/11/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN086?version=1.3.0,ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGCKVersion1.3.0_version=1.3.0.csv
-Monogenic Diabetes,GCK,1.2.0,6/7/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN086?version=1.2.0,ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGCKVersion1.2.0_version=1.2.0.csv
-Monogenic Diabetes,GCK,1.1.0,3/23/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN086?version=1.1.0,ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGCKVersion1.1.0_version=1.1.0.csv
-Monogenic Diabetes,GCK,1.0.0,11/16/2022,https://cspec.genome.network/cspec/ui/svi/doc/GN086?version=1.0.0,ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGCKVersion1.0.0_version=1.0.0.csv
-RASopathy,MRAS,1.4.0,12/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN087?version=1.4.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMRASVersion1.4.0_version=1.4.0.csv
-RASopathy,MRAS,1.3.0,12/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN087?version=1.3.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMRASVersion1.3.0_version=1.3.0.csv
-RASopathy,MRAS,1.2.0,12/2/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN087?version=1.2.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMRASVersion1.2.0_version=1.2.0.csv
-RASopathy,MRAS,1.1.0,9/17/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN087?version=1.1.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMRASVersion1.1.0_version=1.1.0.csv
-RASopathy,MRAS,1.0.0,8/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN087?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMRASVersion1.0.0_version=1.0.0.csv
-InSiGHT Hereditary Colorectal Cancer/Polyposis,APC,2.1.0,11/24/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN089?version=2.1.0,ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforAPCVersion2.1.0_version=2.1.0.csv
-InSiGHT Hereditary Colorectal Cancer/Polyposis,APC,2.0.3,7/24/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN089?version=2.0.3,ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforAPCVersion2.0.3_version=2.0.3.csv
-InSiGHT Hereditary Colorectal Cancer/Polyposis,APC,1.0.0,1/10/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN089?version=1.0.0,ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforAPCVersion1.0.0_version=1.0.0.csv
-von Willebrand Disease,VWF,1.0.0,7/9/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN090?version=1.0.0,ClinGenvonWillebrandDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforVWFVersion1.0.0_version=1.0.0.csv
-Lysosomal Diseases,IDUA,1.0.0,12/5/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN091?version=1.0.0,ClinGenLysosomalDiseasesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforIDUAVersion1.0.0_version=1.0.0.csv
-ENIGMA BRCA1 and BRCA2,BRCA1,1.2.0,1/9/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN092?version=1.2.0,ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA1Version1.2.0_version=1.2.0.csv
-ENIGMA BRCA1 and BRCA2,BRCA1,1.1.0,12/21/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN092?version=1.1.0,ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA1Version1.1.0_version=1.1.0.csv
-ENIGMA BRCA1 and BRCA2,BRCA1,1.0.0,8/9/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN092?version=1.0.0,ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA1Version1.0.0_version=1.0.0.csv
-RASopathy,LZTR1,1.3.0,12/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN094?version=1.3.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforLZTR1Version1.3.0_version=1.3.0.csv
-RASopathy,LZTR1,1.2.0,12/2/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN094?version=1.2.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforLZTR1Version1.2.0_version=1.2.0.csv
-RASopathy,LZTR1,1.1.0,9/17/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN094?version=1.1.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforLZTR1Version1.1.0_version=1.1.0.csv
-RASopathy,LZTR1,1.0.0,8/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN094?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforLZTR1Version1.0.0_version=1.0.0.csv
-Cardiomyopathy,MYBPC3,1.0.0,4/22/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN095?version=1.0.0,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYBPC3Version1.0.0_version=1.0.0.csv
-ENIGMA BRCA1 and BRCA2,BRCA2,1.2.0,1/9/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN097?version=1.2.0,ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA2Version1.2.0_version=1.2.0.csv
-ENIGMA BRCA1 and BRCA2,BRCA2,1.1.0,12/21/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN097?version=1.1.0,ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA2Version1.1.0_version=1.1.0.csv
-ENIGMA BRCA1 and BRCA2,BRCA2,1.0.0,8/9/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN097?version=1.0.0,ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA2Version1.0.0_version=1.0.0.csv
-Cardiomyopathy,TNNI3,1.0.0,4/22/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN098?version=1.0.0,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTNNI3Version1.0.0_version=1.0.0.csv
-Cardiomyopathy,TNNT2,1.0.0,4/22/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN099?version=1.0.0,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTNNT2Version1.0.0_version=1.0.0.csv
-Cardiomyopathy,TPM1,1.0.0,4/22/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN100?version=1.0.0,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTPM1Version1.0.0_version=1.0.0.csv
-Cardiomyopathy,ACTC1,1.0.0,4/22/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN101?version=1.0.0,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforACTC1Version1.0.0_version=1.0.0.csv
-Cardiomyopathy,MYL2,1.0.0,4/22/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN102?version=1.0.0,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYL2Version1.0.0_version=1.0.0.csv
-Cardiomyopathy,MYL3,1.0.0,4/22/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN103?version=1.0.0,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYL3Version1.0.0_version=1.0.0.csv
-Severe Combined Immunodeficiency Disease,FOXN1,1.0.0,7/29/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN113?version=1.0.0,ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforFOXN1Version1.0.0_version=1.0.0.csv
-Severe Combined Immunodeficiency Disease,ADA,1.0.0,10/9/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN114?version=1.0.0,ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforADAVersion1.0.0_version=1.0.0.csv
-InSiGHT Hereditary Colorectal Cancer/Polyposis,MLH1,1.0.0,8/9/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN115?version=1.0.0,ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMLH1Version1.0.0_version=1.0.0.csv
-Severe Combined Immunodeficiency Disease,DCLRE1C,1.0.0,10/9/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN116?version=1.0.0,ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDCLRE1CVersion1.0.0_version=1.0.0.csv
-Severe Combined Immunodeficiency Disease,IL7R,1.0.0,10/9/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN119?version=1.0.0,ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforIL7RVersion1.0.0_version=1.0.0.csv
-Leber Congenital Amaurosis/early onset Retinal Dystrophy,RPE65,1.0.0,10/24/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN120?version=1.0.0,ClinGenLeberCongenitalAmaurosisearlyonsetRetinalDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRPE65Version1.0.0_version=1.0.0.csv
-Severe Combined Immunodeficiency Disease,JAK3,1.0.0,10/9/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN121?version=1.0.0,ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforJAK3Version1.0.0_version=1.0.0.csv
-Severe Combined Immunodeficiency Disease,RAG1,1.0.0,10/9/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN123?version=1.0.0,ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRAG1Version1.0.0_version=1.0.0.csv
-Severe Combined Immunodeficiency Disease,RAG2,1.0.0,10/9/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN124?version=1.0.0,ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRAG2Version1.0.0_version=1.0.0.csv
-Pulmonary Hypertension,BMPR2,1.1.0,4/6/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN125?version=1.1.0,ClinGenPulmonaryHypertensionExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBMPR2Version1.1.0_version=1.1.0.csv
-Pulmonary Hypertension,BMPR2,1.0.0,3/1/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN125?version=1.0.0,ClinGenPulmonaryHypertensionExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBMPR2Version1.0.0_version=1.0.0.csv
-RASopathy,RRAS2,1.3.0,12/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN127?version=1.3.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRRAS2Version1.3.0_version=1.3.0.csv
-RASopathy,RRAS2,1.2.0,12/2/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN127?version=1.2.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRRAS2Version1.2.0_version=1.2.0.csv
-RASopathy,RRAS2,1.1.0,9/17/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN127?version=1.1.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRRAS2Version1.1.0_version=1.1.0.csv
-RASopathy,RRAS2,1.0.0,8/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN127?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRRAS2Version1.0.0_version=1.0.0.csv
-RASopathy,PPP1CB,1.3.0,12/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN128?version=1.3.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPPP1CBVersion1.3.0_version=1.3.0.csv
-RASopathy,PPP1CB,1.2.0,12/2/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN128?version=1.2.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPPP1CBVersion1.2.0_version=1.2.0.csv
-RASopathy,PPP1CB,1.1.0,9/17/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN128?version=1.1.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPPP1CBVersion1.1.0_version=1.1.0.csv
-RASopathy,PPP1CB,1.0.0,8/3/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN128?version=1.0.0,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPPP1CBVersion1.0.0_version=1.0.0.csv
-Severe Combined Immunodeficiency Disease,IL2RG,1.0.0,10/9/2023,https://cspec.genome.network/cspec/ui/svi/doc/GN129?version=1.0.0,ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforIL2RGVersion1.0.0_version=1.0.0.csv
-Hereditary Hemorrhagic Telangiectasia,ACVRL1,1.1.0,3/20/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN135?version=1.1.0,ClinGenHereditaryHemorrhagicTelangiectasiaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforACVRL1Version1.1.0_version=1.1.0.csv
-Hereditary Hemorrhagic Telangiectasia,ACVRL1,1.0.0,3/5/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN135?version=1.0.0,ClinGenHereditaryHemorrhagicTelangiectasiaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforACVRL1Version1.0.0_version=1.0.0.csv
-Hereditary Hemorrhagic Telangiectasia,ENG,1.1.0,3/20/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN136?version=1.1.0,ClinGenHereditaryHemorrhagicTelangiectasiaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforENGVersion1.1.0_version=1.1.0.csv
-Hereditary Hemorrhagic Telangiectasia,ENG,1.0.0,3/5/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN136?version=1.0.0,ClinGenHereditaryHemorrhagicTelangiectasiaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforENGVersion1.0.0_version=1.0.0.csv
-InSiGHT Hereditary Colorectal Cancer/Polyposis,MSH2,1.0.0,8/9/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN137?version=1.0.0,ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMSH2Version1.0.0_version=1.0.0.csv
-InSiGHT Hereditary Colorectal Cancer/Polyposis,MSH6,1.0.0,8/9/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN138?version=1.0.0,ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMSH6Version1.0.0_version=1.0.0.csv
-InSiGHT Hereditary Colorectal Cancer/Polyposis,PMS2,1.0.0,8/9/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN139?version=1.0.0,ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPMS2Version1.0.0_version=1.0.0.csv
-InSiGHT Hereditary Colorectal Cancer/Polyposis,PMS2,1.0.0,8/9/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN139?version=1.0.0,ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPMS2Version1.0.0_version=1.0.0.csv
-Congenital Myopathies,NEB,1.0.0,8/7/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN146?version=1.0.0,ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforNEBVersion1.0.0_version=1.0.0.csv
-Congenital Myopathies,ACTA1,2.0.0,8/27/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN147?version=2.0.0,ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforACTA1Version2.0.0_version=2.0.0.csv
-Congenital Myopathies,ACTA1,1.0.0,8/7/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN147?version=1.0.0,ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforACTA1Version1.0.0_version=1.0.0.csv
-Congenital Myopathies,DNM2,1.0.0,8/7/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN148?version=1.0.0,ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDNM2Version1.0.0_version=1.0.0.csv
-Congenital Myopathies,MTM1,1.0.0,8/7/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN149?version=1.0.0,ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMTM1Version1.0.0_version=1.0.0.csv
-Congenital Myopathies,RYR1,2.0.0,12/12/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN150?version=2.0.0,ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRYR1Version2.0.0_version=2.0.0.csv
-Congenital Myopathies,RYR1,1.0.0,8/7/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN150?version=1.0.0,ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRYR1Version1.0.0_version=1.0.0.csv
-Leber Congenital Amaurosis/early onset Retinal Dystrophy,GUCY2D,1.0.0,1/22/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN167?version=1.0.0,ClinGenLeberCongenitalAmaurosisearlyonsetRetinalDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGUCY2DVersion1.0.0_version=1.0.0.csv
-Congenital Myopathies,ACTA1,1.0.0,8/7/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN169?version=1.0.0,ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforACTA1Version1.0.0_version=1.0.0.csv
-Congenital Myopathies,RYR1,2.0.0,12/12/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN179?version=2.0.0,ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRYR1Version2.0.0_version=2.0.0.csv
-Congenital Myopathies,RYR1,1.0.0,8/7/2024,https://cspec.genome.network/cspec/ui/svi/doc/GN179?version=1.0.0,ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRYR1Version1.0.0_version=1.0.0.csv
-Limb Girdle Muscular Dystrophy,DYSF,1.0.0,1/7/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN180?version=1.0.0,ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDYSFVersion1.0.0_version=1.0.0.csv
-Limb Girdle Muscular Dystrophy,SGCB,1.0.0,1/7/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN184?version=1.0.0,ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSGCBVersion1.0.0_version=1.0.0.csv
-Limb Girdle Muscular Dystrophy,SGCG,1.0.0,1/7/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN185?version=1.0.0,ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSGCGVersion1.0.0_version=1.0.0.csv
-Limb Girdle Muscular Dystrophy,SGCD,1.0.0,1/7/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN186?version=1.0.0,ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSGCDVersion1.0.0_version=1.0.0.csv
-Limb Girdle Muscular Dystrophy,CAPN3,1.0.0,1/7/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN187?version=1.0.0,ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCAPN3Version1.0.0_version=1.0.0.csv
-Limb Girdle Muscular Dystrophy,ANO5,1.0.0,1/7/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN188?version=1.0.0,ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforANO5Version1.0.0_version=1.0.0.csv
-Limb Girdle Muscular Dystrophy,SGCA,1.0.0,1/7/2025,https://cspec.genome.network/cspec/ui/svi/doc/GN189?version=1.0.0,ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSGCAVersion1.0.0_version=1.0.0.csv
diff --git a/VCI/parsing_csr_criteria/get_versions.py b/VCI/parsing_csr_criteria/get_versions.py
deleted file mode 100644
index 5c4e423d1170729c3ed5fc0ec5194d25e220b24f..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/get_versions.py
+++ /dev/null
@@ -1,66 +0,0 @@
-from selenium import webdriver
-from selenium.webdriver.chrome.service import Service
-from selenium.webdriver.common.by import By
-from selenium.webdriver.chrome.options import Options
-import time
-import random
-import pandas as pd
-
-def extract_variant_guideline_data(url: str) -> pd.DataFrame:
-    chrome_driver_path = "/usr/local/bin/chromedriver"  # ← Update this to your actual path
-
-    # Chrome options to minimize detection
-    options = Options()
-    options.add_experimental_option("excludeSwitches", ["enable-automation"])
-    options.add_experimental_option('useAutomationExtension', False)
-    options.add_argument("--disable-blink-features=AutomationControlled")
-    options.add_argument("--headless=new")
-    options.add_argument("--disable-gpu")
-    options.add_argument("--no-sandbox")
-    options.add_argument("--log-level=3")
-
-    service = Service(executable_path=chrome_driver_path)
-    driver = webdriver.Chrome(service=service, options=options)
-
-    driver.execute_cdp_cmd("Page.addScriptToEvaluateOnNewDocument", {
-        "source": "Object.defineProperty(navigator, 'webdriver', {get: () => undefined})"
-    })
-
-    driver.get(url)
-    time.sleep(random.uniform(1, 2))  # Just enough delay for JS to render
-
-    rows = driver.find_elements(By.CSS_SELECTOR, "div.row.version")
-    data = []
-
-    for row in rows:
-        try:
-            link_elem = row.find_element(By.CSS_SELECTOR, "div.title a")
-            genes_elem = row.find_element(By.CSS_SELECTOR, "div.genes")
-            version_elem = row.find_element(By.CSS_SELECTOR, "div.version-num")
-            date_elem = row.find_element(By.CSS_SELECTOR, "div.release-date")
-
-            data.append({
-                "Title": link_elem.text.strip(),
-                "Genes": genes_elem.text.strip(),
-                "Version": version_elem.text.strip(),
-                "Released Date": date_elem.text.strip(),
-                "Link": link_elem.get_attribute("href").strip()
-            })
-
-        except Exception:
-            continue  # Skip bad rows silently
-
-    driver.quit()
-    return pd.DataFrame(data)
-
-
-
-# 🧪 Test block
-if __name__ == "__main__":
-    test_url = "https://cspec.genome.network/cspec/ui/svi/doc/GN037/versions"
-    df = extract_variant_guideline_data(test_url)
-
-    print(df.head())  # Show first few entries
-    import ipdb; ipdb.set_trace()  # Debugging breakpoint
-    #df.to_csv("variant_guideline_output.csv", index=False)
-    print("📄 Data saved to 'variant_guideline_output.csv'")
diff --git a/VCI/parsing_csr_criteria/parse_on_date.py b/VCI/parsing_csr_criteria/parse_on_date.py
deleted file mode 100644
index f310f512ad581164b6a08aa7e7bcd99df4c3f479..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/parse_on_date.py
+++ /dev/null
@@ -1,215 +0,0 @@
-import pandas as pd
-import numpy as np
-from datetime import date, datetime
-import re
-from tqdm import tqdm
-from dateutil.parser import parse
-
-RYR1_VCEP_MAP = {
-    "Malignant Hyperthermia Susceptibility VCEP": "",
-    "Congenital Myopathies VCEP": "",
-}
-
-def extract_doc_id(url: str) -> str:
-    """
-    Extract the *GN…* document identifier from a ClinGen CSPEC URL.
-
-    Parameters
-    ----------
-    url : str
-        A URL like
-        'https://cspec.genome.network/cspec/ui/svi/doc/GN006?version=1.0.0'
-
-    Returns
-    -------
-    str
-        The identifier after `/doc/`, e.g. 'GN006'.
-
-    Raises
-    ------
-    ValueError
-        If the pattern `/doc/<id>` is not found in the URL.
-    """
-    match = re.search(r"/doc/([^/?]+)", url)
-    if not match:
-        raise ValueError(f"No document id found in: {url}")
-    return match.group(1)
-
-
-def closest_before(d: date, dates: list[date]) -> date | None:
-    # keep only the dates that are earlier than d
-    earlier = [x for x in dates if x <= d]
-    # the latest of those is the closest before d
-    return np.argmax(earlier) if earlier else None
-
-def parse_date_CVG(date_str):
-    """
-    Convert date string in MM/DD/YYYY format to datetime date object.
-    """
-    try:
-        return datetime.strptime(date_str, '%m/%d/%Y').date()
-    except (ValueError, TypeError):
-        return None
-
-def parse_erepo_date(date_str):
-    """
-    Convert date string in YYYY-MM-DD format to datetime date object.
-    
-    Parameters:
-    -----------
-    date_str : str
-        Date string in YYYY-MM-DD format
-        
-    Returns:
-    --------
-    datetime.date or None
-        Parsed date as a datetime date object, or None if parsing fails
-    """
-    try:
-        return datetime.strptime(date_str, '%Y-%m-%d').date()
-    except (ValueError, TypeError):
-        return None
-
-def map_gene_disease_to_index(df, cd):
-
-    map_gd = {}
-
-    problem_types = {
-        "no gene, disease": 0,
-        "multiple overlaps": 0,
-        "no gene": 0,
-    }
-    
-    for i, row in df.iterrows():
-        gene, mondo_id = row["hgnc_gene"], row["mondo_id"]
-
-        disease_presence = (cd["disease_id"] == mondo_id)
-        gene_presence = (cd["gene"] == gene)
-        overlap = gene_presence & disease_presence
-
-        if overlap.sum() == 0:
-            # Means we need to search:
-            # Search in gene-centric way:
-            if gene_presence.sum() == 0:
-                problem_types["no gene"] += 1
-                continue
-                
-            df_consider = cd[gene_presence & cd["disease_id"].isna()]
-            if df_consider.shape[0] == 0:
-                problem_types["no gene, disease"] += 1
-                continue
-                #raise ValueError
-            map_gd[(gene, mondo_id)] = df_consider.index[0]
-
-        elif overlap.sum() == 1:
-            # Means we have a unique match
-            map_gd[(gene, mondo_id)] = cd[overlap].index[0]
-
-        else:
-            # Means we have multiple matches
-            problem_types["multiple overlaps"] += 1
-            #raise ValueError
-        
-    return map_gd, problem_types
-
-map_vcep = {
-    #'Mitochondrial Diseases': "MITO", 
-    'Severe Combined Immunodeficiency Disease ': 'Severe Combined Immunodeficiency Disease', 
-    'von Willebrand Disease ': 'von Willebrand Disease',
-}
-
-map_vcep_from_cvg = {
-    "Lysosomal Storage Disorders Variant Curation": "Lysosomal Diseases",
-    "PAH": "Phenylketonuria",
-}
-
-# Skip: LRRC56, KLLN
-
-def main():
-
-    df = pd.read_csv("../clingen_vci_pubmed_fulltext.csv")
-
-    for i, row in df.iterrows():
-        vcep_name = row["expert_panel"]
-        if vcep_name in map_vcep.keys():
-            df.loc[i, "expert_panel"] = map_vcep[vcep_name]
-
-    # Load df with dates:
-    df_full = pd.read_csv("../erepo.tabbed_2025-02-25.txt", sep="\t")
-
-    cd = pd.read_csv("../csr_criteria/cspec_directory.csv")
-    cvg = pd.read_csv("cspec_version_guide_processed.csv")
-
-    for i, row in cvg.iterrows():
-        vcep_name = row["Title"]
-        if vcep_name in map_vcep_from_cvg.keys():
-            cvg.loc[i, "Title"] = map_vcep_from_cvg[vcep_name]
-
-    cvg["unifying_code"] = cvg["Link"].apply(extract_doc_id)
-    cd["unifying_code"] = cd["criteria_link"].apply(lambda x: x.split("/")[-1])
-
-    # Convert dates in version guide:
-    #cvg["date"] = cvg["Released Date"].apply(lambda x: parse(x).date())
-    cvg["date"] = cvg["Released Date"].apply(parse_date_CVG)
-    def map_gene_vcep_to_index(vcep, gene):
-
-        gene_mask = (cvg["Genes"] == gene)
-        vcep_mask = (cvg["Title"] == vcep)
-
-        if (gene_mask.sum() == 0) and ("Mitochondrial" in vcep):
-            # This is probably mitochondrial disease
-            return cvg[(cvg["Title"] == "Mitochondrial Disease Nuclear and Mitochondrial") & cvg["Genes"].isna()]
-        else:
-            return cvg[gene_mask & vcep_mask]
-
-    df_full["Approval Date"] = df_full["Approval Date"].apply(parse_erepo_date)
-    df_full["Published Date"] = df_full["Published Date"].apply(parse_erepo_date)
-
-    counter_invalid = 0
-    row_lists = []
-    path_list = []
-    for i, row in tqdm(df.iterrows(), total=len(df)):
-
-        # if (row["hgnc_gene"] == "GAA"): # CHECKED
-        #     # Use Published as exception:
-        #     app_date = df_full["Published Date"].iloc[row["entry_index"]]
-        #else:
-        app_date = df_full["Approval Date"].iloc[row["entry_index"]]
-            #app_date = parse_erepo_date(app_date)
-
-        out = map_gene_vcep_to_index(row["expert_panel"], row["hgnc_gene"])
-
-        if out.shape[0] == 0:
-            print(f"No VCEP found for {row['hgnc_gene']} in {row['expert_panel']}")
-            # Skip this one entirely
-            path_list.append(None)
-            continue
-
-        # Now compute date lower bound:
-        cbefore = closest_before(app_date, out["date"])
-        if cbefore is None:
-            
-            if (row["hgnc_gene"] == "GAA") or (row["hgnc_gene"] == "MYH7") or (row["hgnc_gene"] == "LDLR"):
-                cbefore = 0
-            elif (row["expert_panel"] == "RASopathy") or (row["hgnc_gene"] == "PTEN"):
-                # This problem needs to be moved to Published date
-                app_date = df_full["Published Date"].iloc[row["entry_index"]]
-                cbefore = closest_before(app_date, out["date"])
-                assert cbefore is not None
-
-            else:
-                counter_invalid += 1
-                row_lists.append(i)
-
-        # Now get the cbefore:
-        out_use = out.iloc[cbefore] 
-        path_list.append(out_use["path"])
-
-    df["path"] = path_list
-    df = df.loc[df["path"].notna()]
-
-    df.to_csv("../clingen_vci_pubmed_fulltext_vceps.csv", index=False)
-
-
-if __name__ == "__main__":
-    main()
diff --git a/VCI/parsing_csr_criteria/scrape_criteria.py b/VCI/parsing_csr_criteria/scrape_criteria.py
deleted file mode 100644
index 3fe44f5ee8d24e08ec3877c9f6d35ea6b2fdf77a..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/scrape_criteria.py
+++ /dev/null
@@ -1,166 +0,0 @@
-from selenium import webdriver
-from selenium.webdriver.chrome.service import Service
-from selenium.webdriver.common.by import By
-import pandas as pd
-import time
-import random
-import os
-from bs4 import BeautifulSoup
-
-# === Configuration ===
-chrome_driver_path = "/usr/local/bin/chromedriver"
-target_url = "https://cspec.genome.network/cspec/ui/svi/doc/GN016"
-
-# === Setup ChromeDriver ===
-options = webdriver.ChromeOptions()
-options.add_argument("--headless=new")
-options.add_argument("--disable-gpu")
-options.add_argument("--no-sandbox")
-options.add_argument("--log-level=3")
-prefs = {
-    "profile.managed_default_content_settings.images": 2,
-    "profile.managed_default_content_settings.fonts": 2
-}
-options.add_experimental_option("prefs", prefs)
-
-service = Service(executable_path=chrome_driver_path)
-driver = webdriver.Chrome(service=service, options=options)
-driver.execute_cdp_cmd("Page.addScriptToEvaluateOnNewDocument", {
-    "source": "Object.defineProperty(navigator, 'webdriver', {get: () => undefined})"
-})
-
-# === Open page ===
-driver.get(target_url)
-time.sleep(2)
-driver.execute_script("window.scrollTo(0, document.body.scrollHeight);")
-time.sleep(1)
-
-expand_buttons = driver.find_elements(By.CSS_SELECTOR, ".panel-title a[data-toggle='collapse']")
-print(f"🧬 Expanding {len(expand_buttons)} gene rule sections...")
-for btn in expand_buttons:
-    try:
-        driver.execute_script("arguments[0].click();", btn)
-        time.sleep(random.uniform(0.3, 0.6))
-    except Exception as e:
-        print(f"⚠️ Error expanding section: {e}")
-time.sleep(2)
-
-html = driver.page_source
-driver.quit()
-
-# ... (unchanged setup) ...
-
-# === Parse HTML ===
-soup = BeautifulSoup(html, "html.parser")
-records = []
-
-rulesets = soup.find_all("div", class_="panel-body")
-for ruleset in rulesets:
-    gene_tag = ruleset.find("span", class_="gene")
-    gene_name = gene_tag.find("span", class_="value").get_text(strip=True) if gene_tag else "Unknown"
-
-    table = ruleset.find("table", class_="criteria-codes")
-    if not table:
-        continue
-
-    all_rows = table.find_all("tr", class_=["criteria-code", "criteria-code parent", "criteria-code child"])
-    i = 0
-    while i < len(all_rows):
-        row = all_rows[i]
-        if "parent" in row.get("class", []):
-            code = row.get("data-cspec-cc-label")
-            code_id = row.get("data-cspec-cc-id")
-
-            if i + 1 < len(all_rows) and "child" in all_rows[i + 1].get("class", []):
-                child_row = all_rows[i + 1]
-
-                # print(f"\n--- Code: {code} ---")
-                # not_applicable_div = child_row.find("div", class_="cc-item not-app")
-                # print(f"Found .not-app section: {not_applicable_div is not None}")
-
-                # strength_divs = child_row.find_all("div", class_="row strength")
-                # print(f"Total strength rows found: {len(strength_divs)}")
-
-                # for idx, s in enumerate(strength_divs):
-                #     s_class = s.get("class", [])
-                #     print(f"  Strength {idx + 1} class: {s_class}")
-                #     if "hide" not in s_class:
-                #         print("  ✅ This strength is VISIBLE")
-                #     else:
-                #         print("  ❌ This strength is HIDDEN")
-
-                # # Then compute visibility
-                # visible_strengths = [div for div in strength_divs if "hide" not in (div.get("class") or [])]
-                # print(f"Visible strengths found: {len(visible_strengths)}")
-
-                # is_not_applicable = not_applicable_div is not None and len(visible_strengths) == 0
-                # mod_type_value = "NA" if is_not_applicable else ""
-
-                # print(f"FINAL DECISION for 'is_not_applicable': {is_not_applicable}")
-
-                # ✅ Correctly locate the TD block
-                td_block = child_row.find("td", class_="strength-specs")
-
-                # ✅ Find .not-app from inside TD
-                not_applicable_div = str(td_block).find("cc-item not-app") if td_block else None
-                #not_applicable_div = td_block.find("div", class_="cc-item not-app") if td_block else None
-
-                # ✅ Find strength rows from inside TD
-                strength_divs = td_block.find_all("div", class_="row strength") if td_block else []
-
-                visible_strengths = [
-                    div for div in strength_divs
-                    if "hide" not in (div.get("class") or [])
-                ]
-
-                # ✅ Determine applicability
-                is_not_applicable = not_applicable_div is not None and len(visible_strengths) == 0
-                #if code == "PM3":
-                #    import ipdb; ipdb.set_trace()
-                mod_type_value = "NA" if is_not_applicable else ""
-
-
-                # === Original ACMG Summary
-                summary_div = child_row.find("div", class_="acmg-summary")
-                if summary_div:
-                    html_div = summary_div.find("div", class_="html")
-                    if html_div:
-                        summary_text = BeautifulSoup(html_div.decode_contents(), "html.parser").get_text(separator="\n").strip()
-                        records.append({
-                            "Gene": gene_name,
-                            "Code": code,
-                            "Strength": "Original ACMG Summary",
-                            "Description": summary_text,
-                            "Modification Type": mod_type_value
-                        })
-
-                # === Visible Strengths
-                if not is_not_applicable:
-                    for spec_div in child_row.find_all("div", class_="strength-spec"):
-                        strength_row = spec_div.find("div", class_="row strength")
-                        if not strength_row or "hide" in strength_row.get("class", []):
-                            continue
-
-                        strength = strength_row.find("div", class_="strength-label").get_text(strip=True)
-
-                        desc_div = spec_div.find("div", class_="html")
-                        description = BeautifulSoup(desc_div.decode_contents(), "html.parser").get_text(separator="\n").strip() if desc_div else ""
-
-                        mod_tag = spec_div.find("div", class_="modification-type")
-                        mod_type = mod_tag.find("span", class_="value").get_text(strip=True) if mod_tag else ""
-
-                        records.append({
-                            "Gene": gene_name,
-                            "Code": code,
-                            "Strength": strength,
-                            "Description": description,
-                            "Modification Type": mod_type
-                        })
-        i += 1
-
-# === Save Results ===
-df = pd.DataFrame(records)
-output_file = "criteria_specifications_final.csv"
-#import ipdb; ipdb.set_trace()
-df.to_csv(output_file, index=False)
-print(f"\n✅ Fixed detection script complete! Data saved to: {os.path.abspath(output_file)}")
diff --git a/VCI/parsing_csr_criteria/scrape_criteria_fn.py b/VCI/parsing_csr_criteria/scrape_criteria_fn.py
deleted file mode 100644
index 3c892ef16fe4e6e8aaea5f52036af29057c2a7a2..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/scrape_criteria_fn.py
+++ /dev/null
@@ -1,127 +0,0 @@
-from selenium import webdriver
-from selenium.webdriver.chrome.service import Service
-from selenium.webdriver.common.by import By
-from bs4 import BeautifulSoup
-import pandas as pd
-import time
-import random
-import os
-
-def extract_criteria_specifications(url, chrome_driver_path="/usr/local/bin/chromedriver", output_file="criteria_specifications_final.csv"):
-    # Setup headless Selenium driver
-    options = webdriver.ChromeOptions()
-    options.add_argument("--headless=new")
-    options.add_argument("--disable-gpu")
-    options.add_argument("--no-sandbox")
-    options.add_argument("--log-level=3")
-    prefs = {
-        "profile.managed_default_content_settings.images": 2,
-        "profile.managed_default_content_settings.fonts": 2
-    }
-    options.add_experimental_option("prefs", prefs)
-
-    service = Service(executable_path=chrome_driver_path)
-    driver = webdriver.Chrome(service=service, options=options)
-    driver.execute_cdp_cmd("Page.addScriptToEvaluateOnNewDocument", {
-        "source": "Object.defineProperty(navigator, 'webdriver', {get: () => undefined})"
-    })
-
-    print(f"🌐 Navigating to {url}")
-    driver.get(url)
-    time.sleep(2)
-    driver.execute_script("window.scrollTo(0, document.body.scrollHeight);")
-    time.sleep(1)
-
-    expand_buttons = driver.find_elements(By.CSS_SELECTOR, ".panel-title a[data-toggle='collapse']")
-    print(f"🧬 Expanding {len(expand_buttons)} gene rule sections...")
-    for btn in expand_buttons:
-        try:
-            driver.execute_script("arguments[0].click();", btn)
-            time.sleep(random.uniform(0.3, 0.6))
-        except Exception as e:
-            print(f"⚠️ Error expanding section: {e}")
-    time.sleep(2)
-
-    html = driver.page_source
-    driver.quit()
-
-    # === Parse HTML ===
-    soup = BeautifulSoup(html, "html.parser")
-    records = []
-
-    rulesets = soup.find_all("div", class_="panel-body")
-    for ruleset in rulesets:
-        gene_tag = ruleset.find("span", class_="gene")
-        gene_name = gene_tag.find("span", class_="value").get_text(strip=True) if gene_tag else "Unknown"
-
-        table = ruleset.find("table", class_="criteria-codes")
-        if not table:
-            continue
-
-        all_rows = table.find_all("tr", class_=["criteria-code", "criteria-code parent", "criteria-code child"])
-        i = 0
-        while i < len(all_rows):
-            row = all_rows[i]
-            if "parent" in row.get("class", []):
-                code = row.get("data-cspec-cc-label")
-                code_id = row.get("data-cspec-cc-id")
-
-                if i + 1 < len(all_rows) and "child" in all_rows[i + 1].get("class", []):
-                    child_row = all_rows[i + 1]
-                    td_block = child_row.find("td", class_="strength-specs")
-
-                    # Custom not-applicable check via string search
-                    not_applicable_div = str(td_block).find("cc-item not-app") if td_block else None
-                    strength_divs = td_block.find_all("div", class_="row strength") if td_block else []
-
-                    visible_strengths = [
-                        div for div in strength_divs
-                        if "hide" not in (div.get("class") or [])
-                    ]
-
-                    is_not_applicable = not_applicable_div is not None and len(visible_strengths) == 0
-                    mod_type_value = "NA" if is_not_applicable else ""
-
-                    # Original ACMG Summary
-                    summary_div = child_row.find("div", class_="acmg-summary")
-                    if summary_div:
-                        html_div = summary_div.find("div", class_="html")
-                        if html_div:
-                            summary_text = BeautifulSoup(html_div.decode_contents(), "html.parser").get_text(separator="\n").strip()
-                            records.append({
-                                "Gene": gene_name,
-                                "Code": code,
-                                "Strength": "Original ACMG Summary",
-                                "Description": summary_text,
-                                "Modification Type": mod_type_value
-                            })
-
-                    # Visible Strengths
-                    if not is_not_applicable:
-                        for spec_div in child_row.find_all("div", class_="strength-spec"):
-                            strength_row = spec_div.find("div", class_="row strength")
-                            if not strength_row or "hide" in strength_row.get("class", []):
-                                continue
-
-                            strength = strength_row.find("div", class_="strength-label").get_text(strip=True)
-
-                            desc_div = spec_div.find("div", class_="html")
-                            description = BeautifulSoup(desc_div.decode_contents(), "html.parser").get_text(separator="\n").strip() if desc_div else ""
-
-                            mod_tag = spec_div.find("div", class_="modification-type")
-                            mod_type = mod_tag.find("span", class_="value").get_text(strip=True) if mod_tag else ""
-
-                            records.append({
-                                "Gene": gene_name,
-                                "Code": code,
-                                "Strength": strength,
-                                "Description": description,
-                                "Modification Type": mod_type
-                            })
-            i += 1
-
-    # === Save and Return ===
-    df = pd.DataFrame(records)
-    #df.to_csv(output_file, index=False)
-    #print(f"\n✅ Extraction complete! Data saved to: {os.path.abspath(output_file)}")
-    return df
diff --git a/VCI/parsing_csr_criteria/scrape_criteria_versions.py b/VCI/parsing_csr_criteria/scrape_criteria_versions.py
deleted file mode 100644
index ec788d67d747cfef56b2b2c32828a04bb045a3a0..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/scrape_criteria_versions.py
+++ /dev/null
@@ -1,60 +0,0 @@
-import pandas as pd
-from tqdm import tqdm
-
-from get_versions import extract_variant_guideline_data
-from scrape_criteria_fn import extract_criteria_specifications
-
-def transform_url(url_original):
-
-    return url_original.replace("api/SequenceVariantInterpretation/id/", "ui/svi/doc/")
-
-def main():
-    cspec_df = pd.read_csv("../csr_criteria/cspec_directory.csv")
-
-    unique_urls = cspec_df["criteria_link"].unique()
-
-    # Take all url's, iterate over + "/versions"
-
-    df_versions_list = []
-
-    IND = 1
-    for url in tqdm(unique_urls, total = len(unique_urls)):
-        url_version = transform_url(url) + "/versions"
-
-        df_versions = extract_variant_guideline_data(url_version)
-
-        #import ipdb; ipdb.set_trace()
-        
-        version_cspec = {}
-        version_fname_list = []
-
-        # Go over all versions:
-        for index, row in df_versions.iterrows():
-            link = row["Link"]
-
-            # Extract the criteria specifications
-            criteria_specifications = extract_criteria_specifications(link)
-
-            version_cspec[index] = criteria_specifications
-        
-            # Save each version_cspec in a dictionary
-            fname = "{}_version={}.csv".format(row["Title"].replace(" ", "").replace("/", ""), row["Version"])
-            criteria_specifications.to_csv(f"version_csv_individual/{fname}", index=False)
-            version_fname_list.append(fname)
-
-
-        df_versions["path"] = version_fname_list
-
-        df_versions_list.append(df_versions)
-
-        IND += 1
-        if (IND % 10) == 0:
-            df_whole = pd.concat(df_versions_list)
-            df_whole.to_csv("cspec_version_guide.csv", index=True)       
-
-    df_whole = pd.concat(df_versions_list)
-    df_whole.to_csv("cspec_version_guide.csv", index=True)
-
-
-if __name__ == "__main__":
-    main()
\ No newline at end of file
diff --git a/VCI/parsing_csr_criteria/tests/.ipynb_checkpoints/examine_vci_cspec-checkpoint.ipynb b/VCI/parsing_csr_criteria/tests/.ipynb_checkpoints/examine_vci_cspec-checkpoint.ipynb
deleted file mode 100644
index 7340361b82e661a95d0eb8d0c0e6cd87b44066ad..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/tests/.ipynb_checkpoints/examine_vci_cspec-checkpoint.ipynb
+++ /dev/null
@@ -1,430 +0,0 @@
-{
- "cells": [
-  {
-   "cell_type": "code",
-   "execution_count": 16,
-   "id": "ef833d9f-1199-4e29-83ba-2d7e47fa90ba",
-   "metadata": {},
-   "outputs": [],
-   "source": [
-    "import os\n",
-    "import numpy as np\n",
-    "import pandas as pd\n",
-    "\n",
-    "DATA_PATH = \"/Users/owenqueen/Desktop/stanford_research/SHERLOCK_HOME/clingen_benchmark/data\""
-   ]
-  },
-  {
-   "cell_type": "code",
-   "execution_count": 2,
-   "id": "1ba8d447-e0a0-4c4a-8422-cfbc14a1f773",
-   "metadata": {},
-   "outputs": [],
-   "source": [
-    "df = pd.read_csv(\"../../clingen_vci_pubmed_fulltext_vceps.csv\")"
-   ]
-  },
-  {
-   "cell_type": "code",
-   "execution_count": 38,
-   "id": "910cfb99-64b2-4a54-98ba-9de34c2dff07",
-   "metadata": {},
-   "outputs": [],
-   "source": [
-    "# /Users/owenqueen/Desktop/stanford_research/SHERLOCK_HOME/clingen_benchmark/data/VCI/parsing_csr_criteria/version_csv_individual\n",
-    "\n",
-    "def get_criteria_per_row(row):\n",
-    "    base_path = row[\"path\"]\n",
-    "    criteria = pd.read_csv(os.path.join(DATA_PATH, \"VCI/parsing_csr_criteria/version_csv_individual\", base_path))\n",
-    "    criteria_trim = criteria.loc[criteria[\"Gene\"].apply(lambda x: x.split(\" \")[0]) == row[\"hgnc_gene\"],:]\n",
-    "    return criteria, criteria_trim"
-   ]
-  },
-  {
-   "cell_type": "code",
-   "execution_count": 26,
-   "id": "255c35dc-dd04-40c7-b233-40a6637da7a5",
-   "metadata": {},
-   "outputs": [],
-   "source": [
-    "clist = []\n",
-    "ctrim_list = []\n",
-    "for i, row in df.iterrows():\n",
-    "    c, ctrim = get_criteria_per_row(row)\n",
-    "    clist.append(c)\n",
-    "    ctrim_list.append(ctrim)"
-   ]
-  },
-  {
-   "cell_type": "code",
-   "execution_count": 27,
-   "id": "5e3c0fde-55d7-4bd0-a9b1-b4bcc5702e75",
-   "metadata": {},
-   "outputs": [],
-   "source": [
-    "size = []\n",
-    "for c in ctrim_list:\n",
-    "    size.append(c.shape[0])"
-   ]
-  },
-  {
-   "cell_type": "code",
-   "execution_count": 28,
-   "id": "467a6806-3778-4a1d-a159-fb49b77f464b",
-   "metadata": {},
-   "outputs": [
-    {
-     "data": {
-      "text/plain": [
-       "(array([ 17,  18,  19,  62,  63,  64,  65,  67,  68,  69,  70,  71,  72,\n",
-       "         73,  74, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130,\n",
-       "        131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143,\n",
-       "        144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156,\n",
-       "        157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 191, 192,\n",
-       "        193, 194, 195, 196, 197, 198, 199, 200, 201, 208, 209, 210, 211,\n",
-       "        212, 213, 216, 217, 218, 219, 220, 223, 224, 225, 226, 227, 228,\n",
-       "        229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 306, 307,\n",
-       "        308, 309, 310, 311, 313, 325, 326, 327, 332, 339, 340, 341, 342,\n",
-       "        351, 352, 353, 354, 362, 363, 364, 388, 390, 391, 392, 393, 394,\n",
-       "        406, 436, 447, 455, 456, 457, 458, 459, 460, 461, 462, 513, 514,\n",
-       "        515, 516, 517, 521, 522, 523, 524, 532, 533, 562, 563, 581, 582,\n",
-       "        583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595,\n",
-       "        596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608,\n",
-       "        609, 610, 611, 612, 613, 614, 615, 619, 620, 639, 651, 654, 655,\n",
-       "        656, 658, 659, 677, 678, 681, 682, 683, 711, 713, 736, 738, 758]),)"
-      ]
-     },
-     "execution_count": 28,
-     "metadata": {},
-     "output_type": "execute_result"
-    }
-   ],
-   "source": [
-    "(np.array(size) == 0).nonzero()"
-   ]
-  },
-  {
-   "cell_type": "code",
-   "execution_count": 32,
-   "id": "29fdb42d-ee60-49c7-ae8f-c570b9bd41d9",
-   "metadata": {},
-   "outputs": [],
-   "source": [
-    "ucount = []\n",
-    "for ind in (np.array(size) == 0).nonzero()[0]:\n",
-    "    ucount.append(clist[ind].Gene.unique().shape[0])"
-   ]
-  },
-  {
-   "cell_type": "code",
-   "execution_count": 30,
-   "id": "2513b7b7-44ca-4e1f-89f8-abf4e85a7abb",
-   "metadata": {},
-   "outputs": [
-    {
-     "data": {
-      "text/plain": [
-       "entry_index                                                       141\n",
-       "variant                     NM_004004.5(GJB2):c.35delG (p.Gly12Valfs)\n",
-       "hgnc_gene                                                        GJB2\n",
-       "disease                                 nonsyndromic genetic deafness\n",
-       "mondo_id                                                MONDO:0019497\n",
-       "assertion                                                  Pathogenic\n",
-       "mode_inheritance                      Autosomal recessive inheritance\n",
-       "expert_panel                                             Hearing Loss\n",
-       "pub_date                                                   2019-07-17\n",
-       "evidence_code                                                     PS4\n",
-       "met_status                                                        met\n",
-       "pmid                                                  PubMed:26969326\n",
-       "comments            3.2% (72/2238) of alleles reported in this stu...\n",
-       "summary             In 1 large study (Sloan-Heggen 2015) and in 1 ...\n",
-       "summary_comments    In 1 large study (Sloan-Heggen 2015) and in 1 ...\n",
-       "path                ClinGenHearingLossExpertPanelSpecificationstot...\n",
-       "Name: 17, dtype: object"
-      ]
-     },
-     "execution_count": 30,
-     "metadata": {},
-     "output_type": "execute_result"
-    }
-   ],
-   "source": [
-    "df.iloc[17]"
-   ]
-  },
-  {
-   "cell_type": "code",
-   "execution_count": 40,
-   "id": "b1e2c9a2-bc9c-452c-8930-62f6776059c1",
-   "metadata": {},
-   "outputs": [],
-   "source": [
-    "def get_criteria_per_row_FULL(row):\n",
-    "    base_path = row[\"path\"]\n",
-    "    criteria = pd.read_csv(os.path.join(DATA_PATH, \"VCI/parsing_csr_criteria/version_csv_individual\", base_path))\n",
-    "    if criteria[\"Gene\"].unique().shape[0]:\n",
-    "        # Aggregate codes:\n",
-    "        criteria[\"aggregate_code\"] = [f\"{row['Code']}_{row['Strength'].replace(\" \", \"\")}\" for i, row in criteria.iterrows()]\n",
-    "        return criteria\n",
-    "    else:     \n",
-    "        criteria_trim = criteria.loc[criteria[\"Gene\"].apply(lambda x: x.split(\" \")[0]) == row[\"hgnc_gene\"],:]\n",
-    "        return criteria_trim"
-   ]
-  },
-  {
-   "cell_type": "code",
-   "execution_count": 41,
-   "id": "23ed83e5-3991-409a-9826-c325b161a521",
-   "metadata": {},
-   "outputs": [],
-   "source": [
-    "# Base operation:\n",
-    "clist = []\n",
-    "for i, row in df.iterrows():\n",
-    "    c = get_criteria_per_row_FULL(row)\n",
-    "    clist.append(c)"
-   ]
-  },
-  {
-   "cell_type": "code",
-   "execution_count": 42,
-   "id": "1313a1bc-05d1-49e4-9857-1980d8d3e5a9",
-   "metadata": {},
-   "outputs": [],
-   "source": [
-    "size = []\n",
-    "for c in clist:\n",
-    "    size.append(c.shape[0])"
-   ]
-  },
-  {
-   "cell_type": "code",
-   "execution_count": 51,
-   "id": "ba8aafaa-cd48-457b-a934-3ba451092f1e",
-   "metadata": {},
-   "outputs": [],
-   "source": [
-    "# Get unique criteria:\n",
-    "path_unique = df[\"path\"].unique().tolist()\n",
-    "all_codes = []\n",
-    "clist_unique = []\n",
-    "for p in path_unique:\n",
-    "    row = df[df[\"path\"] == p].iloc[0]\n",
-    "    c = get_criteria_per_row_FULL(row)\n",
-    "    clist_unique.append(c)\n",
-    "    all_codes.append(df[\"evidence_code\"].loc[df[\"path\"] == p].unique())"
-   ]
-  },
-  {
-   "cell_type": "code",
-   "execution_count": 52,
-   "id": "a4937bd0-b56a-40fd-8db2-4a78227da190",
-   "metadata": {},
-   "outputs": [
-    {
-     "data": {
-      "text/html": [
-       "<div>\n",
-       "<style scoped>\n",
-       "    .dataframe tbody tr th:only-of-type {\n",
-       "        vertical-align: middle;\n",
-       "    }\n",
-       "\n",
-       "    .dataframe tbody tr th {\n",
-       "        vertical-align: top;\n",
-       "    }\n",
-       "\n",
-       "    .dataframe thead th {\n",
-       "        text-align: right;\n",
-       "    }\n",
-       "</style>\n",
-       "<table border=\"1\" class=\"dataframe\">\n",
-       "  <thead>\n",
-       "    <tr style=\"text-align: right;\">\n",
-       "      <th></th>\n",
-       "      <th>Gene</th>\n",
-       "      <th>Code</th>\n",
-       "      <th>Strength</th>\n",
-       "      <th>Description</th>\n",
-       "      <th>Modification Type</th>\n",
-       "    </tr>\n",
-       "  </thead>\n",
-       "  <tbody>\n",
-       "    <tr>\n",
-       "      <th>0</th>\n",
-       "      <td>PAH (HGNC:8582)</td>\n",
-       "      <td>PVS1</td>\n",
-       "      <td>Original ACMG Summary</td>\n",
-       "      <td>Null variant (nonsense, frameshift, canonical ...</td>\n",
-       "      <td>NaN</td>\n",
-       "    </tr>\n",
-       "    <tr>\n",
-       "      <th>1</th>\n",
-       "      <td>PAH (HGNC:8582)</td>\n",
-       "      <td>PVS1</td>\n",
-       "      <td>Very Strong</td>\n",
-       "      <td>Applicable as described in Tayoun et al. 2018....</td>\n",
-       "      <td>Disease-specific</td>\n",
-       "    </tr>\n",
-       "    <tr>\n",
-       "      <th>2</th>\n",
-       "      <td>PAH (HGNC:8582)</td>\n",
-       "      <td>PVS1</td>\n",
-       "      <td>Strong</td>\n",
-       "      <td>Use PVS1_strong with:\\n\\n\\n\\n\\nAny nonsense or...</td>\n",
-       "      <td>Disease-specific</td>\n",
-       "    </tr>\n",
-       "    <tr>\n",
-       "      <th>3</th>\n",
-       "      <td>PAH (HGNC:8582)</td>\n",
-       "      <td>PS1</td>\n",
-       "      <td>Original ACMG Summary</td>\n",
-       "      <td>Same amino acid change as a previously establi...</td>\n",
-       "      <td>NaN</td>\n",
-       "    </tr>\n",
-       "    <tr>\n",
-       "      <th>4</th>\n",
-       "      <td>PAH (HGNC:8582)</td>\n",
-       "      <td>PS1</td>\n",
-       "      <td>Strong</td>\n",
-       "      <td>Same predicted splicing impact as a previously...</td>\n",
-       "      <td>Disease-specific</td>\n",
-       "    </tr>\n",
-       "    <tr>\n",
-       "      <th>...</th>\n",
-       "      <td>...</td>\n",
-       "      <td>...</td>\n",
-       "      <td>...</td>\n",
-       "      <td>...</td>\n",
-       "      <td>...</td>\n",
-       "    </tr>\n",
-       "    <tr>\n",
-       "      <th>57</th>\n",
-       "      <td>PAH (HGNC:8582)</td>\n",
-       "      <td>BP5</td>\n",
-       "      <td>Supporting</td>\n",
-       "      <td>Applicable as described</td>\n",
-       "      <td>No change</td>\n",
-       "    </tr>\n",
-       "    <tr>\n",
-       "      <th>58</th>\n",
-       "      <td>PAH (HGNC:8582)</td>\n",
-       "      <td>BP6</td>\n",
-       "      <td>Original ACMG Summary</td>\n",
-       "      <td>Reputable source recently reports variant as b...</td>\n",
-       "      <td>NaN</td>\n",
-       "    </tr>\n",
-       "    <tr>\n",
-       "      <th>59</th>\n",
-       "      <td>PAH (HGNC:8582)</td>\n",
-       "      <td>BP7</td>\n",
-       "      <td>Original ACMG Summary</td>\n",
-       "      <td>A synonymous variant for which splicing predic...</td>\n",
-       "      <td>NaN</td>\n",
-       "    </tr>\n",
-       "    <tr>\n",
-       "      <th>60</th>\n",
-       "      <td>PAH (HGNC:8582)</td>\n",
-       "      <td>BP7</td>\n",
-       "      <td>Strong</td>\n",
-       "      <td>Applicable as described by Walker et al. (PMID...</td>\n",
-       "      <td>Strength</td>\n",
-       "    </tr>\n",
-       "    <tr>\n",
-       "      <th>61</th>\n",
-       "      <td>PAH (HGNC:8582)</td>\n",
-       "      <td>BP7</td>\n",
-       "      <td>Supporting</td>\n",
-       "      <td>Per SVI recommendations (PMID: 36865205), use ...</td>\n",
-       "      <td>Gene-specific,None</td>\n",
-       "    </tr>\n",
-       "  </tbody>\n",
-       "</table>\n",
-       "<p>62 rows × 5 columns</p>\n",
-       "</div>"
-      ],
-      "text/plain": [
-       "               Gene  Code               Strength  \\\n",
-       "0   PAH (HGNC:8582)  PVS1  Original ACMG Summary   \n",
-       "1   PAH (HGNC:8582)  PVS1            Very Strong   \n",
-       "2   PAH (HGNC:8582)  PVS1                 Strong   \n",
-       "3   PAH (HGNC:8582)   PS1  Original ACMG Summary   \n",
-       "4   PAH (HGNC:8582)   PS1                 Strong   \n",
-       "..              ...   ...                    ...   \n",
-       "57  PAH (HGNC:8582)   BP5             Supporting   \n",
-       "58  PAH (HGNC:8582)   BP6  Original ACMG Summary   \n",
-       "59  PAH (HGNC:8582)   BP7  Original ACMG Summary   \n",
-       "60  PAH (HGNC:8582)   BP7                 Strong   \n",
-       "61  PAH (HGNC:8582)   BP7             Supporting   \n",
-       "\n",
-       "                                          Description   Modification Type  \n",
-       "0   Null variant (nonsense, frameshift, canonical ...                 NaN  \n",
-       "1   Applicable as described in Tayoun et al. 2018....    Disease-specific  \n",
-       "2   Use PVS1_strong with:\\n\\n\\n\\n\\nAny nonsense or...    Disease-specific  \n",
-       "3   Same amino acid change as a previously establi...                 NaN  \n",
-       "4   Same predicted splicing impact as a previously...    Disease-specific  \n",
-       "..                                                ...                 ...  \n",
-       "57                            Applicable as described           No change  \n",
-       "58  Reputable source recently reports variant as b...                 NaN  \n",
-       "59  A synonymous variant for which splicing predic...                 NaN  \n",
-       "60  Applicable as described by Walker et al. (PMID...            Strength  \n",
-       "61  Per SVI recommendations (PMID: 36865205), use ...  Gene-specific,None  \n",
-       "\n",
-       "[62 rows x 5 columns]"
-      ]
-     },
-     "execution_count": 52,
-     "metadata": {},
-     "output_type": "execute_result"
-    }
-   ],
-   "source": [
-    "clist_unique[0]"
-   ]
-  },
-  {
-   "cell_type": "code",
-   "execution_count": 53,
-   "id": "710da496-c9a2-4d4a-a375-4c2e637fed93",
-   "metadata": {},
-   "outputs": [
-    {
-     "data": {
-      "text/plain": [
-       "array(['PM3-Very Strong', 'PM3', 'PP4-Moderate', 'PM3-Strong', 'PP4',\n",
-       "       'PP1', 'PM3-Supporting', 'PS3-Supporting'], dtype=object)"
-      ]
-     },
-     "execution_count": 53,
-     "metadata": {},
-     "output_type": "execute_result"
-    }
-   ],
-   "source": [
-    "# Are the codes in the DF?\n",
-    "all_codes[0]"
-   ]
-  }
- ],
- "metadata": {
-  "kernelspec": {
-   "display_name": "Python 3 (ipykernel)",
-   "language": "python",
-   "name": "python3"
-  },
-  "language_info": {
-   "codemirror_mode": {
-    "name": "ipython",
-    "version": 3
-   },
-   "file_extension": ".py",
-   "mimetype": "text/x-python",
-   "name": "python",
-   "nbconvert_exporter": "python",
-   "pygments_lexer": "ipython3",
-   "version": "3.11.10"
-  }
- },
- "nbformat": 4,
- "nbformat_minor": 5
-}
diff --git a/VCI/parsing_csr_criteria/tests/examine_vci_cspec.ipynb b/VCI/parsing_csr_criteria/tests/examine_vci_cspec.ipynb
deleted file mode 100644
index 1b972f7b8eea56e530ebef0d7599eb5d86ed6642..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/tests/examine_vci_cspec.ipynb
+++ /dev/null
@@ -1,945 +0,0 @@
-{
- "cells": [
-  {
-   "cell_type": "code",
-   "execution_count": 16,
-   "id": "ef833d9f-1199-4e29-83ba-2d7e47fa90ba",
-   "metadata": {},
-   "outputs": [],
-   "source": [
-    "import os\n",
-    "import numpy as np\n",
-    "import pandas as pd\n",
-    "\n",
-    "DATA_PATH = \"/Users/owenqueen/Desktop/stanford_research/SHERLOCK_HOME/clingen_benchmark/data\""
-   ]
-  },
-  {
-   "cell_type": "code",
-   "execution_count": 2,
-   "id": "1ba8d447-e0a0-4c4a-8422-cfbc14a1f773",
-   "metadata": {},
-   "outputs": [],
-   "source": [
-    "df = pd.read_csv(\"../../clingen_vci_pubmed_fulltext_vceps.csv\")"
-   ]
-  },
-  {
-   "cell_type": "code",
-   "execution_count": 105,
-   "id": "945374a9-6b56-4fdb-9e2d-a3a6c24b648b",
-   "metadata": {},
-   "outputs": [
-    {
-     "data": {
-      "text/html": [
-       "<div>\n",
-       "<style scoped>\n",
-       "    .dataframe tbody tr th:only-of-type {\n",
-       "        vertical-align: middle;\n",
-       "    }\n",
-       "\n",
-       "    .dataframe tbody tr th {\n",
-       "        vertical-align: top;\n",
-       "    }\n",
-       "\n",
-       "    .dataframe thead th {\n",
-       "        text-align: right;\n",
-       "    }\n",
-       "</style>\n",
-       "<table border=\"1\" class=\"dataframe\">\n",
-       "  <thead>\n",
-       "    <tr style=\"text-align: right;\">\n",
-       "      <th></th>\n",
-       "      <th>entry_index</th>\n",
-       "      <th>variant</th>\n",
-       "      <th>hgnc_gene</th>\n",
-       "      <th>disease</th>\n",
-       "      <th>mondo_id</th>\n",
-       "      <th>assertion</th>\n",
-       "      <th>mode_inheritance</th>\n",
-       "      <th>expert_panel</th>\n",
-       "      <th>pub_date</th>\n",
-       "      <th>evidence_code</th>\n",
-       "      <th>met_status</th>\n",
-       "      <th>pmid</th>\n",
-       "      <th>comments</th>\n",
-       "      <th>summary</th>\n",
-       "      <th>summary_comments</th>\n",
-       "      <th>path</th>\n",
-       "    </tr>\n",
-       "  </thead>\n",
-       "  <tbody>\n",
-       "    <tr>\n",
-       "      <th>0</th>\n",
-       "      <td>8</td>\n",
-       "      <td>NM_000277.2(PAH):c.331C&gt;T (p.Arg111Ter)</td>\n",
-       "      <td>PAH</td>\n",
-       "      <td>phenylketonuria</td>\n",
-       "      <td>MONDO:0009861</td>\n",
-       "      <td>Pathogenic</td>\n",
-       "      <td>Autosomal recessive inheritance</td>\n",
-       "      <td>Phenylketonuria</td>\n",
-       "      <td>2019-04-09</td>\n",
-       "      <td>PM3-Very Strong</td>\n",
-       "      <td>not_met</td>\n",
-       "      <td>PubMed:26322415</td>\n",
-       "      <td>Detected in 13 patients with: c.611A&gt;G, p.E280...</td>\n",
-       "      <td>Detected with: p.R158Q (P, 11 submitters); p.R...</td>\n",
-       "      <td>Detected with: p.R158Q (P, 11 submitters); p.R...</td>\n",
-       "      <td>ClinGenPhenylketonuriaExpertPanelSpecification...</td>\n",
-       "    </tr>\n",
-       "    <tr>\n",
-       "      <th>1</th>\n",
-       "      <td>23</td>\n",
-       "      <td>NM_000277.2(PAH):c.158G&gt;A (p.Arg53His)</td>\n",
-       "      <td>PAH</td>\n",
-       "      <td>phenylketonuria</td>\n",
-       "      <td>MONDO:0009861</td>\n",
-       "      <td>Uncertain Significance</td>\n",
-       "      <td>Autosomal recessive inheritance</td>\n",
-       "      <td>Phenylketonuria</td>\n",
-       "      <td>2019-04-08</td>\n",
-       "      <td>PM3</td>\n",
-       "      <td>met</td>\n",
-       "      <td>PubMed:26322415</td>\n",
-       "      <td>Patient genotype: c.[158G&gt;A];[728G&gt;A],p.[R53H]...</td>\n",
-       "      <td>Detected in trans with p.R243Q (P, 7 submitter...</td>\n",
-       "      <td>Detected in trans with p.R243Q (P, 7 submitter...</td>\n",
-       "      <td>ClinGenPhenylketonuriaExpertPanelSpecification...</td>\n",
-       "    </tr>\n",
-       "    <tr>\n",
-       "      <th>2</th>\n",
-       "      <td>23</td>\n",
-       "      <td>NM_000277.2(PAH):c.158G&gt;A (p.Arg53His)</td>\n",
-       "      <td>PAH</td>\n",
-       "      <td>phenylketonuria</td>\n",
-       "      <td>MONDO:0009861</td>\n",
-       "      <td>Uncertain Significance</td>\n",
-       "      <td>Autosomal recessive inheritance</td>\n",
-       "      <td>Phenylketonuria</td>\n",
-       "      <td>2019-04-08</td>\n",
-       "      <td>PP4-Moderate</td>\n",
-       "      <td>not_met</td>\n",
-       "      <td>PubMed:26322415</td>\n",
-       "      <td>c.158G&gt;A p.R53H identified on 8 alleles. All p...</td>\n",
-       "      <td>Detected in multiple patients with mild hyperp...</td>\n",
-       "      <td>Detected in multiple patients with mild hyperp...</td>\n",
-       "      <td>ClinGenPhenylketonuriaExpertPanelSpecification...</td>\n",
-       "    </tr>\n",
-       "    <tr>\n",
-       "      <th>3</th>\n",
-       "      <td>26</td>\n",
-       "      <td>NM_000277.2(PAH):c.500A&gt;T (p.Asn167Ile)</td>\n",
-       "      <td>PAH</td>\n",
-       "      <td>phenylketonuria</td>\n",
-       "      <td>MONDO:0009861</td>\n",
-       "      <td>Likely Pathogenic</td>\n",
-       "      <td>Autosomal recessive inheritance</td>\n",
-       "      <td>Phenylketonuria</td>\n",
-       "      <td>2019-04-06</td>\n",
-       "      <td>PP4-Moderate</td>\n",
-       "      <td>not_met</td>\n",
-       "      <td>PubMed:26666653</td>\n",
-       "      <td>364 hyperphenylalaninemic patients from 20 Fre...</td>\n",
-       "      <td>Found in a French patient with HPA and 2 unrel...</td>\n",
-       "      <td>Found in a French patient with HPA and 2 unrel...</td>\n",
-       "      <td>ClinGenPhenylketonuriaExpertPanelSpecification...</td>\n",
-       "    </tr>\n",
-       "    <tr>\n",
-       "      <th>4</th>\n",
-       "      <td>26</td>\n",
-       "      <td>NM_000277.2(PAH):c.500A&gt;T (p.Asn167Ile)</td>\n",
-       "      <td>PAH</td>\n",
-       "      <td>phenylketonuria</td>\n",
-       "      <td>MONDO:0009861</td>\n",
-       "      <td>Likely Pathogenic</td>\n",
-       "      <td>Autosomal recessive inheritance</td>\n",
-       "      <td>Phenylketonuria</td>\n",
-       "      <td>2019-04-06</td>\n",
-       "      <td>PM3-Strong</td>\n",
-       "      <td>not_met</td>\n",
-       "      <td>PubMed:26666653</td>\n",
-       "      <td>Genotype: c. [500A &gt; T] (p.Asn167Ile); [1066-1...</td>\n",
-       "      <td>Patient 664  with genotype N167I/Rl58Q (Pathog...</td>\n",
-       "      <td>Patient 664  with genotype N167I/Rl58Q (Pathog...</td>\n",
-       "      <td>ClinGenPhenylketonuriaExpertPanelSpecification...</td>\n",
-       "    </tr>\n",
-       "    <tr>\n",
-       "      <th>...</th>\n",
-       "      <td>...</td>\n",
-       "      <td>...</td>\n",
-       "      <td>...</td>\n",
-       "      <td>...</td>\n",
-       "      <td>...</td>\n",
-       "      <td>...</td>\n",
-       "      <td>...</td>\n",
-       "      <td>...</td>\n",
-       "      <td>...</td>\n",
-       "      <td>...</td>\n",
-       "      <td>...</td>\n",
-       "      <td>...</td>\n",
-       "      <td>...</td>\n",
-       "      <td>...</td>\n",
-       "      <td>...</td>\n",
-       "      <td>...</td>\n",
-       "    </tr>\n",
-       "    <tr>\n",
-       "      <th>771</th>\n",
-       "      <td>9523</td>\n",
-       "      <td>NM_000180.4(GUCY2D):c.1762C&gt;T (p.Arg588Trp)</td>\n",
-       "      <td>GUCY2D</td>\n",
-       "      <td>GUCY2D-related recessive retinopathy</td>\n",
-       "      <td>MONDO:0100453</td>\n",
-       "      <td>Pathogenic</td>\n",
-       "      <td>Autosomal recessive inheritance</td>\n",
-       "      <td>Leber Congenital Amaurosis/early onset Retinal...</td>\n",
-       "      <td>2025-01-30</td>\n",
-       "      <td>PS3-Supporting</td>\n",
-       "      <td>not_met</td>\n",
-       "      <td>PubMed:36274938</td>\n",
-       "      <td>The variant exhibited &lt;1.5% of wt activity whe...</td>\n",
-       "      <td>The variant exhibited &lt;1.5% of wt activity whe...</td>\n",
-       "      <td>The variant exhibited &lt;1.5% of wt activity whe...</td>\n",
-       "      <td>ClinGenLeberCongenitalAmaurosisearlyonsetRetin...</td>\n",
-       "    </tr>\n",
-       "    <tr>\n",
-       "      <th>772</th>\n",
-       "      <td>9547</td>\n",
-       "      <td>NM_000180.4(GUCY2D):c.3271C&gt;T (p.Arg1091Ter)</td>\n",
-       "      <td>GUCY2D</td>\n",
-       "      <td>GUCY2D-related recessive retinopathy</td>\n",
-       "      <td>MONDO:0100453</td>\n",
-       "      <td>Pathogenic</td>\n",
-       "      <td>Autosomal recessive inheritance</td>\n",
-       "      <td>Leber Congenital Amaurosis/early onset Retinal...</td>\n",
-       "      <td>2025-01-30</td>\n",
-       "      <td>BS3</td>\n",
-       "      <td>not_met</td>\n",
-       "      <td>PubMed:27881908</td>\n",
-       "      <td>AAV-packaged WT or mutant GUCY2D expression co...</td>\n",
-       "      <td>The variant showed successsful rescue of rod a...</td>\n",
-       "      <td>The variant showed successsful rescue of rod a...</td>\n",
-       "      <td>ClinGenLeberCongenitalAmaurosisearlyonsetRetin...</td>\n",
-       "    </tr>\n",
-       "    <tr>\n",
-       "      <th>773</th>\n",
-       "      <td>9547</td>\n",
-       "      <td>NM_000180.4(GUCY2D):c.3271C&gt;T (p.Arg1091Ter)</td>\n",
-       "      <td>GUCY2D</td>\n",
-       "      <td>GUCY2D-related recessive retinopathy</td>\n",
-       "      <td>MONDO:0100453</td>\n",
-       "      <td>Pathogenic</td>\n",
-       "      <td>Autosomal recessive inheritance</td>\n",
-       "      <td>Leber Congenital Amaurosis/early onset Retinal...</td>\n",
-       "      <td>2025-01-30</td>\n",
-       "      <td>PS3</td>\n",
-       "      <td>not_met</td>\n",
-       "      <td>PubMed:27881908</td>\n",
-       "      <td>AAV-packaged WT or mutant GUCY2D expression co...</td>\n",
-       "      <td>Activity is reduced to 25% but is not less tha...</td>\n",
-       "      <td>Activity is reduced to 25% but is not less tha...</td>\n",
-       "      <td>ClinGenLeberCongenitalAmaurosisearlyonsetRetin...</td>\n",
-       "    </tr>\n",
-       "    <tr>\n",
-       "      <th>774</th>\n",
-       "      <td>9551</td>\n",
-       "      <td>NM_000180.4(GUCY2D):c.1724C&gt;T (p.Pro575Leu)</td>\n",
-       "      <td>GUCY2D</td>\n",
-       "      <td>GUCY2D-related recessive retinopathy</td>\n",
-       "      <td>MONDO:0100453</td>\n",
-       "      <td>Benign</td>\n",
-       "      <td>Autosomal recessive inheritance</td>\n",
-       "      <td>Leber Congenital Amaurosis/early onset Retinal...</td>\n",
-       "      <td>2025-01-30</td>\n",
-       "      <td>BS3-Supporting</td>\n",
-       "      <td>not_met</td>\n",
-       "      <td>PubMed:24616660</td>\n",
-       "      <td>The variant exhibited ~75% enzymatic activity ...</td>\n",
-       "      <td>The variant exhibited ~75% enzymatic activity ...</td>\n",
-       "      <td>The variant exhibited ~75% enzymatic activity ...</td>\n",
-       "      <td>ClinGenLeberCongenitalAmaurosisearlyonsetRetin...</td>\n",
-       "    </tr>\n",
-       "    <tr>\n",
-       "      <th>775</th>\n",
-       "      <td>9559</td>\n",
-       "      <td>NM_000180.4(GUCY2D):c.1371C&gt;T (p.Cys457=)</td>\n",
-       "      <td>GUCY2D</td>\n",
-       "      <td>GUCY2D-related recessive retinopathy</td>\n",
-       "      <td>MONDO:0100453</td>\n",
-       "      <td>Benign</td>\n",
-       "      <td>Autosomal recessive inheritance</td>\n",
-       "      <td>Leber Congenital Amaurosis/early onset Retinal...</td>\n",
-       "      <td>2025-01-30</td>\n",
-       "      <td>BA1</td>\n",
-       "      <td>met</td>\n",
-       "      <td>PubMed:18682808</td>\n",
-       "      <td>Seong, et al, 2008, tested 20 Korean patients ...</td>\n",
-       "      <td>This variant is present in gnomAD v.4.1.0 at a...</td>\n",
-       "      <td>This variant is present in gnomAD v.4.1.0 at a...</td>\n",
-       "      <td>ClinGenLeberCongenitalAmaurosisearlyonsetRetin...</td>\n",
-       "    </tr>\n",
-       "  </tbody>\n",
-       "</table>\n",
-       "<p>776 rows × 16 columns</p>\n",
-       "</div>"
-      ],
-      "text/plain": [
-       "     entry_index                                       variant hgnc_gene  \\\n",
-       "0              8       NM_000277.2(PAH):c.331C>T (p.Arg111Ter)       PAH   \n",
-       "1             23        NM_000277.2(PAH):c.158G>A (p.Arg53His)       PAH   \n",
-       "2             23        NM_000277.2(PAH):c.158G>A (p.Arg53His)       PAH   \n",
-       "3             26       NM_000277.2(PAH):c.500A>T (p.Asn167Ile)       PAH   \n",
-       "4             26       NM_000277.2(PAH):c.500A>T (p.Asn167Ile)       PAH   \n",
-       "..           ...                                           ...       ...   \n",
-       "771         9523   NM_000180.4(GUCY2D):c.1762C>T (p.Arg588Trp)    GUCY2D   \n",
-       "772         9547  NM_000180.4(GUCY2D):c.3271C>T (p.Arg1091Ter)    GUCY2D   \n",
-       "773         9547  NM_000180.4(GUCY2D):c.3271C>T (p.Arg1091Ter)    GUCY2D   \n",
-       "774         9551   NM_000180.4(GUCY2D):c.1724C>T (p.Pro575Leu)    GUCY2D   \n",
-       "775         9559     NM_000180.4(GUCY2D):c.1371C>T (p.Cys457=)    GUCY2D   \n",
-       "\n",
-       "                                  disease       mondo_id  \\\n",
-       "0                         phenylketonuria  MONDO:0009861   \n",
-       "1                         phenylketonuria  MONDO:0009861   \n",
-       "2                         phenylketonuria  MONDO:0009861   \n",
-       "3                         phenylketonuria  MONDO:0009861   \n",
-       "4                         phenylketonuria  MONDO:0009861   \n",
-       "..                                    ...            ...   \n",
-       "771  GUCY2D-related recessive retinopathy  MONDO:0100453   \n",
-       "772  GUCY2D-related recessive retinopathy  MONDO:0100453   \n",
-       "773  GUCY2D-related recessive retinopathy  MONDO:0100453   \n",
-       "774  GUCY2D-related recessive retinopathy  MONDO:0100453   \n",
-       "775  GUCY2D-related recessive retinopathy  MONDO:0100453   \n",
-       "\n",
-       "                  assertion                 mode_inheritance  \\\n",
-       "0                Pathogenic  Autosomal recessive inheritance   \n",
-       "1    Uncertain Significance  Autosomal recessive inheritance   \n",
-       "2    Uncertain Significance  Autosomal recessive inheritance   \n",
-       "3         Likely Pathogenic  Autosomal recessive inheritance   \n",
-       "4         Likely Pathogenic  Autosomal recessive inheritance   \n",
-       "..                      ...                              ...   \n",
-       "771              Pathogenic  Autosomal recessive inheritance   \n",
-       "772              Pathogenic  Autosomal recessive inheritance   \n",
-       "773              Pathogenic  Autosomal recessive inheritance   \n",
-       "774                  Benign  Autosomal recessive inheritance   \n",
-       "775                  Benign  Autosomal recessive inheritance   \n",
-       "\n",
-       "                                          expert_panel    pub_date  \\\n",
-       "0                                      Phenylketonuria  2019-04-09   \n",
-       "1                                      Phenylketonuria  2019-04-08   \n",
-       "2                                      Phenylketonuria  2019-04-08   \n",
-       "3                                      Phenylketonuria  2019-04-06   \n",
-       "4                                      Phenylketonuria  2019-04-06   \n",
-       "..                                                 ...         ...   \n",
-       "771  Leber Congenital Amaurosis/early onset Retinal...  2025-01-30   \n",
-       "772  Leber Congenital Amaurosis/early onset Retinal...  2025-01-30   \n",
-       "773  Leber Congenital Amaurosis/early onset Retinal...  2025-01-30   \n",
-       "774  Leber Congenital Amaurosis/early onset Retinal...  2025-01-30   \n",
-       "775  Leber Congenital Amaurosis/early onset Retinal...  2025-01-30   \n",
-       "\n",
-       "       evidence_code met_status             pmid  \\\n",
-       "0    PM3-Very Strong    not_met  PubMed:26322415   \n",
-       "1                PM3        met  PubMed:26322415   \n",
-       "2       PP4-Moderate    not_met  PubMed:26322415   \n",
-       "3       PP4-Moderate    not_met  PubMed:26666653   \n",
-       "4         PM3-Strong    not_met  PubMed:26666653   \n",
-       "..               ...        ...              ...   \n",
-       "771   PS3-Supporting    not_met  PubMed:36274938   \n",
-       "772              BS3    not_met  PubMed:27881908   \n",
-       "773              PS3    not_met  PubMed:27881908   \n",
-       "774   BS3-Supporting    not_met  PubMed:24616660   \n",
-       "775              BA1        met  PubMed:18682808   \n",
-       "\n",
-       "                                              comments  \\\n",
-       "0    Detected in 13 patients with: c.611A>G, p.E280...   \n",
-       "1    Patient genotype: c.[158G>A];[728G>A],p.[R53H]...   \n",
-       "2    c.158G>A p.R53H identified on 8 alleles. All p...   \n",
-       "3    364 hyperphenylalaninemic patients from 20 Fre...   \n",
-       "4    Genotype: c. [500A > T] (p.Asn167Ile); [1066-1...   \n",
-       "..                                                 ...   \n",
-       "771  The variant exhibited <1.5% of wt activity whe...   \n",
-       "772  AAV-packaged WT or mutant GUCY2D expression co...   \n",
-       "773  AAV-packaged WT or mutant GUCY2D expression co...   \n",
-       "774  The variant exhibited ~75% enzymatic activity ...   \n",
-       "775  Seong, et al, 2008, tested 20 Korean patients ...   \n",
-       "\n",
-       "                                               summary  \\\n",
-       "0    Detected with: p.R158Q (P, 11 submitters); p.R...   \n",
-       "1    Detected in trans with p.R243Q (P, 7 submitter...   \n",
-       "2    Detected in multiple patients with mild hyperp...   \n",
-       "3    Found in a French patient with HPA and 2 unrel...   \n",
-       "4    Patient 664  with genotype N167I/Rl58Q (Pathog...   \n",
-       "..                                                 ...   \n",
-       "771  The variant exhibited <1.5% of wt activity whe...   \n",
-       "772  The variant showed successsful rescue of rod a...   \n",
-       "773  Activity is reduced to 25% but is not less tha...   \n",
-       "774  The variant exhibited ~75% enzymatic activity ...   \n",
-       "775  This variant is present in gnomAD v.4.1.0 at a...   \n",
-       "\n",
-       "                                      summary_comments  \\\n",
-       "0    Detected with: p.R158Q (P, 11 submitters); p.R...   \n",
-       "1    Detected in trans with p.R243Q (P, 7 submitter...   \n",
-       "2    Detected in multiple patients with mild hyperp...   \n",
-       "3    Found in a French patient with HPA and 2 unrel...   \n",
-       "4    Patient 664  with genotype N167I/Rl58Q (Pathog...   \n",
-       "..                                                 ...   \n",
-       "771  The variant exhibited <1.5% of wt activity whe...   \n",
-       "772  The variant showed successsful rescue of rod a...   \n",
-       "773  Activity is reduced to 25% but is not less tha...   \n",
-       "774  The variant exhibited ~75% enzymatic activity ...   \n",
-       "775  This variant is present in gnomAD v.4.1.0 at a...   \n",
-       "\n",
-       "                                                  path  \n",
-       "0    ClinGenPhenylketonuriaExpertPanelSpecification...  \n",
-       "1    ClinGenPhenylketonuriaExpertPanelSpecification...  \n",
-       "2    ClinGenPhenylketonuriaExpertPanelSpecification...  \n",
-       "3    ClinGenPhenylketonuriaExpertPanelSpecification...  \n",
-       "4    ClinGenPhenylketonuriaExpertPanelSpecification...  \n",
-       "..                                                 ...  \n",
-       "771  ClinGenLeberCongenitalAmaurosisearlyonsetRetin...  \n",
-       "772  ClinGenLeberCongenitalAmaurosisearlyonsetRetin...  \n",
-       "773  ClinGenLeberCongenitalAmaurosisearlyonsetRetin...  \n",
-       "774  ClinGenLeberCongenitalAmaurosisearlyonsetRetin...  \n",
-       "775  ClinGenLeberCongenitalAmaurosisearlyonsetRetin...  \n",
-       "\n",
-       "[776 rows x 16 columns]"
-      ]
-     },
-     "execution_count": 105,
-     "metadata": {},
-     "output_type": "execute_result"
-    }
-   ],
-   "source": [
-    "df"
-   ]
-  },
-  {
-   "cell_type": "code",
-   "execution_count": 38,
-   "id": "910cfb99-64b2-4a54-98ba-9de34c2dff07",
-   "metadata": {},
-   "outputs": [],
-   "source": [
-    "# /Users/owenqueen/Desktop/stanford_research/SHERLOCK_HOME/clingen_benchmark/data/VCI/parsing_csr_criteria/version_csv_individual\n",
-    "\n",
-    "def get_criteria_per_row(row):\n",
-    "    base_path = row[\"path\"]\n",
-    "    criteria = pd.read_csv(os.path.join(DATA_PATH, \"VCI/parsing_csr_criteria/version_csv_individual\", base_path))\n",
-    "    criteria_trim = criteria.loc[criteria[\"Gene\"].apply(lambda x: x.split(\" \")[0]) == row[\"hgnc_gene\"],:]\n",
-    "    return criteria, criteria_trim"
-   ]
-  },
-  {
-   "cell_type": "code",
-   "execution_count": 26,
-   "id": "255c35dc-dd04-40c7-b233-40a6637da7a5",
-   "metadata": {},
-   "outputs": [],
-   "source": [
-    "clist = []\n",
-    "ctrim_list = []\n",
-    "for i, row in df.iterrows():\n",
-    "    c, ctrim = get_criteria_per_row(row)\n",
-    "    clist.append(c)\n",
-    "    ctrim_list.append(ctrim)"
-   ]
-  },
-  {
-   "cell_type": "code",
-   "execution_count": 27,
-   "id": "5e3c0fde-55d7-4bd0-a9b1-b4bcc5702e75",
-   "metadata": {},
-   "outputs": [],
-   "source": [
-    "size = []\n",
-    "for c in ctrim_list:\n",
-    "    size.append(c.shape[0])"
-   ]
-  },
-  {
-   "cell_type": "code",
-   "execution_count": 28,
-   "id": "467a6806-3778-4a1d-a159-fb49b77f464b",
-   "metadata": {},
-   "outputs": [
-    {
-     "data": {
-      "text/plain": [
-       "(array([ 17,  18,  19,  62,  63,  64,  65,  67,  68,  69,  70,  71,  72,\n",
-       "         73,  74, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130,\n",
-       "        131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143,\n",
-       "        144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156,\n",
-       "        157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 191, 192,\n",
-       "        193, 194, 195, 196, 197, 198, 199, 200, 201, 208, 209, 210, 211,\n",
-       "        212, 213, 216, 217, 218, 219, 220, 223, 224, 225, 226, 227, 228,\n",
-       "        229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 306, 307,\n",
-       "        308, 309, 310, 311, 313, 325, 326, 327, 332, 339, 340, 341, 342,\n",
-       "        351, 352, 353, 354, 362, 363, 364, 388, 390, 391, 392, 393, 394,\n",
-       "        406, 436, 447, 455, 456, 457, 458, 459, 460, 461, 462, 513, 514,\n",
-       "        515, 516, 517, 521, 522, 523, 524, 532, 533, 562, 563, 581, 582,\n",
-       "        583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595,\n",
-       "        596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608,\n",
-       "        609, 610, 611, 612, 613, 614, 615, 619, 620, 639, 651, 654, 655,\n",
-       "        656, 658, 659, 677, 678, 681, 682, 683, 711, 713, 736, 738, 758]),)"
-      ]
-     },
-     "execution_count": 28,
-     "metadata": {},
-     "output_type": "execute_result"
-    }
-   ],
-   "source": [
-    "(np.array(size) == 0).nonzero()"
-   ]
-  },
-  {
-   "cell_type": "code",
-   "execution_count": 32,
-   "id": "29fdb42d-ee60-49c7-ae8f-c570b9bd41d9",
-   "metadata": {},
-   "outputs": [],
-   "source": [
-    "ucount = []\n",
-    "for ind in (np.array(size) == 0).nonzero()[0]:\n",
-    "    ucount.append(clist[ind].Gene.unique().shape[0])"
-   ]
-  },
-  {
-   "cell_type": "code",
-   "execution_count": 30,
-   "id": "2513b7b7-44ca-4e1f-89f8-abf4e85a7abb",
-   "metadata": {},
-   "outputs": [
-    {
-     "data": {
-      "text/plain": [
-       "entry_index                                                       141\n",
-       "variant                     NM_004004.5(GJB2):c.35delG (p.Gly12Valfs)\n",
-       "hgnc_gene                                                        GJB2\n",
-       "disease                                 nonsyndromic genetic deafness\n",
-       "mondo_id                                                MONDO:0019497\n",
-       "assertion                                                  Pathogenic\n",
-       "mode_inheritance                      Autosomal recessive inheritance\n",
-       "expert_panel                                             Hearing Loss\n",
-       "pub_date                                                   2019-07-17\n",
-       "evidence_code                                                     PS4\n",
-       "met_status                                                        met\n",
-       "pmid                                                  PubMed:26969326\n",
-       "comments            3.2% (72/2238) of alleles reported in this stu...\n",
-       "summary             In 1 large study (Sloan-Heggen 2015) and in 1 ...\n",
-       "summary_comments    In 1 large study (Sloan-Heggen 2015) and in 1 ...\n",
-       "path                ClinGenHearingLossExpertPanelSpecificationstot...\n",
-       "Name: 17, dtype: object"
-      ]
-     },
-     "execution_count": 30,
-     "metadata": {},
-     "output_type": "execute_result"
-    }
-   ],
-   "source": [
-    "df.iloc[17]"
-   ]
-  },
-  {
-   "cell_type": "code",
-   "execution_count": 102,
-   "id": "b1e2c9a2-bc9c-452c-8930-62f6776059c1",
-   "metadata": {},
-   "outputs": [],
-   "source": [
-    "def convert_row_code(row):\n",
-    "    code, strength = row[\"Code\"], row[\"Strength\"]\n",
-    "\n",
-    "    if strength.startswith(\"Original ACMG\"):\n",
-    "        return code\n",
-    "    else:\n",
-    "        return f\"{code}_{strength.replace(' ', '')}\"\n",
-    "\n",
-    "def cascade_descriptions(criteria_df):\n",
-    "\n",
-    "    modify_criteria_df = criteria_df.copy()\n",
-    "\n",
-    "    for code in modify_criteria_df[\"Code\"].unique():\n",
-    "        in_code = modify_criteria_df.loc[modify_criteria_df[\"Code\"] == code]\n",
-    "\n",
-    "        mask_in = in_code[\"Strength\"].apply(lambda x: x.startswith(\"Original ACMG\"))\n",
-    "        if not (mask_in.sum() == 1):\n",
-    "            print(in_code)\n",
-    "            raise ValueError\n",
-    "\n",
-    "        org_row = in_code[mask_in].iloc[0]\n",
-    "        org_desc = org_row[\"Description\"]\n",
-    "\n",
-    "        for i in range(in_code.shape[0]):\n",
-    "            strength = in_code[\"Strength\"].iloc[i]\n",
-    "            if not strength.startswith(\"Original ACMG\"):\n",
-    "                new_description = \"General code description: \" + org_desc + \"\\n\\n\" + \"Detailed code description: \" + in_code[\"Description\"].iloc[i]\n",
-    "            else:\n",
-    "                new_description = \"General code description: \" + org_desc\n",
-    "                \n",
-    "            modify_criteria_df.loc[\n",
-    "                (modify_criteria_df[\"Code\"] == code) & (modify_criteria_df[\"Strength\"] == strength),\n",
-    "                \"Description\"\n",
-    "            ] = new_description\n",
-    "\n",
-    "    return modify_criteria_df\n",
-    "    \n",
-    "\n",
-    "def get_criteria_per_row_FULL(row):\n",
-    "    base_path = row[\"path\"]\n",
-    "    criteria = pd.read_csv(os.path.join(DATA_PATH, \"VCI/parsing_csr_criteria/version_csv_individual\", base_path))\n",
-    "    if criteria[\"Gene\"].unique().shape[0] == 1:\n",
-    "        # Aggregate codes:\n",
-    "        criteria[\"aggregate_code\"] = [convert_row_code(row) for i, row in criteria.iterrows()]\n",
-    "        return cascade_descriptions(criteria)\n",
-    "    else:     \n",
-    "        print(\"HERE\")\n",
-    "        criteria_trim = criteria.loc[criteria[\"Gene\"].apply(lambda x: x.split(\" \")[0]) == row[\"hgnc_gene\"],:]\n",
-    "        criteria_trim[\"aggregate_code\"] = [convert_row_code(row) for i, row in criteria_trim.iterrows()]\n",
-    "        return cascade_descriptions(criteria_trim)"
-   ]
-  },
-  {
-   "cell_type": "code",
-   "execution_count": 41,
-   "id": "23ed83e5-3991-409a-9826-c325b161a521",
-   "metadata": {},
-   "outputs": [],
-   "source": [
-    "# Base operation:\n",
-    "clist = []\n",
-    "for i, row in df.iterrows():\n",
-    "    c = get_criteria_per_row_FULL(row)\n",
-    "    clist.append(c)"
-   ]
-  },
-  {
-   "cell_type": "code",
-   "execution_count": 42,
-   "id": "1313a1bc-05d1-49e4-9857-1980d8d3e5a9",
-   "metadata": {},
-   "outputs": [],
-   "source": [
-    "size = []\n",
-    "for c in clist:\n",
-    "    size.append(c.shape[0])"
-   ]
-  },
-  {
-   "cell_type": "code",
-   "execution_count": 103,
-   "id": "ba8aafaa-cd48-457b-a934-3ba451092f1e",
-   "metadata": {},
-   "outputs": [
-    {
-     "name": "stdout",
-     "output_type": "stream",
-     "text": [
-      "HERE\n"
-     ]
-    },
-    {
-     "name": "stderr",
-     "output_type": "stream",
-     "text": [
-      "/var/folders/3q/fmvp_t4528b2sghqyyn20hw80000gn/T/ipykernel_11715/3675522798.py:49: SettingWithCopyWarning: \n",
-      "A value is trying to be set on a copy of a slice from a DataFrame.\n",
-      "Try using .loc[row_indexer,col_indexer] = value instead\n",
-      "\n",
-      "See the caveats in the documentation: https://pandas.pydata.org/pandas-docs/stable/user_guide/indexing.html#returning-a-view-versus-a-copy\n",
-      "  criteria_trim[\"aggregate_code\"] = [convert_row_code(row) for i, row in criteria_trim.iterrows()]\n"
-     ]
-    }
-   ],
-   "source": [
-    "# Get unique criteria:\n",
-    "path_unique = df[\"path\"].unique().tolist()\n",
-    "all_codes = []\n",
-    "clist_unique = []\n",
-    "for p in path_unique:\n",
-    "    row = df[df[\"path\"] == p].iloc[0]\n",
-    "    c = get_criteria_per_row_FULL(row)\n",
-    "    clist_unique.append(c)\n",
-    "    all_codes.append(df[\"evidence_code\"].loc[df[\"path\"] == p].unique())"
-   ]
-  },
-  {
-   "cell_type": "code",
-   "execution_count": 104,
-   "id": "a4937bd0-b56a-40fd-8db2-4a78227da190",
-   "metadata": {},
-   "outputs": [
-    {
-     "data": {
-      "text/html": [
-       "<div>\n",
-       "<style scoped>\n",
-       "    .dataframe tbody tr th:only-of-type {\n",
-       "        vertical-align: middle;\n",
-       "    }\n",
-       "\n",
-       "    .dataframe tbody tr th {\n",
-       "        vertical-align: top;\n",
-       "    }\n",
-       "\n",
-       "    .dataframe thead th {\n",
-       "        text-align: right;\n",
-       "    }\n",
-       "</style>\n",
-       "<table border=\"1\" class=\"dataframe\">\n",
-       "  <thead>\n",
-       "    <tr style=\"text-align: right;\">\n",
-       "      <th></th>\n",
-       "      <th>Gene</th>\n",
-       "      <th>Code</th>\n",
-       "      <th>Strength</th>\n",
-       "      <th>Description</th>\n",
-       "      <th>Modification Type</th>\n",
-       "      <th>aggregate_code</th>\n",
-       "    </tr>\n",
-       "  </thead>\n",
-       "  <tbody>\n",
-       "    <tr>\n",
-       "      <th>0</th>\n",
-       "      <td>PAH (HGNC:8582)</td>\n",
-       "      <td>PVS1</td>\n",
-       "      <td>Original ACMG Summary</td>\n",
-       "      <td>General code description: Null variant (nonsen...</td>\n",
-       "      <td>NaN</td>\n",
-       "      <td>PVS1</td>\n",
-       "    </tr>\n",
-       "    <tr>\n",
-       "      <th>1</th>\n",
-       "      <td>PAH (HGNC:8582)</td>\n",
-       "      <td>PVS1</td>\n",
-       "      <td>Very Strong</td>\n",
-       "      <td>General code description: Null variant (nonsen...</td>\n",
-       "      <td>Disease-specific</td>\n",
-       "      <td>PVS1_VeryStrong</td>\n",
-       "    </tr>\n",
-       "    <tr>\n",
-       "      <th>2</th>\n",
-       "      <td>PAH (HGNC:8582)</td>\n",
-       "      <td>PVS1</td>\n",
-       "      <td>Strong</td>\n",
-       "      <td>General code description: Null variant (nonsen...</td>\n",
-       "      <td>Disease-specific</td>\n",
-       "      <td>PVS1_Strong</td>\n",
-       "    </tr>\n",
-       "    <tr>\n",
-       "      <th>3</th>\n",
-       "      <td>PAH (HGNC:8582)</td>\n",
-       "      <td>PS1</td>\n",
-       "      <td>Original ACMG Summary</td>\n",
-       "      <td>General code description: Same amino acid chan...</td>\n",
-       "      <td>NaN</td>\n",
-       "      <td>PS1</td>\n",
-       "    </tr>\n",
-       "    <tr>\n",
-       "      <th>4</th>\n",
-       "      <td>PAH (HGNC:8582)</td>\n",
-       "      <td>PS1</td>\n",
-       "      <td>Strong</td>\n",
-       "      <td>General code description: Same amino acid chan...</td>\n",
-       "      <td>Disease-specific</td>\n",
-       "      <td>PS1_Strong</td>\n",
-       "    </tr>\n",
-       "    <tr>\n",
-       "      <th>...</th>\n",
-       "      <td>...</td>\n",
-       "      <td>...</td>\n",
-       "      <td>...</td>\n",
-       "      <td>...</td>\n",
-       "      <td>...</td>\n",
-       "      <td>...</td>\n",
-       "    </tr>\n",
-       "    <tr>\n",
-       "      <th>57</th>\n",
-       "      <td>PAH (HGNC:8582)</td>\n",
-       "      <td>BP5</td>\n",
-       "      <td>Supporting</td>\n",
-       "      <td>General code description: Variant found in a c...</td>\n",
-       "      <td>No change</td>\n",
-       "      <td>BP5_Supporting</td>\n",
-       "    </tr>\n",
-       "    <tr>\n",
-       "      <th>58</th>\n",
-       "      <td>PAH (HGNC:8582)</td>\n",
-       "      <td>BP6</td>\n",
-       "      <td>Original ACMG Summary</td>\n",
-       "      <td>General code description: Reputable source rec...</td>\n",
-       "      <td>NaN</td>\n",
-       "      <td>BP6</td>\n",
-       "    </tr>\n",
-       "    <tr>\n",
-       "      <th>59</th>\n",
-       "      <td>PAH (HGNC:8582)</td>\n",
-       "      <td>BP7</td>\n",
-       "      <td>Original ACMG Summary</td>\n",
-       "      <td>General code description: A synonymous variant...</td>\n",
-       "      <td>NaN</td>\n",
-       "      <td>BP7</td>\n",
-       "    </tr>\n",
-       "    <tr>\n",
-       "      <th>60</th>\n",
-       "      <td>PAH (HGNC:8582)</td>\n",
-       "      <td>BP7</td>\n",
-       "      <td>Strong</td>\n",
-       "      <td>General code description: A synonymous variant...</td>\n",
-       "      <td>Strength</td>\n",
-       "      <td>BP7_Strong</td>\n",
-       "    </tr>\n",
-       "    <tr>\n",
-       "      <th>61</th>\n",
-       "      <td>PAH (HGNC:8582)</td>\n",
-       "      <td>BP7</td>\n",
-       "      <td>Supporting</td>\n",
-       "      <td>General code description: A synonymous variant...</td>\n",
-       "      <td>Gene-specific,None</td>\n",
-       "      <td>BP7_Supporting</td>\n",
-       "    </tr>\n",
-       "  </tbody>\n",
-       "</table>\n",
-       "<p>62 rows × 6 columns</p>\n",
-       "</div>"
-      ],
-      "text/plain": [
-       "               Gene  Code               Strength  \\\n",
-       "0   PAH (HGNC:8582)  PVS1  Original ACMG Summary   \n",
-       "1   PAH (HGNC:8582)  PVS1            Very Strong   \n",
-       "2   PAH (HGNC:8582)  PVS1                 Strong   \n",
-       "3   PAH (HGNC:8582)   PS1  Original ACMG Summary   \n",
-       "4   PAH (HGNC:8582)   PS1                 Strong   \n",
-       "..              ...   ...                    ...   \n",
-       "57  PAH (HGNC:8582)   BP5             Supporting   \n",
-       "58  PAH (HGNC:8582)   BP6  Original ACMG Summary   \n",
-       "59  PAH (HGNC:8582)   BP7  Original ACMG Summary   \n",
-       "60  PAH (HGNC:8582)   BP7                 Strong   \n",
-       "61  PAH (HGNC:8582)   BP7             Supporting   \n",
-       "\n",
-       "                                          Description   Modification Type  \\\n",
-       "0   General code description: Null variant (nonsen...                 NaN   \n",
-       "1   General code description: Null variant (nonsen...    Disease-specific   \n",
-       "2   General code description: Null variant (nonsen...    Disease-specific   \n",
-       "3   General code description: Same amino acid chan...                 NaN   \n",
-       "4   General code description: Same amino acid chan...    Disease-specific   \n",
-       "..                                                ...                 ...   \n",
-       "57  General code description: Variant found in a c...           No change   \n",
-       "58  General code description: Reputable source rec...                 NaN   \n",
-       "59  General code description: A synonymous variant...                 NaN   \n",
-       "60  General code description: A synonymous variant...            Strength   \n",
-       "61  General code description: A synonymous variant...  Gene-specific,None   \n",
-       "\n",
-       "     aggregate_code  \n",
-       "0              PVS1  \n",
-       "1   PVS1_VeryStrong  \n",
-       "2       PVS1_Strong  \n",
-       "3               PS1  \n",
-       "4        PS1_Strong  \n",
-       "..              ...  \n",
-       "57   BP5_Supporting  \n",
-       "58              BP6  \n",
-       "59              BP7  \n",
-       "60       BP7_Strong  \n",
-       "61   BP7_Supporting  \n",
-       "\n",
-       "[62 rows x 6 columns]"
-      ]
-     },
-     "execution_count": 104,
-     "metadata": {},
-     "output_type": "execute_result"
-    }
-   ],
-   "source": [
-    "clist_unique[0]"
-   ]
-  },
-  {
-   "cell_type": "code",
-   "execution_count": 95,
-   "id": "710da496-c9a2-4d4a-a375-4c2e637fed93",
-   "metadata": {},
-   "outputs": [
-    {
-     "data": {
-      "text/plain": [
-       "array(['PM3-Very Strong', 'PM3', 'PP4-Moderate', 'PM3-Strong', 'PP4',\n",
-       "       'PP1', 'PM3-Supporting', 'PS3-Supporting'], dtype=object)"
-      ]
-     },
-     "execution_count": 95,
-     "metadata": {},
-     "output_type": "execute_result"
-    }
-   ],
-   "source": [
-    "# Are the codes in the DF?\n",
-    "all_codes[0]"
-   ]
-  },
-  {
-   "cell_type": "code",
-   "execution_count": 96,
-   "id": "a4bd0689-9375-45fb-b7f5-7ba4833870fd",
-   "metadata": {},
-   "outputs": [
-    {
-     "data": {
-      "text/plain": [
-       "'Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.\\nNote: May be used as stronger evidence with increasing segregation data.'"
-      ]
-     },
-     "execution_count": 96,
-     "metadata": {},
-     "output_type": "execute_result"
-    }
-   ],
-   "source": [
-    "clist_unique[0].loc[clist_unique[0][\"Code\"] == \"PP1\"][\"Description\"].iloc[0]"
-   ]
-  },
-  {
-   "cell_type": "code",
-   "execution_count": 71,
-   "id": "8899563c-04ec-45b6-89a9-8a5e691cc4ac",
-   "metadata": {},
-   "outputs": [
-    {
-     "data": {
-      "text/plain": [
-       "'3 affected segregations + 0 unaffected segregations OR\\n\\n\\n2 affected segregations + 3 unaffected segregations'"
-      ]
-     },
-     "execution_count": 71,
-     "metadata": {},
-     "output_type": "execute_result"
-    }
-   ],
-   "source": []
-  }
- ],
- "metadata": {
-  "kernelspec": {
-   "display_name": "Python 3 (ipykernel)",
-   "language": "python",
-   "name": "python3"
-  },
-  "language_info": {
-   "codemirror_mode": {
-    "name": "ipython",
-    "version": 3
-   },
-   "file_extension": ".py",
-   "mimetype": "text/x-python",
-   "name": "python",
-   "nbconvert_exporter": "python",
-   "pygments_lexer": "ipython3",
-   "version": "3.11.10"
-  }
- },
- "nbformat": 4,
- "nbformat_minor": 5
-}
diff --git a/VCI/parsing_csr_criteria/tests/posthoc_process_cvg.py b/VCI/parsing_csr_criteria/tests/posthoc_process_cvg.py
deleted file mode 100644
index 3ae4a38bfc6095c35a55d381f3bca60cc8d47a01..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/tests/posthoc_process_cvg.py
+++ /dev/null
@@ -1,39 +0,0 @@
-import pandas as pd
-import re
-
-def extract_panel_name(title):
-    """
-    Extract the panel name from a ClinGen title.
-    For example:
-    "ClinGen PAH Expert Panel Specifications..." -> "PAH"
-    "ClinGen Monogenic Diabetes Expert Panel Specifications..." -> "Monogenic Diabetes"
-    """
-    # Pattern to match text between "ClinGen" and "Expert Panel"
-    pattern = r"ClinGen\s+(.*?)\s+Expert Panel"
-    match = re.search(pattern, title)
-    if match:
-        return match.group(1).strip()
-    return None
-
-def main():
-    # Read the CSV file
-    df = pd.read_csv("../cspec_version_guide.csv").iloc[:, 1:]
-    
-    # Apply the extraction function to the Title column
-    df['Title'] = df['Title'].apply(extract_panel_name)
-
-    # Unroll genes in lists:
-    df["Genes"] = df["Genes"].apply(lambda x: x.split(",") if isinstance(x, str) else x)
-
-    # Explode the Genes column to create separate rows for each gene
-    df = df.explode('Genes')
-    
-    # Clean up any whitespace in gene names
-    df['Genes'] = df['Genes'].str.strip()
-
-    df.to_csv("cspec_version_guide_processed.csv", index=False)
-
-
-
-if __name__ == "__main__":
-    main()
\ No newline at end of file
diff --git a/VCI/parsing_csr_criteria/tests/test_vcep_name_mapping.py b/VCI/parsing_csr_criteria/tests/test_vcep_name_mapping.py
deleted file mode 100644
index cc91e673998acb98f1ec6fe53e8e35bad7d48922..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/tests/test_vcep_name_mapping.py
+++ /dev/null
@@ -1,55 +0,0 @@
-import pandas as pd
-import re
-
-def extract_panel_name(title):
-    """
-    Extract the panel name from a ClinGen title.
-    For example:
-    "ClinGen PAH Expert Panel Specifications..." -> "PAH"
-    "ClinGen Monogenic Diabetes Expert Panel Specifications..." -> "Monogenic Diabetes"
-    """
-    # Pattern to match text between "ClinGen" and "Expert Panel"
-    pattern = r"ClinGen\s+(.*?)\s+Expert Panel"
-    match = re.search(pattern, title)
-    if match:
-        return match.group(1).strip()
-    return None
-
-map_vcep = {
-    'Mitochondrial Diseases': "MITO", 
-    'Severe Combined Immunodeficiency Disease ': 'Severe Combined Immunodeficiency Disease', 
-    'von Willebrand Disease ': 'von Willebrand Disease'
-}
-
-def main():
-    # Read the CSV file
-    df = pd.read_csv("../cspec_version_guide.csv")
-    
-    # Apply the extraction function to the Title column
-    df['Title'] = df['Title'].apply(extract_panel_name)
-
-    pmft = pd.read_csv("../../clingen_vci_pubmed_fulltext.csv")
-
-    #pmft["expert_panel"] = pmft["expert_panel"].map(map_vcep, na_action="ignore")
-
-    # See if they match:
-    counter, out_counter = 0, 0
-    out_vceps = []
-
-    pmft_unique = pmft["expert_panel"].unique()
-
-    for i, vcep_name in enumerate(pmft_unique):
-        #vcep_name = row["expert_panel"]
-
-        if vcep_name in map_vcep.keys():
-            vcep_name = map_vcep[vcep_name]
-        if (df['Title'] == vcep_name).sum() > 0:
-            counter += 1
-        else:
-            out_counter += 1
-            out_vceps.append(vcep_name)
-    print(f"Counter: {counter}")
-    print(f"Out counter: {out_counter}")
-    print(out_vceps)
-if __name__ == "__main__":
-    main()
\ No newline at end of file
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenACADVLExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenACADVLExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
deleted file mode 100644
index e1b09c24b2881bbb61db051bb4dfc1db03641c55..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenACADVLExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
+++ /dev/null
@@ -1,255 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-ACADVL (HGNC:92),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-ACADVL (HGNC:92),PVS1,Very Strong,"Loss of function is a known mechanism for VLCAD Deficiency. The specifications below are based on published guidance for assigning strength of evidence for PVS1 (Abou Tayoun et al., 2018; PMID: 30192042). There are multiple transcripts for ACADVL. The major isoform, NM_000018.4, encodes a 655 amino acid precursor protein that contains a 40 amino acid N-terminal target sequence that is removed during uptake (Aoyama et al., 1995; PMID: 7668252). In a joint project between NCBI and EMBL-EBI (MANE), NM_000018.4 was designated as the most relevant transcript.
-Nonsense or Frameshift:
-
-
-
-
-Use caution when interpreting LOF variants at the 3’ end of the gene.
-
-
-All nonsense and frameshift variants will meet PVS1 unless the variant is predicted to be missed by nonsense-mediated decay (NMD).
-
-
-NMD is not predicted if the variant is in the last exon (exon 20) or in the last 50 nucleotides of the penultimate exon (exon 19).
-Canonical Splice Site (+1, +2, -1, -2):
-
-
-All donor/acceptor sites follow the GT/AG rule, except for the donor splice site of intron 8, which begins with GC. PVS1 should not be applied for variants in the splice donor site of intron 8 since the impact of GC donor splice sites is not well understood.
-
-
-For +1 or +2 GT donor splice site variants, the exon immediately 5’ of the variant is predicted to be skipped. For -1 or -2 AG acceptor splice site variants, the exon immediately 3’ of the variants is predicted to be skipped. For the predicted in frame/out of frame consequences for exon skipping in ACADVL (NM_000018.4), see Appendix 1.
-Deletions:
-
-
-For single or multi-exon deletions that result in an out-of-frame consequence, use PVS1 unless NMD is not predicted to occur. If NMD is not predicted to occur, use PVS1_Moderate.
-
-
-If a deletion results in an in-frame consequence, the deletion must encompass one or more exons in order to apply PVS1. Consult Appendix 1 and the PVS1 decision tree to assign a strength.
-Duplications:
-
-
-Single and multi-exon duplications have not been reported in ACADVL. Consult the PVS1 decision tree to assign the strength.
-Initiation codon:
-
-
-The next in-frame methionine is at position 6 (on transcript NM_000018). However, the first 40 amino acids comprise the leader sequence in the precursor peptide and are important for proper localization of the protein (Aoyama et al., 1995; PMID: 7668252). Therefore, initiator codon variants will meet PVS1_Strong.",Disease-specific
-ACADVL (HGNC:92),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-ACADVL (HGNC:92),PS1,Strong,Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.,No change
-ACADVL (HGNC:92),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",NA
-ACADVL (HGNC:92),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-ACADVL (HGNC:92),PS3,Strong,"Functional evidence from non-patient derived material with only a single variant best reflects the variant-level phenotype. Apply patient-derived evidence in PP4.
-
-
-Apply criteria at the level determined by validation parameters (see flowchart below). VLCAD assays available now do not meet the criteria that is being proposed now regarding the types of controls etc. but the published VLCAD assays are well established with many positive and negative controls being run.
-
-
-Hesse et al., 2018 (PMID 30194637) reviewed enzymatic testing in lymphocytes as a confirmatory tool in newborns identified by screening. Molecular testing was performed after in most patients.
-
-
-If an enzyme activity assay has >20% activity it cannot be weighted above PS3_supporting regardless of flowchart results.",Disease-specific
-ACADVL (HGNC:92),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",NA
-ACADVL (HGNC:92),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-ACADVL (HGNC:92),PM1,Moderate,"Examples of mutational hot spots:
-It has been cited that the CpG dinucleotides in the codon for arginine326 and arginine429 are mutational hot spots, since CrT (R326C and R429W) and GrA (R326H and R429Q) mutations of the CpG di- nucleotide are present in both codons. Article for reference is Clear Correlation of Genotype with Disease Phenotype in Very–Long-Chain Acyl-CoA Dehydrogenase Deficiency – by Andresen et al., 1999 (PMID 9973285).
-
-
-Please refer to “Structural Basis for Substrate Fatty Acyl Chain Specificity: Crystal Structure of Human Very-Long-Chain acyl-CoA Dehydrogenase” by McAndrew et al., 2008 (PMID 18227065) (note – numbering in this reference is for the mature peptide without the mitochondrial signal peptide, so amino acid position numbers are lower by 40 than numbering based on NM-000018.4) and “Compared effects of missense mutations in Very-Long-Chain Acyl-CoA Dehydrogenase deficiency: Combined analysis by structural, functional and pharmacological approaches” by Gobin-Limballe et al., 2010 (PMID 20060901) for identifying important structural regions for proper enzyme function such as binding sites and active sites of the enzyme. Based on this and information from UniProt the following regions are designated to be important functional domains:
-
-
-p.214-223, p.249-251, p.460-466, p.562: Nucleotide and substrate binding.
-
-
-p.481-516: Membrane binding.
-
-
-p.1-40: Mitochondrial signal peptide.
-
-
-Curators may seek approval from the expert panel for identifying new hot spots or critical regions as discovered in literature searches, in uniport, HGMD, etc. for inclusion.",Disease-specific
-ACADVL (HGNC:92),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-ACADVL (HGNC:92),PM2,Supporting,"Variants with a highest population minor allele frequency (MAF) <0.001 (0.1%) in any continental population with >2000 alleles in gnomAD will meet PM2_supporting.
-
-
-The 0.001 cutoff is based on a disease frequency of 1:100,000, genetic heterogeneity of 100%, penetrance of 75%, and maximum allelic contribution of 20%, based on the most common pathogenic ACADVL variant, c.848T>C (p.Val283Ala): gnomAD MAF: 0.002238 (289/129106; 1 homozygote; European Non-Finnish) and overall frequency: 0.001224 (346/282744; 2 homozygotes). This variant would not meet PM2_supporting, but it is assumed that the most common variants have already been identified so a conservative cutoff was chosen.
-
-
-See Appendix 2 for calculations.
-
-
-It is acceptable for an ACADVL variant to be present in controls because VLCAD deficiency is a recessive condition. It is also possible for homozygous ACADVL variants to be present in population databases due to later onset of the condition. If homozygous variants are present, the number should be noted and discussed with an expert.
-
-
-SVI guidance: use PM2 as Supporting (not Moderate) based on absence or rarity not being in the odds range expected for a moderate piece of evidence. This EP will track the impact of not using Moderate for PM2.",Disease-specific
-ACADVL (HGNC:92),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-ACADVL (HGNC:92),PM3,Moderate,"Details of the cDNA change must be used to describe any variants used as evidence for PM3. If the variant is described only as an amino acid change, this is not sufficient. Probands must also meet PP4 criteria to be counted.
-
-
-If more than one case has the same genotype and the variants are not confirmed in trans, then only one case should be used for assigning points to avoid overcounting evidence if the variants are actually in cis and hence inherited together in multiple individuals or potentially counting the same case twice. If the variants are confirmed to be in trans, more than one individual with the same genotype can be counted as long as the reports do not represent the same case.
-
-
-Following SVI guidance for PM3, use the scoring system below to determine the strength of evidence for PM3.
-
-
-These variant interpretation guidelines should be used to determine the classification of the “other variant” in order to determine the appropriate number of points to assign.
-
-
-For a variant to be “confirmed in trans” in a compound heterozygous patient, parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed. Otherwise, the phase of the variants is unknown. Parental testing is not required for homozygous cases.",Disease-specific
-ACADVL (HGNC:92),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-ACADVL (HGNC:92),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,No change
-ACADVL (HGNC:92),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-ACADVL (HGNC:92),PM5,Moderate,"These variant interpretation guidelines should be used to determine the classification of the other missense change in order to determine whether this rule can be applied.
-
-
-Use PM5_Supporting if the other variant is Likely Pathogenic.",Disease-specific
-ACADVL (HGNC:92),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-ACADVL (HGNC:92),PM6,Moderate,"Assumed de novo, but without confirmation of paternity and maternity.",No change
-ACADVL (HGNC:92),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-ACADVL (HGNC:92),PP1,Supporting,"Following SVI guidance, use the scoring system below to determine the strength of evidence for PP1.
-
-
-For segregation counting, do not count probands as a segregation.
-o Affected segregations = # affected individuals in the family with the variants - 1.
-
-
-Affected segregations are defined as affected family members (typically siblings) who harbor the variant in question and a second variant on the remaining allele.
-
-
-Unaffected segregations are defined as unaffected family members, typically siblings, who are at risk to inherit the two variants identified in the proband. These individuals should be either wild-type for both variants identified in the proband, or a heterozygous carrier for a single variant.
-
-
-Unaffected, carrier parents DO NOT count as unaffected segregations.
-
-
-There may be scenarios where individuals other than siblings could be counted as segregations, such as in families where one parent is affected with the autosomal recessive disorder, in large families with multiple branches, or in consanguineous families.",Disease-specific
-ACADVL (HGNC:92),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-ACADVL (HGNC:92),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-ACADVL (HGNC:92),PP3,Supporting,"Missense changes with a REVEL score >0.75 will meet PP3.
-
-
-For in-frame deletions and insertions, use PROVEAN and Mutation Taster. Results must be consistent to count.
-
-
-For non-canonical splice site variants, use Splice AI, MaxEntScn and NNSplice. Based on data from Jaganathan et al., 2019 (PMID: 30661751), Houdayer et al., 2012 (PMID: 22505045) and Tang et al., 2016 (PMID: 27313609), PP3 can be applied if there is, a SpliceAI “high score” (Δ Score ≥ 0.5 “confidently predicted splice variants”) (exclude any results with Δ Score ≤ 0.2 from consideration of pathogenicity, <0.2 are not “predicted to alter splicing”), >15% reduction using MaxEntScn and >5% reduction using NNSplice. Two out of the three predictors must be consistent to count.
-
-
-For SpliceAI’s cryptic splice-site rules, the creation of a new splice-site with Δ Score ≥ 0.5 may be enough to produce a large proportion of aberrant transcripts.
-
-
-If a new splice site is predicted to be generated, this rule can be applied if the newly generated splice site is significantly stronger than the wild type site (Δ Score ≥ 0.5 using SpliceAI; >15% difference using MaxEntScn).
-
-
-Do not apply this rule for canonical splice site changes meeting PVS1.",Disease-specific
-ACADVL (HGNC:92),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-ACADVL (HGNC:92),PP4,Moderate,"Abnormal tests that are consistent with VLCAD deficiency include deficient VLCAD enzyme activity in patient cells (leukocytes, fibroblasts, liver, heart, or skeletal muscle, or amniocytes), abnormal C14:1 acylcarnitine values from newborn screening (NBS), and abnormal acylcarnitine values from follow-up plasma analysis.
-
-
-To award a given tier of evidence, at least one proband harboring the variant must meet at least one of the minimum requirements below. If multiple analyses are completed, only one result needs to be within the allowed ranges to meet this rule as values can fluctuate due to age or diet: 
-
-
-PP4_moderate (Must meet at least one of the below criteria):
-
-
-VLCAD enzyme activity (β-Oxidation Flux) ≤20% of normal.
-
-
-NBS C14:1 Levels ≥ 1.0 μM AND:
-
-
-VLCAD enzyme activity (β-Oxidation Flux) 21-27% of normal OR Assertion of reduced VLCAD activity without specific levels OR Follow-Up Plasma Acylcarnitine analysis “consistent with VLCADD” without specific levels.",Disease-specific
-ACADVL (HGNC:92),PP4,Supporting,"Abnormal tests that are consistent with VLCAD deficiency include deficient VLCAD enzyme activity in patient cells (leukocytes, fibroblasts, liver, heart, or skeletal muscle, or amniocytes), abnormal C14:1 acylcarnitine values from newborn screening (NBS), and abnormal acylcarnitine values from follow-up plasma analysis.
-
-
-To award a given tier of evidence, at least one proband harboring the variant must meet at least one of the minimum requirements below. If multiple analyses are completed, only one result needs to be within the allowed ranges to meet this rule as values can fluctuate due to age or diet: 
-
-
-PP4_supporting (Must meet at least one of the below criteria):
-
-
-VLCAD enzyme activity (β-Oxidation Flux) 21-27% of normal.
-
-
-Assertion of reduced VLCAD activity without specific levels.
-
-
-NBS C14:1 Levels from >0.8 μM.
-
-
-Assertion of abnormal NBS “consistent with VLCADD” without specific levels AND: Follow-Up Plasma Acylcarnitine analysis “consistent with VLCADD” without specific levels.",Disease-specific
-ACADVL (HGNC:92),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-ACADVL (HGNC:92),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-ACADVL (HGNC:92),BA1,Stand Alone,"Variants with a highest population minor allele frequency (MAF) ≥0.007 (0.7%) in any continental population with >2000 alleles in gnomAD will meet BA1.
-
-
-See Appendix 2 for calculations.",Disease-specific
-ACADVL (HGNC:92),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-ACADVL (HGNC:92),BS1,Strong,"Variants with a highest population minor allele frequency (MAF) ≥0.0035 (0.35%) in any continental population with >2000 alleles in gnomAD will meet BS1.
-
-
-See Appendix 2 for calculations.",Disease-specific
-ACADVL (HGNC:92),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",NA
-ACADVL (HGNC:92),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-ACADVL (HGNC:92),BS3,Strong,"In vitro expression:
-
-
-
-
-
-
-50% enzyme activity
-Splicing assays:
-
-
-
-
-
-
-For non-canonical splicing variants, use BS3 if there is evidence demonstrating normal splicing with no evidence of abnormal splicing (RT-PCR and/or RNA sequencing).
-
-
-These studies can be performed using patient-derived cells or heterologous cultured cells.
-
-
-Any variants meeting the requirement for in vitro expression or splicing assays can meet BS3, but if the variant meets the description for both, BS3 should only be counted once.",Disease-specific
-ACADVL (HGNC:92),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-ACADVL (HGNC:92),BS4,Strong,Lack of segregation in affected members of a family.,No change
-ACADVL (HGNC:92),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-ACADVL (HGNC:92),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-ACADVL (HGNC:92),BP2,Supporting,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.,No change
-ACADVL (HGNC:92),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-ACADVL (HGNC:92),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-ACADVL (HGNC:92),BP4,Supporting,"Missense changes with a REVEL score <0.5 will meet BP4.
-
-
-For in-frame deletions and insertions, use PROVEAN and Mutation Taster. Results must be consistent to count.
-For non-canonical splice site variants, use Splice AI, MaxEntScn and NNSplice. Based on data from Jaganathan et al., 2019 (PMID: 30661751), Houdayer et al., 2012 (PMID: 22505045) and Tang et al., 2016 (PMID: 27313609), PP3 can be applied if there is a with Δ Score ≤ 0.2 , <10% reduction using MaxEntScn and <2% reduction using NNSplice. Two out of the three predictors must be consistent to count.
-
-
-Do not apply this rule if there is evidence for creation of a cryptic splice site.
-
-
-Can be used with BP7 code.",Disease-specific
-ACADVL (HGNC:92),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-ACADVL (HGNC:92),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-ACADVL (HGNC:92),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-ACADVL (HGNC:92),BP7,Supporting,Can be used with BP4 code.,No change
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
deleted file mode 100644
index 729952bc5e0036a689918a0d0a447011f9a2416d..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
+++ /dev/null
@@ -1,104 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-AKT3 (HGNC:393),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-AKT3 (HGNC:393),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-AKT3 (HGNC:393),PS1,Strong,No change.,None
-AKT3 (HGNC:393),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-AKT3 (HGNC:393),PS2,Strong,"Award the PS2_Strong point if Criteria 1 AND Criteria 2 are fulfilled.  
-
-
-  Criteria 1. The variant is present at a detectable allele fraction but is absent from parental samples with confirmed maternity and paternity.
-
-
-  Criteria 2. The variant is present at a detectable allele fraction in an affected tissue sample but is absent from or detected at a lower allelic fraction in another tissue (e.g. if present in 5% of brain tissue but absent from the blood or skin this point can be awarded).
-
-
-For the sake of implementation, these criteria are intended to apply to high-confidence somatic mutations identified by the reporting CLIA laboratory. The expert panel recognizes that in practice there may be significant heterogeneity in the technical methods and thresholds used to identify such variants as 'high confidence', and flags the need to establish consensus statistical frameworks (e.g. Phred-scaled genotype qualities) or experimental approaches (e.g., confirmation of somatic variants by sequencing on orthogonal platforms) by which quality thresholds can be consistently applied.","Disease-specific,Strength"
-AKT3 (HGNC:393),PS2,Moderate,"Award the PS2_Moderate point if Criteria 1 is fulfilled, OR if parents are not available but Criteria 2 is fulfilled.","Disease-specific,Strength"
-AKT3 (HGNC:393),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-AKT3 (HGNC:393),PS3,Strong,"Follow recommendations set forth by the SVI in conjunction with specifications added by the BMVCEP for quality metrics and minimum validation controls required. (Supplemental Document 1) Animal models are considered in a different manner.
-
-
-Award PS4_Strong if the animal model generated with the variant of interest expressed in neural progenitors shows a complementary brain phenotype.
-
-
-Award PS3 if the functional assay meets the acceptability criteria delimited in (PMID: 31892348) with specifications added by the BMVCEP. Quality metrics and minimum validation controls required can be found in Supplementary Document 1.
-
-
-Animal models are considered in a different manner. Award PS4_Strong if the animal model generated with the variant of interest expressed in neural progenitors show a complementary brain phenotype.
-
-
-Caveat: Studies of cell lines derived from the affected patient as the only source of functional characterization are by themselves insufficient to provide strong evidence of pathogenicity. This is because cells derived from patient affected tissue are likely to exhibit the desired phenotype since the patient tissue exhibits the phenotype. It is therefore impossible to determine whether the variant of interest was solely responsible for that phenotype. Instead, functional readout of patient-derived cells are now included in PS4.",Disease-specific
-AKT3 (HGNC:393),PS3,Moderate,Follow recommendations set forth by the SVI in conjunction with specifications added by the BMVCEP for quality metrics and minimum validation controls required (PMID: 31892348). Animal models are considered in a different manner. Award PS4_Moderate if the animal model generated with the variant of interest expressed in non-neural tissues show an increased cancer burden.,Strength
-AKT3 (HGNC:393),PS3,Supporting,Follow recommendations set forth by the SVI in conjunction with specifications added by the BMVCEP for quality metrics and minimum validation controls required (PMID: 31892348).,Strength
-AKT3 (HGNC:393),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-AKT3 (HGNC:393),PS4,Very Strong,"Points are assigned for phenotype according to (Table 2A). Phenotype criteria can only be used if the variant meets criteria for (PM2). Strength of evidence is determined by points according to (Table 2B). PS4_VeryStrong ≥ 16 points. For PS4, for cases reported in the literature, we recommend assigning each one to the SINGLE category below that is associated with the highest point value (Table 2A). The total score obtained for all reported cases with a particular variant will determine the strength of PS4 assigned according to the scale (Table 2B)
-*
-.
-
-
-PS4_VeryStrong ≥ 16 points.
-
-
-*
-Applicable if the variant is absent/rare from controls according to PM2 to ensure the variant is not simply present due to beinging common in the general population.","Disease-specific,Strength"
-AKT3 (HGNC:393),PS4,Strong,Points are assigned for phenotype according to (Table 2A). Phenotype criteria can only be used if the variant is absent from controls (PM2). Strength of evidence is determined by points according to (Table 2B). PS4_Strong = 3.5-15.75 points.,Disease-specific
-AKT3 (HGNC:393),PS4,Moderate,Points are assigned for phenotype according to (Table 2A). Phenotype criteria can only be used if the variant is absent from controls (PM2). Strength of evidence is determined by points according to (Table 2B). PS4_Moderate = 1.5-3.25 points.,Strength
-AKT3 (HGNC:393),PS4,Supporting,Points are assigned for phenotype according to (Table 2A). Phenotype criteria can only be used if the variant is absent from controls (PM2). Strength of evidence is determined by points according to (Table 2B). PS4_Supporting = 0.5 – 1.25 points.,Strength
-AKT3 (HGNC:393),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-AKT3 (HGNC:393),PM1,Supporting,Residues affecting critical functional domains provided in Table 4 for each gene.,Strength
-AKT3 (HGNC:393),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-AKT3 (HGNC:393),PM2,Supporting,Absent/rare from controls in an ethnically-matched cohort population sample ( ≥1).,Disease-specific
-AKT3 (HGNC:393),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-AKT3 (HGNC:393),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,NA
-AKT3 (HGNC:393),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-AKT3 (HGNC:393),PM5,Moderate,No change.,None
-AKT3 (HGNC:393),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-AKT3 (HGNC:393),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",NA
-AKT3 (HGNC:393),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,
-AKT3 (HGNC:393),PP2,Supporting,"Missense constraint computed in ExAC/gnomAD was utilized. Award PP2 if the z-score > 3.09. (applicable to MTOR, PIK3CA and AKT3 but not PIK3R2).",Disease-specific
-AKT3 (HGNC:393),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",NA
-AKT3 (HGNC:393),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-AKT3 (HGNC:393),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-AKT3 (HGNC:393),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-AKT3 (HGNC:393),BA1,Stand Alone,"Allele frequency (>0.0926%). An allele frequency (>0.0926%) was approved.
- Note: this was adjusted from ACMG Guidelines due to maintaining the 5x threshold for benign (consistent with previously established guidelines)",Disease-specific
-AKT3 (HGNC:393),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-AKT3 (HGNC:393),BS1,Strong,Allele frequency (>0.0185%). An allele frequency (>0.0185%) was approved. (Supplemental Table 3).,Disease-specific
-AKT3 (HGNC:393),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-AKT3 (HGNC:393),BS2,Strong,"Award BS2 if ≥3 homozygotes present in gnomAD or ≥3 heterozygous in well phenotyped family members.
-Clinical laboratories are encouraged to accumulate more than 2 (≥3) instances of well phenotyped family members before applying this strong criterion. To be considered for this point, the variant should be either germline (most common), or somatic in a relevant tissue. Homozygous occurrences in gnomAD or ExAC can also be counted for this point (≥3).",Disease-specific
-AKT3 (HGNC:393),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-AKT3 (HGNC:393),BS3,Strong,Follow recommendations set forth by the SVI in conjunction with specifications added by the Brain Malformation Group for quality metrics and minimum validation controls required.,Disease-specific
-AKT3 (HGNC:393),BS3,Supporting,Follow recommendations set forth by the SVI in conjunction with specifications added by the Brain Malformation Group for quality metrics and minimum validation controls required.,Strength
-AKT3 (HGNC:393),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",NA
-AKT3 (HGNC:393),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-AKT3 (HGNC:393),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-AKT3 (HGNC:393),BP2,Supporting,Observed in cis or trans with a known pathogenic variant in the same gene.,None
-AKT3 (HGNC:393),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-AKT3 (HGNC:393),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-AKT3 (HGNC:393),BP4,Supporting,"Award BP4 for a synonymous, intronic positions (except canonical splice sites) or non-coding variants in the UTRs, if two out of three of the splicing prediction tools predicted no impact on splicing function.
-Not applicable for any variant type except for synonymous, intronic positions (except canonical splice sites) and non-coding variants in the UTRs,. This criterion can be applied when two of three splicing prediction tools predict no splicing change. The splicing prediction tools used are: varSEAK, spliceAI and MaxEntScan.",Disease-specific
-AKT3 (HGNC:393),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-AKT3 (HGNC:393),BP5,Supporting,No change.,None
-AKT3 (HGNC:393),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-AKT3 (HGNC:393),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-AKT3 (HGNC:393),BP7,Supporting,"For synonymous, intronic positions (except canonical splice sites) and non-coding variants in the UTRs, if the nucleotide is non-conserved award this point (PhyloP score <0.1).",Disease-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
deleted file mode 100644
index ba1020ec1298f17e2b22eabceb21158c13cd621e..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
+++ /dev/null
@@ -1,81 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-AKT3 (HGNC:393),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-AKT3 (HGNC:393),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-AKT3 (HGNC:393),PS1,Strong,No change.,None
-AKT3 (HGNC:393),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-AKT3 (HGNC:393),PS2,Strong,"Award the PS2_Strong point if Criteria 1 AND Criteria 2 are fulfilled.
-Criteria 1: if the variant is present at a detectable allelic fraction in a proband with the disease but is absent from parental samples with confirmed maternity and paternity.
-Criteria 2: can also be awarded if the variant is present at a detectable allele fraction in an affected tissue sample but is absent from or detected at a lower allelic fraction in another tissue (e.g. if present in 5% of brain tissue but absent from the blood or skin this point can be awarded).","Disease-specific,Strength"
-AKT3 (HGNC:393),PS2,Moderate,"Award the PS2_Moderate point if Criteria 1 is fulfilled, OR if parents are not available but Criteria 2 is fulfilled. 
- Criteria 1: if the variant is present at a detectable allelic fraction in a proband with the disease but is absent from parental samples with confirmed maternity and paternity. 
-Criteria 2: can also be awarded if the variant is present at a detectable allele fraction in an affected tissue sample but is absent from or detected at a lower allelic fraction in another tissue (e.g. if present in 5% of brain tissue but absent from the blood or skin this point can be awarded).","Disease-specific,Strength"
-AKT3 (HGNC:393),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-AKT3 (HGNC:393),PS3,Strong,"Follow recommendations set forth by the SVI in conjunction with specifications added by the Brain Malformation Group for quality metrics and minimum validation controls required. 
-Animal models are considered in a different manner. Award PS4_Strong if the animal model generated with the variant of interest expressed in neural progenitors show a complementary brain phenotype.",Disease-specific
-AKT3 (HGNC:393),PS3,Moderate,"Follow recommendations set forth by the SVI in conjunction with specifications added by the Brain Malformation Group for quality metrics and minimum validation controls required. 
-Animal models are considered in a different manner. Award PS4_Moderate if the animal model generated with the variant of interest expressed in non-neural tissues show an increased cancer burden.",Strength
-AKT3 (HGNC:393),PS3,Supporting,Follow recommendations set forth by the SVI in conjunction with specifications added by the Brain Malformation Group for quality metrics and minimum validation controls required.,Strength
-AKT3 (HGNC:393),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-AKT3 (HGNC:393),PS4,Very Strong,"Points are assigned for phenotype according to (Table 2A). Phenotype criteria can only be used if the variant is absent from controls (PM2). Strength of evidence is determined by points according to (Table 2B).
-PS4_VeryStrong = >16 points.","Disease-specific,Strength"
-AKT3 (HGNC:393),PS4,Strong,"Points are assigned for phenotype according to (Table 2A). Phenotype criteria can only be used if the variant is absent from controls (PM2). Strength of evidence is determined by points according to (Table 2B).
-PS4 = 3.5-15.99 points.",Disease-specific
-AKT3 (HGNC:393),PS4,Moderate,"Points are assigned for phenotype according to (Table 2A). Phenotype criteria can only be used if the variant is absent from controls (PM2). Strength of evidence is determined by points according to (Table 2B).
-PS4_Moderate = 1.5-3.49 points.",Strength
-AKT3 (HGNC:393),PS4,Supporting,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls. Points are assigned for phenotype according to (Supplementary Table 3). Strength of evidence is determined by points according to (Supplementary Table 2).
-PS4_Supporting = 0.5 - 1.49 points.",Strength
-AKT3 (HGNC:393),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-AKT3 (HGNC:393),PM1,Supporting,Residues affecting critical functional domains provided in Table 4 for each gene.,Strength
-AKT3 (HGNC:393),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-AKT3 (HGNC:393),PM2,Supporting,Absent/rare from controls in an ethnically-matched cohort population sample ( ≥1).,Disease-specific
-AKT3 (HGNC:393),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-AKT3 (HGNC:393),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,NA
-AKT3 (HGNC:393),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-AKT3 (HGNC:393),PM5,Moderate,No change.,None
-AKT3 (HGNC:393),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-AKT3 (HGNC:393),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",NA
-AKT3 (HGNC:393),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,
-AKT3 (HGNC:393),PP2,Supporting,"Missense constraint computed in ExAC/gnomAD was utilized. Award PP2 if the z-score > 3.09. (applicable to MTOR, PIK3CA and AKT3 but not PIK3R2).",Disease-specific
-AKT3 (HGNC:393),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",NA
-AKT3 (HGNC:393),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-AKT3 (HGNC:393),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-AKT3 (HGNC:393),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-AKT3 (HGNC:393),BA1,Stand Alone,Allele frequency (≥0.185%).,Disease-specific
-AKT3 (HGNC:393),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-AKT3 (HGNC:393),BS1,Strong,Allele frequency (≥0.037%).,Disease-specific
-AKT3 (HGNC:393),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-AKT3 (HGNC:393),BS2,Strong,Award BS2 if ≥3 homozygotes present in gnomAD or well phenotyped family members.,Disease-specific
-AKT3 (HGNC:393),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-AKT3 (HGNC:393),BS3,Strong,Follow recommendations set forth by the SVI in conjunction with specifications added by the Brain Malformation Group for quality metrics and minimum validation controls required.,Disease-specific
-AKT3 (HGNC:393),BS3,Supporting,Follow recommendations set forth by the SVI in conjunction with specifications added by the Brain Malformation Group for quality metrics and minimum validation controls required.,Strength
-AKT3 (HGNC:393),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",NA
-AKT3 (HGNC:393),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-AKT3 (HGNC:393),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-AKT3 (HGNC:393),BP2,Supporting,No change.,None
-AKT3 (HGNC:393),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-AKT3 (HGNC:393),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-AKT3 (HGNC:393),BP4,Supporting,"Award BP4 for a synonymous, intronic positions (except canonical splice sites) or non-coding variants in the UTRs, if two out of three of the splicing prediction tools predicted no impact on splicing function.",Disease-specific
-AKT3 (HGNC:393),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-AKT3 (HGNC:393),BP5,Supporting,No change.,None
-AKT3 (HGNC:393),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-AKT3 (HGNC:393),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-AKT3 (HGNC:393),BP7,Supporting,"For synonymous, intronic positions (except canonical splice sites) and non-coding variants in the UTRs, if the nucleotide is non-conserved award this point (PhyloP score <0.1).",Disease-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
deleted file mode 100644
index 794d2950d75c63997c1a1adfeb9143b494d0d60c..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
+++ /dev/null
@@ -1,108 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-CDH1 (HGNC:1748),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7)
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact
- • Use caution in the presence of multiple transcripts",
-CDH1 (HGNC:1748),PVS1,Very Strong,"Per ClinGen SVI guidelines with the exception of canonical splice sites
-
-
-
-
-Apply to initiation codon variant",
-CDH1 (HGNC:1748),PVS1,Strong,"Per ClinGen SVI guidelines
-Other CDH1 caveats:
-
-
-
-
-Use the strong strength of evidence for canonical splice sites
-
-
-CDH1 Exonic deletions or tandem duplications of in-frame exons
-
-
-Truncations in NMD-resistant zone located upstream the most 3’ well-characterized pathogenic variant c.2506G>T (p.Glu836*). Use PVS1_moderate if premature stop is downstream of this variant",
-CDH1 (HGNC:1748),PVS1,Moderate,"Per ClinGen SVI guidelines
- Other CDH1 caveats:
-
-
-
-
-G to non-G variants disrupting the last nucleotide of an exon
-
-
-Canonical splice sites located in exons demonstrated experimentally to result in in-frame partial skipping/insertion (e.g., Exon 3 donor site)",
-CDH1 (HGNC:1748),PVS1,Supporting,Per ClinGen SVI guidelines,
-CDH1 (HGNC:1748),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level",
-CDH1 (HGNC:1748),PS1,Strong,Per original ACMG/AMP guidelines,
-CDH1 (HGNC:1748),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity",
-CDH1 (HGNC:1748),PS2,Very Strong,≥Two patients with DGC &/or LBC w/ parental confirmation,
-CDH1 (HGNC:1748),PS2,Strong,One patient with DGC &/or LBC w/ parental confirmation,
-CDH1 (HGNC:1748),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established",
-CDH1 (HGNC:1748),PS3,Strong,RNA assay demonstrating abnormal out-of-frame transcripts,
-CDH1 (HGNC:1748),PS3,Supporting,RNA assay demonstrating abnormal in-frame transcripts,
-CDH1 (HGNC:1748),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-CDH1 (HGNC:1748),PS4,Very Strong,Sixteen families meet HDGC criteria,
-CDH1 (HGNC:1748),PS4,Strong,Four families meet HDGC criteria,
-CDH1 (HGNC:1748),PS4,Moderate,Two families meet HDGC criteria,
-CDH1 (HGNC:1748),PS4,Supporting,One family meets HDGC criteria,
-CDH1 (HGNC:1748),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation,NA
-CDH1 (HGNC:1748),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium
-Caveat: Population data for indels may be poorly called by next generation sequencing",
-CDH1 (HGNC:1748),PM2,Moderate,"Less than one out of 100,000 alleles in gnomAD cohort; if present in >=2 individuals, must be present in less than one out of 50,000 alleles within a sub-population",
-CDH1 (HGNC:1748),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase",NA
-CDH1 (HGNC:1748),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-CDH1 (HGNC:1748),PM4,Moderate,Per original ACMG/AMP guidelines,
-CDH1 (HGNC:1748),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
-Example: Arg156His is pathogenic; now you observe Arg156Cys
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level",NA
-CDH1 (HGNC:1748),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity",
-CDH1 (HGNC:1748),PM6,Very Strong,≥Four patients with DGC &/or LBC w/o parental confirmation,
-CDH1 (HGNC:1748),PM6,Strong,≥Two patients with DGC &/or LBC w/o parental confirmation,
-CDH1 (HGNC:1748),PM6,Moderate,One patient with DGC &/or LBC w/o parental confirmation,
-CDH1 (HGNC:1748),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease
-Note: May be used as stronger evidence with increasing segregation data",
-CDH1 (HGNC:1748),PP1,Strong,≥Seven meioses across ≥2 families,
-CDH1 (HGNC:1748),PP1,Moderate,Five-six meioses across ≥1 families,
-CDH1 (HGNC:1748),PP1,Supporting,Three-four meioses across ≥1 families,
-CDH1 (HGNC:1748),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease,NA
-CDH1 (HGNC:1748),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-CDH1 (HGNC:1748),PP3,Moderate,Variants affecting the same splice site as a well-characterized variant with similar or worse in silico/ RNA predictions,
-CDH1 (HGNC:1748),PP3,Supporting,"At least three in silico splicing predictors in agreement (.Human Splicing Finder (HSF), Maximum Entropy (MaxEnt), Berkeley Drosophilia Genome Project (BDGP), or ESEfinder)",
-CDH1 (HGNC:1748),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology,NA
-CDH1 (HGNC:1748),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-CDH1 (HGNC:1748),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium",
-CDH1 (HGNC:1748),BA1,Stand Alone,MAF cutoff of 0.2%,
-CDH1 (HGNC:1748),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-CDH1 (HGNC:1748),BS1,Stand Alone,MAF cutoff of 0.1%,
-CDH1 (HGNC:1748),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age",
-CDH1 (HGNC:1748),BS2,Strong,"Variant seen in ≥10 individuals w/o DCG, SRC tumors, or LBC & whose families do not suggest HDGC",
-CDH1 (HGNC:1748),BS2,Supporting,"Variant seen in ≥3 individuals w/o DCG, SRC tumors, or LBC & whose families do not suggest HDGC",
-CDH1 (HGNC:1748),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-CDH1 (HGNC:1748),BS3,Strong,Functional RNA studies demonstrating no impact on transcript composition,
-CDH1 (HGNC:1748),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation",
-CDH1 (HGNC:1748),BS4,Strong,Per original ACMG/AMP guidelines,
-CDH1 (HGNC:1748),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease,NA
-CDH1 (HGNC:1748),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-CDH1 (HGNC:1748),BP2,Strong,"Variant observed in trans w/known pathogenic variant (phase confirmed) OR observed in the homozygous state in individual w/o personal &/or family history of DGC, LBC, or SRC tumors",
-CDH1 (HGNC:1748),BP2,Supporting,Variant is observed in cis (or phase is unknown) w/ a pathogenic variant,
-CDH1 (HGNC:1748),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-CDH1 (HGNC:1748),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-CDH1 (HGNC:1748),BP4,Supporting,"Splicing predictions only. At least three in silico splicing predictors in agreement (Human Splicing Finder (HSF), Maximum Entropy (MaxEnt), Berkeley Drosophilia Genome Project (BDGP), or ESEfinder)",
-CDH1 (HGNC:1748),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-CDH1 (HGNC:1748),BP5,Supporting,Per original ACMG/AMP guidelines,
-CDH1 (HGNC:1748),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-CDH1 (HGNC:1748),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-CDH1 (HGNC:1748),BP7,Supporting,Synonymous variants where nucleotide is not highly conserved; variant is the reference nucleotide in one primate and/or >3 mammal species,
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
deleted file mode 100644
index 068a23c16d4fbd140a30d8238773a3a7b3ebf9d5..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
+++ /dev/null
@@ -1,101 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-CDH1 (HGNC:1748),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-CDH1 (HGNC:1748),PVS1,Very Strong,Per modified CDH1 PVS1 decision tree.,
-CDH1 (HGNC:1748),PVS1,Strong,"Per modified CDH1 PVS1 decision tree.
-Other CDH1 caveats:
-
-
-
-
-Use PVS1_Strong as the default strength of evidence for canonical splice site variants and follow the site-specific recommendations in the splicing table. 
-
-
-CDH1 Exonic deletions or tandem duplications of in-frame exons (exon 4,5,8,9,12,13,15).",
-CDH1 (HGNC:1748),PVS1,Moderate,"Per modified CDH1 PVS1 decision tree.
-Other CDH1 caveats:
-
-
-
-
-G to non-G variants disrupting the last nucleotide of an exon.
-
-
-Canonical splice sites predicted or demonstrated experimentally to result in in-frame partial skipping/insertion (e.g., Exon 3 donor site).",
-CDH1 (HGNC:1748),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",NA
-CDH1 (HGNC:1748),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-CDH1 (HGNC:1748),PS2,Very Strong,≥Two patients meet the HDGC individual phenotype criteria w/ parental confirmation.,
-CDH1 (HGNC:1748),PS2,Strong,One patient meets the HDGC individual phenotype criteria w/ parental confirmation.,
-CDH1 (HGNC:1748),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-CDH1 (HGNC:1748),PS3,Strong,RNA assay demonstrating abnormal out-of-frame transcripts.,
-CDH1 (HGNC:1748),PS3,Moderate,RNA assay demonstrating abnormal in-frame transcript.,
-CDH1 (HGNC:1748),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-CDH1 (HGNC:1748),PS4,Very Strong,≥Sixteen families meet HDGC criteria.,
-CDH1 (HGNC:1748),PS4,Strong,Four - Fifteen families meet HDGC criteria.,
-CDH1 (HGNC:1748),PS4,Moderate,Two or three families meet HDGC criteria.,
-CDH1 (HGNC:1748),PS4,Supporting,One family meets HDGC criteria.,
-CDH1 (HGNC:1748),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-CDH1 (HGNC:1748),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-CDH1 (HGNC:1748),PM2,Supporting,"≤ One out of 100,000 alleles in gnomAD cohort; if present in ≥2 individuals within a subpopulation, must be present in ≤ One out of 50,000 alleles.",
-CDH1 (HGNC:1748),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-CDH1 (HGNC:1748),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-CDH1 (HGNC:1748),PM4,Moderate,"Only apply to stop-loss variants
-Variant example: CDH1 c.2647T>C (p.Ter883Glnext*29).",
-CDH1 (HGNC:1748),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-CDH1 (HGNC:1748),PM5,Supporting,PM5_supporting is applicable to nonsense and frameshift variants that are predicted/proved to undergo NMD or located upstream of the last known pathogenic truncating variant. Site-specific recommendations for the application of PM5_Supporting for canonical splicing variants.,
-CDH1 (HGNC:1748),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-CDH1 (HGNC:1748),PM6,Very Strong,Four patients meet the HDGC individual phenotype criteria w/o parental confirmation.,
-CDH1 (HGNC:1748),PM6,Strong,≥Two patients meet the HDGC individual phenotype criteria w/o parental confirmation.,
-CDH1 (HGNC:1748),PM6,Moderate,One patient meets the HDGC individual phenotype criteria w/o parental confirmation,
-CDH1 (HGNC:1748),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-CDH1 (HGNC:1748),PP1,Strong,≥Seven informative meioses across ≥2 families.,
-CDH1 (HGNC:1748),PP1,Moderate,Five-six informative meioses across ≥1 family.,
-CDH1 (HGNC:1748),PP1,Supporting,Three-four informative meioses across ≥1 family.,
-CDH1 (HGNC:1748),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-CDH1 (HGNC:1748),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-CDH1 (HGNC:1748),PP3,Moderate,Variants affecting the same splice site as a well-characterized variant with similar or worse in silico/ RNA predictions.,
-CDH1 (HGNC:1748),PP3,Supporting,"At least three in silico splicing predictors in agreement (SpliceAI, MaxEntScan, SSF, GeneSplicer, HSF, TraP, varSEAK).",
-CDH1 (HGNC:1748),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-CDH1 (HGNC:1748),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-CDH1 (HGNC:1748),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-CDH1 (HGNC:1748),BA1,Stand Alone,MAF cutoff of 0.2%.,
-CDH1 (HGNC:1748),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-CDH1 (HGNC:1748),BS1,Strong,MAF cutoff of 0.1%.,
-CDH1 (HGNC:1748),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-CDH1 (HGNC:1748),BS2,Strong,"Variant seen in ≥10 individuals w/o GC, DGC, gSRC tumors, or LBC & whose families do not suggest HDGC.",
-CDH1 (HGNC:1748),BS2,Supporting,"Variant seen in ≥3 individuals w/o GC, DGC, SRC tumors, or LBC & whose families do not suggest HDGC.",
-CDH1 (HGNC:1748),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-CDH1 (HGNC:1748),BS3,Strong,Functional RNA studies demonstrating no impact on transcript composition.,
-CDH1 (HGNC:1748),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-CDH1 (HGNC:1748),BS4,Strong,Per original ACMG/AMP guidelines.,
-CDH1 (HGNC:1748),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-CDH1 (HGNC:1748),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-CDH1 (HGNC:1748),BP2,Strong,"Variant observed in trans w/known pathogenic variant (phase confirmed) OR observed in the homozygous state in individual w/o personal &/or family history of DGC, LBC, or SRC tumors.",
-CDH1 (HGNC:1748),BP2,Supporting,"Variant is observed in cis (or phase is unknown) w/ a pathogenic variant
-OR observed in the homozygous state in gnomAD.",
-CDH1 (HGNC:1748),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-CDH1 (HGNC:1748),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-CDH1 (HGNC:1748),BP4,Supporting,"Splicing predictions only. At least three in silico splicing predictors in agreement (SpliceAI, MaxEntScan, SSF, GeneSplicer, HSF, TraP, varSEAK).",
-CDH1 (HGNC:1748),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-CDH1 (HGNC:1748),BP5,Supporting,Per original ACMG/AMP guidelines.,
-CDH1 (HGNC:1748),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-CDH1 (HGNC:1748),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-CDH1 (HGNC:1748),BP7,Supporting,Synonymous and intronic variants at or beyond +7 to -21 locations.,
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3_version=3.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3_version=3.0.0.csv
deleted file mode 100644
index a57a8b726e62be2484ae37639b4e00344ad40323..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3_version=3.0.0.csv
+++ /dev/null
@@ -1,101 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-CDH1 (HGNC:1748),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-CDH1 (HGNC:1748),PVS1,Very Strong,Per modified CDH1 PVS1 decision tree.,
-CDH1 (HGNC:1748),PVS1,Strong,"Per modified CDH1 PVS1 decision tree.
-Other CDH1 caveats:
-
-
-
-
-Use PVS1_Strong as the default strength of evidence for canonical splice site variants and follow the site-specific recommendations in the splicing table. 
-
-
-CDH1 Exonic deletions or tandem duplications of in-frame exons (exon 4,5,8,9,12,13,15).",
-CDH1 (HGNC:1748),PVS1,Moderate,"Per modified CDH1 PVS1 decision tree.
-Other CDH1 caveats:
-
-
-
-
-G to non-G variants disrupting the last nucleotide of an exon.
-
-
-Canonical splice sites predicted or demonstrated experimentally to result in in-frame partial skipping/insertion (e.g., Exon 3 donor site).",
-CDH1 (HGNC:1748),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",NA
-CDH1 (HGNC:1748),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-CDH1 (HGNC:1748),PS2,Very Strong,≥Two patients meet the HDGC individual phenotype criteria w/ parental confirmation.,
-CDH1 (HGNC:1748),PS2,Strong,One patient meets the HDGC individual phenotype criteria w/ parental confirmation.,
-CDH1 (HGNC:1748),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-CDH1 (HGNC:1748),PS3,Strong,RNA assay demonstrating abnormal out-of-frame transcripts.,
-CDH1 (HGNC:1748),PS3,Moderate,RNA assay demonstrating abnormal in-frame transcript.,
-CDH1 (HGNC:1748),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-CDH1 (HGNC:1748),PS4,Very Strong,≥Sixteen families meet HDGC criteria.,
-CDH1 (HGNC:1748),PS4,Strong,Four - Fifteen families meet HDGC criteria.,
-CDH1 (HGNC:1748),PS4,Moderate,Two or three families meet HDGC criteria.,
-CDH1 (HGNC:1748),PS4,Supporting,One family meets HDGC criteria.,
-CDH1 (HGNC:1748),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-CDH1 (HGNC:1748),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-CDH1 (HGNC:1748),PM2,Supporting,"≤ One out of 100,000 alleles in gnomAD cohort; if present in ≥2 individuals within a subpopulation, must be present in ≤ One out of 50,000 alleles.",
-CDH1 (HGNC:1748),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-CDH1 (HGNC:1748),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-CDH1 (HGNC:1748),PM4,Moderate,"Only apply to stop-loss variants
-Variant example: CDH1 c.2647T>C (p.Ter883Glnext*29).",
-CDH1 (HGNC:1748),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-CDH1 (HGNC:1748),PM5,Supporting,PM5_supporting is applicable to nonsense and frameshift variants that are predicted/proved to undergo NMD. Site-specific recommendations for the application of PM5_Supporting for canonical splicing variants are provided in the splicing table.,
-CDH1 (HGNC:1748),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-CDH1 (HGNC:1748),PM6,Very Strong,Four patients meet the HDGC individual phenotype criteria w/o parental confirmation.,
-CDH1 (HGNC:1748),PM6,Strong,≥Two patients meet the HDGC individual phenotype criteria w/o parental confirmation.,
-CDH1 (HGNC:1748),PM6,Moderate,One patient meets the HDGC individual phenotype criteria w/o parental confirmation,
-CDH1 (HGNC:1748),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-CDH1 (HGNC:1748),PP1,Strong,≥Seven informative meioses across ≥2 families.,
-CDH1 (HGNC:1748),PP1,Moderate,Five-six informative meioses across ≥1 family.,
-CDH1 (HGNC:1748),PP1,Supporting,Three-four informative meioses across ≥1 family.,
-CDH1 (HGNC:1748),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-CDH1 (HGNC:1748),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-CDH1 (HGNC:1748),PP3,Moderate,Variants affecting the same splice site as a well-characterized variant with similar or worse in silico/ RNA predictions.,
-CDH1 (HGNC:1748),PP3,Supporting,"At least three in silico splicing predictors in agreement (SpliceAI, MaxEntScan, SSF, GeneSplicer, HSF, TraP, varSEAK).",
-CDH1 (HGNC:1748),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-CDH1 (HGNC:1748),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-CDH1 (HGNC:1748),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-CDH1 (HGNC:1748),BA1,Stand Alone,MAF cutoff of 0.2%.,
-CDH1 (HGNC:1748),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-CDH1 (HGNC:1748),BS1,Strong,MAF cutoff of 0.1%.,
-CDH1 (HGNC:1748),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-CDH1 (HGNC:1748),BS2,Strong,"Variant seen in ≥10 individuals w/o GC, DGC, gSRC tumors, or LBC & whose families do not suggest HDGC.",
-CDH1 (HGNC:1748),BS2,Supporting,"Variant seen in ≥3 individuals w/o GC, DGC, SRC tumors, or LBC & whose families do not suggest HDGC.",
-CDH1 (HGNC:1748),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-CDH1 (HGNC:1748),BS3,Strong,Functional RNA studies demonstrating no impact on transcript composition.,
-CDH1 (HGNC:1748),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-CDH1 (HGNC:1748),BS4,Strong,Per original ACMG/AMP guidelines.,
-CDH1 (HGNC:1748),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-CDH1 (HGNC:1748),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-CDH1 (HGNC:1748),BP2,Strong,"Variant observed in trans w/known pathogenic variant (phase confirmed) OR observed in the homozygous state in individual w/o personal &/or family history of DGC, LBC, or SRC tumors.",
-CDH1 (HGNC:1748),BP2,Supporting,"Variant is observed in cis (or phase is unknown) w/ a pathogenic variant
-OR observed in the homozygous state in gnomAD.",
-CDH1 (HGNC:1748),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-CDH1 (HGNC:1748),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-CDH1 (HGNC:1748),BP4,Supporting,"Splicing predictions only. At least three in silico splicing predictors in agreement (SpliceAI, MaxEntScan, SSF, GeneSplicer, HSF, TraP, varSEAK).",
-CDH1 (HGNC:1748),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-CDH1 (HGNC:1748),BP5,Supporting,Per original ACMG/AMP guidelines.,
-CDH1 (HGNC:1748),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-CDH1 (HGNC:1748),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-CDH1 (HGNC:1748),BP7,Supporting,Synonymous and intronic variants at or beyond +7 to -21 locations.,
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH1Version1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH1Version1.0.0_version=1.0.0.csv
deleted file mode 100644
index 741ac7a39e755ecfae3b4eff0e269a117e34f888..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH1Version1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,101 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-CDH1 (HGNC:1748),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-CDH1 (HGNC:1748),PVS1,Very Strong,Per ClinGen SVI guidelines with the exception of canonical splice sites.,
-CDH1 (HGNC:1748),PVS1,Strong,"Per modified CDH1 PVS1 decision tree. Other CDH1 caveats:
-
-
-
-
-Use the strong strength of evidence for canonical splice sites.
-
-
-CDH1 Exonic deletions or tandem duplications of in-frame exons.
-
-
-Truncations in NMD-resistant zone located upstream the most 3’ well-characterized pathogenic variant c.2506G>T (p.Glu836*). Use PVS1_moderate if premature stop is downstream of this variant.",
-CDH1 (HGNC:1748),PVS1,Moderate,"Per modified CDH1 PVS1 decision tree. Other CDH1 caveats:
-
-
-
-
-G to non-G variants disrupting the last nucleotide of an exon.
-
-
-Canonical splice sites located in exons demonstrated experimentally to result in in-frame partial skipping/insertion (e.g., Exon 3 donor site).",
-CDH1 (HGNC:1748),PVS1,Supporting,Per ClinGen SVI guidelines,
-CDH1 (HGNC:1748),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-CDH1 (HGNC:1748),PS1,Strong,Per original ACMG/AMP guidelines.,
-CDH1 (HGNC:1748),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-CDH1 (HGNC:1748),PS2,Very Strong,≥Two patients with DGC &/or LBC w/ parental confirmation.,
-CDH1 (HGNC:1748),PS2,Strong,One patient with DGC &/or LBC w/ parental confirmation.,
-CDH1 (HGNC:1748),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-CDH1 (HGNC:1748),PS3,Strong,RNA assay demonstrating abnormal out-of-frame transcripts.,
-CDH1 (HGNC:1748),PS3,Supporting,RNA assay demonstrating abnormal in-frame transcripts.,
-CDH1 (HGNC:1748),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-CDH1 (HGNC:1748),PS4,Very Strong,Sixteen families meet HDGC criteria.,
-CDH1 (HGNC:1748),PS4,Strong,Four families meet HDGC criteria.,
-CDH1 (HGNC:1748),PS4,Moderate,Two families meet HDGC criteria.,
-CDH1 (HGNC:1748),PS4,Supporting,One family meets HDGC criteria.,
-CDH1 (HGNC:1748),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-CDH1 (HGNC:1748),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-CDH1 (HGNC:1748),PM2,Moderate,"<One out of 100,000 alleles in gnomAD cohort; if present in >2 individuals, must be present in <One out of 50,000 alleles within a sub-population.",
-CDH1 (HGNC:1748),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-CDH1 (HGNC:1748),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-CDH1 (HGNC:1748),PM4,Moderate,Per original ACMG/AMP guidelines.,
-CDH1 (HGNC:1748),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",NA
-CDH1 (HGNC:1748),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-CDH1 (HGNC:1748),PM6,Very Strong,≥Four patients with DGC &/or LBC w/o parental confirmation.,
-CDH1 (HGNC:1748),PM6,Strong,≥Two patients with DGC &/or LBC w/o parental confirmation.,
-CDH1 (HGNC:1748),PM6,Moderate,One patient with DGC &/or LBC w/o parental confirmation.,
-CDH1 (HGNC:1748),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-CDH1 (HGNC:1748),PP1,Strong,≥Seven meioses across ≥2 families.,
-CDH1 (HGNC:1748),PP1,Moderate,Five-six informative meioses across ≥1 family.,
-CDH1 (HGNC:1748),PP1,Supporting,Three-four informative meioses across ≥1 family.,
-CDH1 (HGNC:1748),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-CDH1 (HGNC:1748),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-CDH1 (HGNC:1748),PP3,Moderate,Variants affecting the same splice site as a well-characterized variant with similar or worse in silico/ RNA predictions.,
-CDH1 (HGNC:1748),PP3,Supporting,"At least three in silico splicing predictors in agreement (.Human Splicing Finder (HSF), Maximum Entropy (MaxEnt), Berkeley Drosophilia Genome Project (BDGP), or ESEfinder).",
-CDH1 (HGNC:1748),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-CDH1 (HGNC:1748),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-CDH1 (HGNC:1748),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-CDH1 (HGNC:1748),BA1,Stand Alone,MAF cutoff of 0.2%.,
-CDH1 (HGNC:1748),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-CDH1 (HGNC:1748),BS1,Strong,MAF cutoff of 0.1%.,
-CDH1 (HGNC:1748),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-CDH1 (HGNC:1748),BS2,Strong,"Variant seen in ≥10 individuals w/o DCG, SRC tumors, or LBC & whose families do not suggest HDGC.",
-CDH1 (HGNC:1748),BS2,Supporting,"Variant seen in ≥3 individuals w/o DCG, SRC tumors, or LBC & whose families do not suggest HDGC.",
-CDH1 (HGNC:1748),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-CDH1 (HGNC:1748),BS3,Strong,Functional RNA studies demonstrating no impact on transcript composition.,
-CDH1 (HGNC:1748),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-CDH1 (HGNC:1748),BS4,Strong,Per original ACMG/AMP guidelines.,
-CDH1 (HGNC:1748),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-CDH1 (HGNC:1748),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-CDH1 (HGNC:1748),BP2,Strong,"Variant observed in trans w/known pathogenic variant (phase confirmed) OR observed in the homozygous state in individual w/o personal &/or family history of DGC, LBC, or SRC tumors.",
-CDH1 (HGNC:1748),BP2,Supporting,Variant is observed in cis (or phase is unknown) w/ a pathogenic variant.,
-CDH1 (HGNC:1748),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-CDH1 (HGNC:1748),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-CDH1 (HGNC:1748),BP4,Supporting,"Splicing predictions only. At least three in silico splicing predictors in agreement (Human Splicing Finder (HSF), Maximum Entropy (MaxEnt), Berkeley Drosophilia Genome Project (BDGP), or ESEfinder).",
-CDH1 (HGNC:1748),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-CDH1 (HGNC:1748),BP5,Supporting,Per original ACMG/AMP guidelines.,
-CDH1 (HGNC:1748),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-CDH1 (HGNC:1748),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-CDH1 (HGNC:1748),BP7,Supporting,Synonymous variants where nucleotide is not highly conserved; variant is the reference nucleotide in one primate and/or >3 mammal species.,
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
deleted file mode 100644
index cee7ef1cd5a401e6ad58ab724f783a261e9a9dcc..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
+++ /dev/null
@@ -1,72 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-MYH7 (HGNC:7577),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-MYH7 (HGNC:7577),PVS1,Moderate,Null Variant in gene with evidence supporting LOF as disease mechanism,Modified rule strength
-MYH7 (HGNC:7577),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MYH7 (HGNC:7577),PS1,Strong,Different nucleotide change (same amino acid) as a previously established pathogenic variant,No change
-MYH7 (HGNC:7577),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-MYH7 (HGNC:7577),PS2,Strong,De novo (paternity confirmed) in a patient with disease and no family history,"Disease-specific,Gene-specific"
-MYH7 (HGNC:7577),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-MYH7 (HGNC:7577),PS3,Strong,Functional studies of mammalian knock-in models supportive of a damaging effect on the gene or gene product,"Disease-specific,Gene-specific"
-MYH7 (HGNC:7577),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-MYH7 (HGNC:7577),PS4,Strong,Prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls -OR- Variant identified in ≥15 probands with consistent phenotypes,"Disease-specific,Gene-specific"
-MYH7 (HGNC:7577),PS4,Moderate,Variant identified in >=6 probands with consistent phenotypes,Modified rule strength
-MYH7 (HGNC:7577),PS4,Supporting,Variant identified in >=2 probands with consistent phenotypes,Modified rule strength
-MYH7 (HGNC:7577),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-MYH7 (HGNC:7577),PM1,Moderate,Hotspot/est. functional domain (amino acids 181-937) without benign variation,"Disease-specific,Gene-specific"
-MYH7 (HGNC:7577),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-MYH7 (HGNC:7577),PM2,Moderate,Absent/extremely rare (<0.004%) from large population studies.,"Disease-specific,Gene-specific"
-MYH7 (HGNC:7577),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-MYH7 (HGNC:7577),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-MYH7 (HGNC:7577),PM4,Moderate,Protein length changes due to in-frame deletions/insertions of any size in a non-repeat region or stop-loss variants,"Disease-specific,Gene-specific"
-MYH7 (HGNC:7577),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MYH7 (HGNC:7577),PM5,Moderate,Missense change at an amino acid residue where a different missense change previously established as pathogenic,No change
-MYH7 (HGNC:7577),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-MYH7 (HGNC:7577),PM6,Moderate,Confirmed de novo without confirmation of paternity,"Disease-specific,Gene-specific"
-MYH7 (HGNC:7577),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-MYH7 (HGNC:7577),PP1,Strong,Variant segregates with >= 7 meioses,Modified rule strength
-MYH7 (HGNC:7577),PP1,Moderate,Variant segragates in >=5 meioses,Modified rule strength
-MYH7 (HGNC:7577),PP1,Supporting,Variant segragates in >=3 meioses,"Disease-specific,Gene-specific"
-MYH7 (HGNC:7577),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-MYH7 (HGNC:7577),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-MYH7 (HGNC:7577),PP3,Supporting,Multiple lines of computational evidence support a deleterious effect on the gene or gene product,No change
-MYH7 (HGNC:7577),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-MYH7 (HGNC:7577),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MYH7 (HGNC:7577),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-MYH7 (HGNC:7577),BA1,Stand Alone,Allele frequency is >= 0.1% based on the filtering allele frequency (FAF) in ExAC,"Disease-specific,Gene-specific"
-MYH7 (HGNC:7577),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-MYH7 (HGNC:7577),BS1,Strong,Allele frequency is >=0.02% based on the filtering allele frequency (FAF) in ExAC provided there is no conflicting information,"Disease-specific,Gene-specific"
-MYH7 (HGNC:7577),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",NA
-MYH7 (HGNC:7577),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-MYH7 (HGNC:7577),BS3,Strong,Functional studies of mammalian knock-in models supportive of no damaging effect on protein function or splicing,No change
-MYH7 (HGNC:7577),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-MYH7 (HGNC:7577),BS4,Strong,Non-segregation in affected members of a family,"Disease-specific,Gene-specific"
-MYH7 (HGNC:7577),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-MYH7 (HGNC:7577),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-MYH7 (HGNC:7577),BP2,Supporting,Observed as comp het (in trans) or double het in genes with overlapping function (e.g. sarcomere genes) without increased disease severity -OR- Observed in cis with a pathogenic variant in any inheritance pattern,"Disease-specific,Gene-specific"
-MYH7 (HGNC:7577),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-MYH7 (HGNC:7577),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-MYH7 (HGNC:7577),BP4,Supporting,Multiple lines of computational evidence suggest no impact on gene or gene product,No change
-MYH7 (HGNC:7577),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-MYH7 (HGNC:7577),BP5,Supporting,Variant found in a case with an alternate molecular basis for disease,"Disease-specific,Gene-specific"
-MYH7 (HGNC:7577),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MYH7 (HGNC:7577),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-MYH7 (HGNC:7577),BP7,Supporting,A silent variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site -AND- the nucleotide is not highly conserved,No change
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforACTC1Version1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforACTC1Version1.0.0_version=1.0.0.csv
deleted file mode 100644
index 48e7468ee479757f6ea777da5c8b3fe7ead20233..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforACTC1Version1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,871 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-ACTC1 (HGNC:143),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-ACTC1 (HGNC:143),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-ACTC1 (HGNC:143),PS1,Strong,"No cardiomyopathy specifications. Apply as outlined by Richards 
-et al
-. 2015
-1
-.
-
-
-Example of when rule should NOT be applied. NM_000256.3(
-MYBPC3
-): c.2308G>A (p.Asp770Asn) has an established impact on splicing leading to nonsense mediated decay (NMD) and should not be used to provide evidence for other variants observed to result in the same amino acid change.",No change
-ACTC1 (HGNC:143),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-ACTC1 (HGNC:143),PS2,Strong,"Refer to SVI guidance on number/combination of cases required based on phenotype specificity
-2
-.
-
-
-For most cardiomyopathies, it is recommended to default to 
-Phenotype consistency: “Phenotype consistent with gene but not highly specific”
-. Clinical judgment is required for shifting to a higher or lower category. 
-
-
-For use as a STRONG or VERY STRONG criterion, ideally parents have been thoroughly clinically evaluated without evidence of cardiomyopathy (ideally using a combination of ECG and echocardiogram or cardiac MRI for maximum sensitivity).
-
-
-A family history consistent with 
-de novo
- inheritance should not have any clinical signs or symptoms suggestive of cardiomyopathy in a 1
-st
- or 2
-nd
- degree relative, for example: 
-
-
-
-
-Sudden death under 60 years of age
-
-
-Heart transplant
-
-
-Implantable cardiac defibrillator (ICD) under 60 years of age
-
-
-Features of cardiomyopathy (e.g., systolic dysfunction, hypertrophy, left ventricular enlargement in an individual without risk factors).
-
-
-Other related/overlapping cardiomyopathies
-
-
-
-
-Examples of non-suspicious family history may include non-specific clinical features (e.g., palpitations, syncope, borderline/inconclusive echocardiogram findings, heart attack if age appropriate and suspected to result from coronary artery disease), but every attempt should be made to clarify features. 
-
-
-Generally, this criterion is only applicable in the ABSENCE of any other possible disease-causing variants.  If other pathogenic or likely pathogenic variants are present, consider decreasing points assigned or overall weight.",Disease-specific
-ACTC1 (HGNC:143),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-ACTC1 (HGNC:143),PS3,Strong,"In vitro splicing assays (e.g., RNA studies)
-
-
-In vitro
- splicing assays may be considered as 
-STRONG
- evidence, providing the following criteria are met.
-
-
-
-
-Prior knowledge of predominant transcripts in cardiac tissue
-
-
-
-
-Analysis undertaken using RNA extracted from cardiac tissue from the individual with the variant
-
-
-Analysis undertaken using RNA extracted from whole blood providing the relevant transcripts (isoforms) are expressed in blood and are at sufficient levels to assess splice disruption.
-
-
-Assay shows a clear, reproducible and convincing effect on splicing (i.e. a distinct splice product, present at a level comparable to the splice product from the wild-type allele), which is not observed in controls
-
-
-
-
-Confirmation of abnormal splice product by Sanger sequencing
-
-
-
-
-NOTE:
- Mini-gene assay in non-patient derived cell lines are NOT considered to provide STRONG evidence.
-
-
-NOTE:
-  Whether to activate this rule needs to be reconciled with the variant spectrum and disease mechanism for the gene at hand (i.e., consider whether the effect is likely to lead to LOF or an in-frame alteration and whether this type of effect is expected to be disease causing) (Abou Tayoun 
-et al.
- 2018
-3
-).",Disease-specific
-ACTC1 (HGNC:143),PS3,Moderate,"In vivo models (e.g., variant knock-in animal models)
-
-
-Mammalian variant-specific knock-in animal models that produce a phenotype consistent with the clinical phenotype in humans (e.g., structural and/or functional cardiac abnormalities, premature death, arrhythmia) may be considered as 
-MODERATE
- evidence
-
-
-NOTE:
- The following assays/models do NOT meet criteria
-
-
-
-
-Assays that are known to be associated with non-specific cardiac phenotypes (e.g., morpholino-induced pericardial edema in zebrafish)
-
-
-In vivo evidence that is not variant specific, such as whole gene alterations (i.e., cDNA or whole gene transgenic mice and whole or partial gene knock-out mice)",Disease-specific
-ACTC1 (HGNC:143),PS3,Supporting,"In vitro
- 
-assays (e.g., biochemical assays of myofilament function, motility assays, human iPSC-CM)
-
-
-While some 
-in vitro
- assays may provide evidence that a variant in a cardiomyopathy gene has an effect on protein and/or myofilament function, at present, there are no validated “gold-standard” assays that are considered to reliably predict the clinical phenotype.
-
-
-As such, in the cardiomyopathy genes listed in these guidelines, data from individual 
-in vitro
- studies are unlikely to meet the criteria required to assign this rule at more than SUPPORTING level.",Disease-specific
-ACTC1 (HGNC:143),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-ACTC1 (HGNC:143),PS4,Strong,"Currently few well-designed case-control studies have been performed for inherited cardiomyopathies.  Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). 
-
-
-Cohorts used in these analyses should meet the following criteria: 
-
-
-
-
-The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype*). 
-
-
-When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded.  This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).
-
-
-
-
-
-
-The controls should not be derived from study populations that might be enriched for the specified disorder.
-
-
-The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).
-
-
-The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).
-
-
-The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).
-
-
-The population diversity of the case and control cohorts are broadly similar.
-
-
-Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh 
-et al.
- 2017
-5
-, 
-DECIPHER
-).
-
-
-
-
-To account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:
-
-
-
-
-STRONG
- evidence requires the lower bound of the 95% confidence interval (CI) around the odds ratio (OR) estimate to be 
-≥20
-
-
-
-
-A PS4 calculator is available at 
-www.cardiodb.org
-.
-
-
-If multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered).  
-
-
-*RELEVANT PHENOTYPES:
-
-
-
-
-Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. 
-
-
-For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. 
-
-
-Additional considerations for LVNC and end-stage HCM: 
-
-
-Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson 
-et al.
- 2017
-6
-; Oechslin 
-et al.
- 2017
-7
-; Hershberger 
-et al.
- 2017
-8
-; Ross 
-et al.
- 2020
-9
-), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).
-
-
-
-
-
-
-
-
-HCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",Disease-specific
-ACTC1 (HGNC:143),PS4,Moderate,"Currently few well-designed case-control studies have been performed for inherited cardiomyopathies.  Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). 
-
-
-Cohorts used in these analyses should meet the following criteria: 
-
-
-
-
-The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype*). 
-
-
-When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded.  This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).
-
-
-
-
-
-
-The controls should not be derived from study populations that might be enriched for the specified disorder.
-
-
-The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).
-
-
-The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).
-
-
-The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).
-
-
-The population diversity of the case and control cohorts are broadly similar.
-
-
-Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh 
-et al.
- 2017
-5
-, 
-DECIPHER
-).
-
-
-
-
-To account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:
-
-
-
-
-MODERATE
- evidence requires the lower bound of the 95% CI around the OR to be 
-≥10
-
-
-
-
-A PS4 calculator is available at 
-www.cardiodb.org
-.
-
-
-If multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered).  
-
-
-*RELEVANT PHENOTYPES:
-
-
-
-
-Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. 
-
-
-For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. 
-
-
-Additional considerations for LVNC and end-stage HCM: 
-
-
-Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson 
-et al.
- 2017
-6
-; Oechslin 
-et al.
- 2017
-7
-; Hershberger 
-et al.
- 2017
-8
-; Ross 
-et al.
- 2020
-9
-), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).
-
-
-
-
-
-
-
-
-HCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",Disease-specific
-ACTC1 (HGNC:143),PS4,Supporting,"Currently few well-designed case-control studies have been performed for inherited cardiomyopathies.  Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). 
-
-
-Cohorts used in these analyses should meet the following criteria: 
-
-
-
-
-The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype*). 
-
-
-When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded.  This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).
-
-
-
-
-
-
-The controls should not be derived from study populations that might be enriched for the specified disorder.
-
-
-The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).
-
-
-The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).
-
-
-The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).
-
-
-The population diversity of the case and control cohorts are broadly similar.
-
-
-Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh 
-et al.
- 2017
-5
-, 
-DECIPHER
-).
-
-
-
-
-To account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:
-
-
-
-
-SUPPORTING
- evidence requires the lower bound of the 95% CI around the OR to be 
-≥5
-
-
-
-
-A PS4 calculator is available at 
-www.cardiodb.org
-.
-
-
-If multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered).  
-
-
-*RELEVANT PHENOTYPES:
-
-
-
-
-Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. 
-
-
-For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. 
-
-
-Additional considerations for LVNC and end-stage HCM: 
-
-
-Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson 
-et al.
- 2017
-6
-; Oechslin 
-et al.
- 2017
-7
-; Hershberger 
-et al.
- 2017
-8
-; Ross 
-et al.
- 2020
-9
-), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).
-
-
-
-
-
-
-
-
-HCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",Disease-specific
-ACTC1 (HGNC:143),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-ACTC1 (HGNC:143),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-ACTC1 (HGNC:143),PM2,Supporting,"The values used to calculate the PM2 thresholds were derived from studies in Northern European populations that have been relatively well-characterized with regards to disease prevalence and variant spectrum. These thresholds can be applied to any population where disease prevalence is considered comparable (1/500 or lower), where the most frequent pathogenic variant accounts for no more than 2% of cases (e.g., has an allele frequency of ≤0.02 in cases based on the upper bound of 95% CI), and where the penetrance of a pathogenic variant is expected to be at least 50% (Kelly 
-et al.
- 2018
-10
-).
-
-
-A threshold of 
-≤0.00004
- in the subpopulation with the highest frequency when using the upper bound of the 95% CI activates this rule.
-
-
-
-
-Alternatively, this is equivalent to the variant NOT being observed more than once (≤1 allele) in gnomAD v.2.1.1 in one of the non-founder populations (e.g., absence required from the Other and Ashkenazi Jewish subpopulations).
-
-
-Applying a threshold of ≤0.00004 (upper bound of 95% CI of the allele frequency in gnomAD) is equivalent to the variant being seen in a single subpopulation and that subpopulation meets any of the following:
-
-
-Allele Count (AC) in Allele Number (AN)
-
-
-≤1 in ≥120,000
-
-
-≤2 in ≥160,000
-
-
-≤3 in ≥195,000
-
-
-≤4 in ≥230,000
-
-
-
-
-
-
-
-
-gnomAD is the preferred database for this calculation, but currently only displays the filtering allele frequency (FAF), which is equivalent to a lower bound estimate of the 95% CI, when the upper bound is what is needed.
-
-
-
-
-Confidence interval tools, such as 
-Confit-de-MAF
-, can be used to determine the upper bound of the 95% CI of the observed allele frequency.
-
-
-
-
-Due to current technical limitations of next generation sequencing technologies, minor allele frequencies for complex variants (e.g., large indels) may not be accurately represented in population databases.
-
-
-Caution should be used when a variant is only identified, or over-represented, in one of the smaller gnomAD populations, as the gnomAD allele frequencies may not accurately represent the true population frequency.
-
-
-Population databases may contain affected or pre-symptomatic individuals for diseases with reduced penetrance/variable onset.",Disease-specific
-ACTC1 (HGNC:143),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-ACTC1 (HGNC:143),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-ACTC1 (HGNC:143),PM4,Moderate,"Strength of rule should be carefully considered and may require downgrading to SUPPORTING based on the predicted impact of the variant, including the size of the deletion/insertion, its location, and conservation of the region. 
-
-
-For genes where PVS1 is not applicable (i.e., where there is no evidence that pLOF variants cause disease), consider using this rule at MODERATE or SUPPORTING strength for truncating variants that do NOT undergo nonsense mediated decay (NMD).",General recommendation
-ACTC1 (HGNC:143),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-ACTC1 (HGNC:143),PM5,Moderate,"This criterion can be used at MODERATE if a different missense variant at the same codon has been classified as 
-pathogenic
- using these modified guidelines without application of PM5.
-
-
-The impact of the amino acid change being evaluated needs to be compared to the impact of the amino acid change that is established as pathogenic (e.g., a change of Ala to His is less severe than Ala to Cys change). Consider reducing the strength of this rule to SUPPORTING if the predicted impact is not expected to be equivalent or more severe.
-
-
-PM5 should not be combined with PM1.  If both are applicable at MODERATE weight, use of PM5 is most appropriate since it is variant specific.",General recommendation
-ACTC1 (HGNC:143),PM5,Supporting,"This criterion can be considered at SUPPORTING if a different missense variant at the same codon has been classified as 
-likely pathogenic
- using these modified guidelines without application of PM5.
-
-
-The impact of the amino acid change being evaluated needs to be compared to the impact of the amino acid change that is established as likely pathogenic (e.g., a change of Ala to His is less severe than Ala to Cys change). Consider reducing the strength of this rule to NOT APPLICABLE if the predicted impact is not expected to be equivalent or more severe.
-
-
-PM5 should not be combined with PM1.  The one with the higher strength should be applied, but if both are applicable at SUPPORTING weight, use of PM5 is most appropriate since it is variant specific.",General recommendation
-ACTC1 (HGNC:143),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-ACTC1 (HGNC:143),PM6,Moderate,"Refer to SVI guidance on number/combination of cases required based on phenotype specificity
-2
-.
-
-
-For most cardiomyopathies, it is recommended to default to “phenotype consistent with gene but not highly specific”. Clinical judgment is required for shifting to a higher or lower phenotypic consistency. 
-
-
-See PS2 for additional considerations.",Disease-specific
-ACTC1 (HGNC:143),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-ACTC1 (HGNC:143),PP1,Strong,"Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at 
-≥7
- 
-segregations
- (LOD score of 2.1) for 
-STRONG
-.
-
-
-Although rare for inherited cardiomyopathies, when the phenotype/presentation of a variant within and across families is highly specific (e.g., early-onset severe RCM in all affected individuals), the following thresholds as proposed by Jarvik and Browning (2016)
-11
- can be considered: 
-
-
-
-
-STRONG evidence requires ≥5 segregations (LOD score of 1.5)
-
-
-
-
-Only genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance.
-
-
-Phenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis.  
-
-
-Important considerations include:
-
-
-
-
-Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant.  If linkage disequilibrium is a concern, consider downgrading strength of segregation. 
-
-
-Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1.
-
-
-Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. 
-
-
-Caution is needed when distantly related (≥3
-rd
- degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).",Disease-specific
-ACTC1 (HGNC:143),PP1,Moderate,"Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at 
-≥5
- 
-segregations
- (LOD score of 1.5) for 
-MODERATE
-.
-
-
-Although rare for inherited cardiomyopathies, when the phenotype/presentation of a variant within and across families is highly specific (e.g., early-onset severe RCM in all affected individuals), the following thresholds as proposed by Jarvik and Browning (2016)
-11
- can be considered: 
-
-
-
-
-MODERATE evidence requires ≥4 segregations (LOD score of 1.2)
-
-
-
-
-Only genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance.
-
-
-Phenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis.  
-
-
-Important considerations include:
-
-
-
-
-Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant.  If linkage disequilibrium is a concern, consider downgrading strength of segregation. 
-
-
-Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1 (see below).
-
-
-Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. 
-
-
-Caution is needed when distantly related (≥3
-rd
- degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).",Disease-specific
-ACTC1 (HGNC:143),PP1,Supporting,"Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at 
-≥3
- 
-segregations
- (LOD score of 0.9) for 
-SUPPORTING
-. The thresholds as proposed by Jarvik and Browning (2016)
-11
- are the same at ≥3 segregations (LOD score of 0.9) for supporting.
-
-
-Only genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance.
-
-
-Phenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis.  
-
-
-Important considerations include:
-
-
-
-
-Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant.  If linkage disequilibrium is a concern, consider downgrading strength of segregation. 
-
-
-Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1 (see below).
-
-
-Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. 
-
-
-Caution is needed when distantly related (≥3
-rd
- degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).",Disease-specific
-ACTC1 (HGNC:143),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-ACTC1 (HGNC:143),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-ACTC1 (HGNC:143),PP3,Supporting,"As many 
-in silico
- algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. Meta-predictors, such as REVEL, are preferred over multiple individual predictors.
-
-
-Use of REVEL (Ioannidis 
-et al.
- 2016
-12
-) is recommended at thresholds of 
-≥0.70 for PP3
-.
-
-
-Clinical judgment is needed if any individual algorithms or conservation data are contradictory to REVEL data.
-
-
-Positive predictive value for benign/no impact predictions is generally higher than for pathogenic/impact predictions.
-
-
-SpliceAI
-13
- is recommended for evaluation of predicted splice impacts.",Disease-specific
-ACTC1 (HGNC:143),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-ACTC1 (HGNC:143),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-ACTC1 (HGNC:143),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-ACTC1 (HGNC:143),BA1,Stand Alone,"Allele frequency is 
-≥0.001
- based on the 
-filtering allele frequency (FAF)
- in 
-gnomAD
- in the subpopulation with the highest frequency (popmax).
-
-
-The values used to calculate the BA1 threshold were derived from studies in Northern European populations that have been relatively well-characterized with regards to disease prevalence and variant spectrum. These thresholds can be applied to any population where disease prevalence is considered comparable (1/300 or lower).
-
-
-The threshold is applicable when assessing variants in the context of autosomal dominant cardiomyopathy. 
-
-
-gnomAD is the preferred database for this calculation. If a subpopulation specific FAF other than the popmax is needed, this value can be calculated using the AlleleFrequencyApp on the 
-CardioDB website
-.
-
-
-
-
-Using the Inverse AF tab, enter in the population size and the number of alleles identified and it will calculate the FAF.  
-
-
-Set confidence to 0.95 (95%).
-
-
-If the FAF is ≥0.001, this rule can be applied.
-
-
-
-
-The FAF by platform (e.g., exome vs. genome; v.2.1.1 vs. v.3.1.1) should be considered, the larger population is most likely to have the most accurate representation of “true” population allele frequency.
-
-
-Caution is needed when considering any population cohorts that are smaller than the smallest subpopulations within gnomAD v.2.1.1 (e.g., ~5000 individuals or ~10,000 alleles). Despite this conservative nature of this threshold and approach, in smaller cohorts, the observed allele frequency may less accurately reflect the true allele frequency. Traditionally, once a variant is classified as Benign, it is rarely re-evaluated and so the highest confidence is needed to establish that classification on an allele frequency alone.",Disease-specific
-ACTC1 (HGNC:143),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-ACTC1 (HGNC:143),BS1,Strong,"Allele frequency is 
-≥0.0001 for
- 
-ACTC1
- based on the 
-filtering allele frequency (FAF)
- in 
-gnomAD
- in the subpopulation with the highest frequency (popmax).
-
-
-Criterion BS1 may only be used as standalone evidence to classify a variant as Likely Benign in the absence of conflicting data. See SVI guidance (Tavtigian 
-et al.
- 2018
-14
-; Tavtigian 
-et al.
- 2020
-15
-). 
-
-
-See BA1 for additional specifications that also apply to BS1.","Disease-specific,Gene-specific"
-ACTC1 (HGNC:143),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",NA
-ACTC1 (HGNC:143),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-ACTC1 (HGNC:143),BS3,Strong,See PS3 specifications.,Disease-specific
-ACTC1 (HGNC:143),BS3,Moderate,See PS3 specifications.,Disease-specific
-ACTC1 (HGNC:143),BS3,Supporting,See PS3 specifications.,Disease-specific
-ACTC1 (HGNC:143),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-ACTC1 (HGNC:143),BS4,Strong,"Any non-segregations should be carefully evaluated to rule out a phenocopy or the presence of a second disease-causing variant before considering it as conflicting or benign evidence. 
-
-
-
-
-The presence of “phenocopies” (e.g., athlete’s heart, hypertensive heart disease, ischemic cardiomyopathy, alcoholic cardiomyopathy, diabetic cardiomyopathy) can mimic non-segregation (i.e., lack of segregation) among affected individuals. 
-
-
-Families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent ‘non-segregation’.
-
-
-
-
-Because of these possibilities, 
-multiple (≥2) non-segregations
- that are highly unlikely to be phenocopies or due to alternate variants (e.g., those without a possible alternate cause) 
-are required to apply this rule
-.  A higher number of non-segregations is necessary for instances where alternative causes are possible (e.g., non-segregation in a sibling with childhood onset cardiomyopathy versus a grandparent with hypertension and HCM).
-
-
-Careful consideration of the above points is required when using this data as conflicting evidence, especially when overall evidence supports likely pathogenic or pathogenic.",Disease-specific
-ACTC1 (HGNC:143),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-ACTC1 (HGNC:143),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-ACTC1 (HGNC:143),BP2,Supporting,"Other variants must be pathogenic as defined by these specifications.
-
-
-Testing of parents or other informative relatives is often required to determine 
-cis
-/
-trans
- status.
-
-
-If a variant is seen in 
-trans
- (or as double heterozygous) with another pathogenic variant in ≥2 cases and the phenotype is not more severe than when either of the two variants are seen in isolation, this rule may be applied (i.e., high confidence this variant is NOT contributing to disease).
-
-
-
-
-<1% of cases of HCM have >1 pathogenic or likely pathogenic variant (0.6%; Alfares 
-et al.
- 2015
-16
-).
-
-
-
-
-This rule cannot be applied when the variant has only been observed in 
-cis
- with a pathogenic variant as its significance in isolation is unknown in this scenario. 
-
-
-Caution is needed if using this criterion as a primary piece of evidence for classifying a variant as likely benign/benign (i.e., only 2 SUPPORTING criteria are sufficient for a likely benign classification).",Disease-specific
-ACTC1 (HGNC:143),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-ACTC1 (HGNC:143),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-ACTC1 (HGNC:143),BP4,Supporting,"As many 
-in silico
- algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. Meta-predictors, such as REVEL, are preferred over multiple individual predictors.
-
-
-Use of REVEL (Ioannidis et al. 2016
-12
-) is recommended at thresholds of 
-≤0.40 for BP4
-.
-
-
-Clinical judgment is needed if any individual algorithms or conservation data are contradictory to REVEL data.
-
-
-Positive predictive value for benign/no impact predictions is generally higher than for pathogenic/impact predictions.
-
-
-SpliceAI
-13
- is recommended for evaluation of predicted splice impacts.",Disease-specific
-ACTC1 (HGNC:143),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-ACTC1 (HGNC:143),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-ACTC1 (HGNC:143),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-ACTC1 (HGNC:143),BP7,Supporting,"Also applicable to 
-intronic variants outside the splice consensus sequence (-4 and +7 outward)
- for which splicing prediction algorithms predict no impact to the splice consensus sequence NOR the creation of a new splice site AND the nucleotide is not highly conserved.
-
-
-Rule can be combined with BP4 to make a variant likely benign per Richards 
-et al.
- 2015
-1
-.",General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYBPC3Version1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYBPC3Version1.0.0_version=1.0.0.csv
deleted file mode 100644
index 3d99e6449106128aa4139c37d4cfa9e84260c6ad..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYBPC3Version1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,952 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-MYBPC3 (HGNC:7551),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-MYBPC3 (HGNC:7551),PVS1,Very Strong,"Currently only applicable to 
-MYBPC3
- where LOF is an established disease mechanism.
-
-
-Refer to SVI guidance for the interpretation of this criterion (Abou Tayoun 
-et al.
- 2018
-1
-).
-
-
-SpliceAI
-2
- is recommended for evaluation of predicted splice impacts.
-
-
-Factors to consider when assessing the consequences of putative LOF variants in the 
-MYBPC3
- gene:
-
-
-
-
-Codon p.1254 is located 50 nucleotides upstream of the most 3' exon-exon junction (exon 33:34) in 
-MYBPC3.
- As such, nonsense variants introducing a premature termination codon after this point may escape nonsense mediated decay (NMD) and consequently not result in protein haploinsufficiency (Nagy & Maquat 1998
-3
-).
-
-
-When assessing variants predicted to affect splicing of micro-exons (exons 10, 11 and 14), be aware that 
-in silico
- splice site predictions may be less reliable in this setting and the consequences of variants affecting splice sites at these exons less predictable (Frank-Hansen 
-et al.
- 2008
-4
-).
-
-
-When assessing variants affecting splice sites of in-frame exons (exons 2-4, 8-11, 14, 20, 22, 24-27), be aware that although most of these exons encode domains that have been shown to play critical roles in protein function, and/or harbor functionally important residues (Carrier 
-et al
-. 2015
-5
-), in general, the consequences of in-frame deletions are less predictable.
-
-
-
-
-For canonical splice site variants where other canonical splice variants have been reported, application of the PS1 rule may be considered if the other variant affecting the same slice site is 1) predicted to have a similar or more deleterious effect and 2) has been classified as pathogenic according to these modified guidelines without use of PS1 for other splice variants.
-
-
-For genes where haploinsufficiency is NOT an established mechanism, see PM4 for truncating variants that do NOT undergo NMD.",Gene-specific
-MYBPC3 (HGNC:7551),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MYBPC3 (HGNC:7551),PS1,Strong,"No cardiomyopathy specifications. Apply as outlined by Richards 
-et al
-. 2015
-6
-.
-
-
-Example of when rule should NOT be applied. NM_000256.3(
-MYBPC3
-): c.2308G>A (p.Asp770Asn) has an established impact on splicing leading to nonsense mediated decay (NMD) and should not be used to provide evidence for other variants observed to result in the same amino acid change.",No change
-MYBPC3 (HGNC:7551),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-MYBPC3 (HGNC:7551),PS2,Strong,"Refer to SVI guidance on number/combination of cases required based on phenotype specificity
-7
-.
-
-
-For most cardiomyopathies, it is recommended to default to 
-Phenotype consistency: “Phenotype consistent with gene but not highly specific”
-. Clinical judgment is required for shifting to a higher or lower category. 
-
-
-For use as a STRONG or VERY STRONG criterion, ideally parents have been thoroughly clinically evaluated without evidence of cardiomyopathy (ideally using a combination of ECG and echocardiogram or cardiac MRI for maximum sensitivity).
-
-
-A family history consistent with 
-de novo
- inheritance should not have any clinical signs or symptoms suggestive of cardiomyopathy in a 1
-st
- or 2
-nd
- degree relative, for example: 
-
-
-
-
-Sudden death under 60 years of age
-
-
-Heart transplant
-
-
-Implantable cardiac defibrillator (ICD) under 60 years of age
-
-
-Features of cardiomyopathy (e.g., systolic dysfunction, hypertrophy, left ventricular enlargement in an individual without risk factors).
-
-
-Other related/overlapping cardiomyopathies
-
-
-
-
-Examples of non-suspicious family history may include non-specific clinical features (e.g., palpitations, syncope, borderline/inconclusive echocardiogram findings, heart attack if age appropriate and suspected to result from coronary artery disease), but every attempt should be made to clarify features. 
-
-
-Generally, this criterion is only applicable in the ABSENCE of any other possible disease-causing variants.  If other pathogenic or likely pathogenic variants are present, consider decreasing points assigned or overall weight.",Disease-specific
-MYBPC3 (HGNC:7551),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-MYBPC3 (HGNC:7551),PS3,Strong,"In vitro splicing assays (e.g., RNA studies)
-
-
-In vitro
- splicing assays may be considered as 
-STRONG
- evidence, providing the following criteria are met.
-
-
-
-
-Prior knowledge of predominant transcripts in cardiac tissue
-
-
-
-
-Analysis undertaken using RNA extracted from cardiac tissue from the individual with the variant
-
-
-Analysis undertaken using RNA extracted from whole blood providing the relevant transcripts (isoforms) are expressed in blood and are at sufficient levels to assess splice disruption.
-
-
-Assay shows a clear, reproducible and convincing effect on splicing (i.e. a distinct splice product, present at a level comparable to the splice product from the wild-type allele), which is not observed in controls
-
-
-
-
-Confirmation of abnormal splice product by Sanger sequencing
-
-
-
-
-NOTE:
- Mini-gene assay in non-patient derived cell lines are NOT considered to provide STRONG evidence.
-
-
-NOTE:
-  Whether to activate this rule needs to be reconciled with the variant spectrum and disease mechanism for the gene at hand (i.e., consider whether the effect is likely to lead to LOF or an in-frame alteration and whether this type of effect is expected to be disease causing) (Abou Tayoun 
-et al.
- 2018
-1
-).",Disease-specific
-MYBPC3 (HGNC:7551),PS3,Moderate,"In vivo models (e.g., variant knock-in animal models)
-
-
-Mammalian variant-specific knock-in animal models that produce a phenotype consistent with the clinical phenotype in humans (e.g., structural and/or functional cardiac abnormalities, premature death, arrhythmia) may be considered as 
-MODERATE
- evidence
-
-
-NOTE:
- The following assays/models do NOT meet criteria
-
-
-
-
-Assays that are known to be associated with non-specific cardiac phenotypes (e.g., morpholino-induced pericardial edema in zebrafish)
-
-
-In vivo evidence that is not variant specific, such as whole gene alterations (i.e., cDNA or whole gene transgenic mice and whole or partial gene knock-out mice)",Disease-specific
-MYBPC3 (HGNC:7551),PS3,Supporting,"In vitro
- 
-assays (e.g., biochemical assays of myofilament function, motility assays, human iPSC-CM)
-
-
-While some 
-in vitro
- assays may provide evidence that a variant in a cardiomyopathy gene has an effect on protein and/or myofilament function, at present, there are no validated “gold-standard” assays that are considered to reliably predict the clinical phenotype.
-
-
-As such, in the cardiomyopathy genes listed in these guidelines, data from individual 
-in vitro
- studies are unlikely to meet the criteria required to assign this rule at more than SUPPORTING level.",Disease-specific
-MYBPC3 (HGNC:7551),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-MYBPC3 (HGNC:7551),PS4,Strong,"{Currently few well-designed case-control studies have been performed for inherited cardiomyopathies.  Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). 
-
-
-Cohorts used in these analyses should meet the following criteria: 
-
-
-
-
-The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype*). 
-
-
-When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded.  This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).
-
-
-
-
-
-
-The controls should not be derived from study populations that might be enriched for the specified disorder.
-
-
-The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).
-
-
-The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).
-
-
-The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).
-
-
-The population diversity of the case and control cohorts are broadly similar.
-
-
-Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh 
-et al.
- 2017
-9
-, 
-DECIPHER
-).
-
-
-
-
-To account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:
-
-
-
-
-STRONG
- evidence requires the lower bound of the 95% confidence interval (CI) around the odds ratio (OR) estimate to be 
-≥20
-
-
-
-
-A PS4 calculator is available at 
-www.cardiodb.org
-.
-
-
-If multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered).  
-
-
-*RELEVANT PHENOTYPES:
-
-
-
-
-Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. 
-
-
-For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. 
-
-
-Additional considerations for LVNC and end-stage HCM: 
-
-
-Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson 
-et al.
- 2017
-10
-; Oechslin 
-et al.
- 2017
-11
-; Hershberger 
-et al.
- 2017
-12
-; Ross 
-et al.
- 2020
-13
-), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).
-
-
-
-
-
-
-
-
-HCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",Disease-specific
-MYBPC3 (HGNC:7551),PS4,Moderate,"Currently few well-designed case-control studies have been performed for inherited cardiomyopathies.  Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). 
-
-
-Cohorts used in these analyses should meet the following criteria: 
-
-
-
-
-The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype*). 
-
-
-When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded.  This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).
-
-
-
-
-
-
-The controls should not be derived from study populations that might be enriched for the specified disorder.
-
-
-The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).
-
-
-The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).
-
-
-The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).
-
-
-The population diversity of the case and control cohorts are broadly similar.
-
-
-Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh 
-et al.
- 2017
-9
-, 
-DECIPHER
-).
-
-
-
-
-To account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:
-
-
-
-
-MODERATE
- evidence requires the lower bound of the 95% CI around the OR to be 
-≥10
-
-
-
-
-A PS4 calculator is available at 
-www.cardiodb.org
-.
-
-
-If multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered).  
-
-
-*RELEVANT PHENOTYPES:
-
-
-
-
-Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. 
-
-
-For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. 
-
-
-Additional considerations for LVNC and end-stage HCM: 
-
-
-Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson 
-et al.
- 2017
-10
-; Oechslin 
-et al.
- 2017
-11
-; Hershberger 
-et al.
- 2017
-12
-; Ross 
-et al.
- 2020
-13
-), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).
-
-
-
-
-
-
-
-
-HCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",Disease-specific
-MYBPC3 (HGNC:7551),PS4,Supporting,"Currently few well-designed case-control studies have been performed for inherited cardiomyopathies.  Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). 
-
-
-Cohorts used in these analyses should meet the following criteria: 
-
-
-
-
-The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype*). 
-
-
-When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded.  This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).
-
-
-
-
-
-
-The controls should not be derived from study populations that might be enriched for the specified disorder.
-
-
-The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).
-
-
-The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).
-
-
-The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).
-
-
-The population diversity of the case and control cohorts are broadly similar.
-
-
-Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh 
-et al.
- 2017
-9
-, 
-DECIPHER
-).
-
-
-
-
-To account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:
-
-
-
-
-SUPPORTING
- evidence requires the lower bound of the 95% CI around the OR to be 
-≥5
-
-
-
-
-A PS4 calculator is available at 
-www.cardiodb.org
-.
-
-
-If multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered).  
-
-
-*RELEVANT PHENOTYPES:
-
-
-
-
-Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. 
-
-
-For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. 
-
-
-Additional considerations for LVNC and end-stage HCM: 
-
-
-Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson 
-et al.
- 2017
-10
-; Oechslin 
-et al.
- 2017
-11
-; Hershberger 
-et al.
- 2017
-12
-; Ross 
-et al.
- 2020
-13
-), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).
-
-
-
-
-
-
-
-
-HCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",Disease-specific
-MYBPC3 (HGNC:7551),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-MYBPC3 (HGNC:7551),PM1,Moderate,"Applicable to missense variants in 
-MYBPC3
- in the specific regions listed below (Walsh 
-et al.
- 2019
-14
-). 
-
-
-
-
-Transcripts ENST00000545968 and NM_000256.3
-
-
-Codons 485-502 and 1248-1266
-
-
-
-
-Data from HCM case cohorts was used to derive these cluster regions. Therefore, this rule should NOT be applied when additional evidence for the variant supports that the variant causes a phenotype other than HCM (e.g., variant seen in multiple DCM cases).
-
-
-Enrichment was not observed for DCM in any genes.
-
-
-Rule should NOT be combined with PM5 because presence of pathogenic variants in the same codon/region were used to determine clustering and would be double-counting evidence.","Disease-specific,Gene-specific"
-MYBPC3 (HGNC:7551),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-MYBPC3 (HGNC:7551),PM2,Supporting,"The values used to calculate the PM2 thresholds were derived from studies in Northern European populations that have been relatively well-characterized with regards to disease prevalence and variant spectrum. These thresholds can be applied to any population where disease prevalence is considered comparable (1/500 or lower), where the most frequent pathogenic variant accounts for no more than 2% of cases (e.g., has an allele frequency of ≤0.02 in cases based on the upper bound of 95% CI), and where the penetrance of a pathogenic variant is expected to be at least 50% (Kelly 
-et al.
- 2018
-15
-).
-
-
-A threshold of 
-≤0.00004
- in the subpopulation with the highest frequency when using the upper bound of the 95% CI activates this rule.
-
-
-
-
-Alternatively, this is equivalent to the variant NOT being observed more than once (≤1 allele) in gnomAD v.2.1.1 in one of the non-founder populations (e.g., absence required from the Other and Ashkenazi Jewish subpopulations).
-
-
-Applying a threshold of ≤0.00004 (upper bound of 95% CI of the allele frequency in gnomAD) is equivalent to the variant being seen in a single subpopulation and that subpopulation meets any of the following:
-
-
-Allele Count (AC) in Allele Number (AN)
-
-
-≤1 in ≥120,000
-
-
-≤2 in ≥160,000
-
-
-≤3 in ≥195,000
-
-
-≤4 in ≥230,000
-
-
-
-
-
-
-
-
-gnomAD is the preferred database for this calculation, but currently only displays the filtering allele frequency (FAF), which is equivalent to a lower bound estimate of the 95% CI, when the upper bound is what is needed.
-
-
-
-
-Confidence interval tools, such as 
-Confit-de-MAF
-, can be used to determine the upper bound of the 95% CI of the observed allele frequency.
-
-
-
-
-Due to current technical limitations of next generation sequencing technologies, minor allele frequencies for complex variants (e.g., large indels) may not be accurately represented in population databases.
-
-
-Caution should be used when a variant is only identified, or over-represented, in one of the smaller gnomAD populations, as the gnomAD allele frequencies may not accurately represent the true population frequency.
-
-
-Population databases may contain affected or pre-symptomatic individuals for diseases with reduced penetrance/variable onset.",Disease-specific
-MYBPC3 (HGNC:7551),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-MYBPC3 (HGNC:7551),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-MYBPC3 (HGNC:7551),PM4,Moderate,"Strength of rule should be carefully considered and may require downgrading to SUPPORTING based on the predicted impact of the variant, including the size of the deletion/insertion, its location, and conservation of the region. 
-
-
-For genes where PVS1 is not applicable (i.e., where there is no evidence that pLOF variants cause disease), consider using this rule at MODERATE or SUPPORTING strength for truncating variants that do NOT undergo nonsense mediated decay (NMD).",General recommendation
-MYBPC3 (HGNC:7551),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MYBPC3 (HGNC:7551),PM5,Moderate,"This criterion can be used at MODERATE if a different missense variant at the same codon has been classified as 
-pathogenic
- using these modified guidelines without application of PM5.
-
-
-The impact of the amino acid change being evaluated needs to be compared to the impact of the amino acid change that is established as pathogenic (e.g., a change of Ala to His is less severe than Ala to Cys change). Consider reducing the strength of this rule to SUPPORTING if the predicted impact is not expected to be equivalent or more severe.
-
-
-PM5 should not be combined with PM1.  If both are applicable at MODERATE weight, use of PM5 is most appropriate since it is variant specific.",General recommendation
-MYBPC3 (HGNC:7551),PM5,Supporting,"This criterion can be considered at SUPPORTING if a different missense variant at the same codon has been classified as 
-likely pathogenic
- using these modified guidelines without application of PM5.
-
-
-The impact of the amino acid change being evaluated needs to be compared to the impact of the amino acid change that is established as likely pathogenic (e.g., a change of Ala to His is less severe than Ala to Cys change). Consider reducing the strength of this rule to NOT APPLICABLE if the predicted impact is not expected to be equivalent or more severe.
-
-
-PM5 should not be combined with PM1.  The one with the higher strength should be applied, but if both are applicable at SUPPORTING weight, use of PM5 is most appropriate since it is variant specific.",General recommendation
-MYBPC3 (HGNC:7551),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-MYBPC3 (HGNC:7551),PM6,Moderate,"Refer to SVI guidance on number/combination of cases required based on phenotype specificity
-7
-.
-
-
-For most cardiomyopathies, it is recommended to default to “phenotype consistent with gene but not highly specific”. Clinical judgment is required for shifting to a higher or lower phenotypic consistency. 
-
-
-See PS2 for additional considerations.",Disease-specific
-MYBPC3 (HGNC:7551),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-MYBPC3 (HGNC:7551),PP1,Strong,"Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at 
-≥7
- 
-segregations
- (LOD score of 2.1) for 
-STRONG
-.
-
-
-Although rare for inherited cardiomyopathies, when the phenotype/presentation of a variant within and across families is highly specific (e.g., early-onset severe RCM in all affected individuals), the following thresholds as proposed by Jarvik and Browning (2016)
-16
- can be considered: 
-
-
-
-
-STRONG evidence requires ≥5 segregations (LOD score of 1.5)
-
-
-
-
-Only genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance.
-
-
-Phenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis.  
-
-
-Important considerations include:
-
-
-
-
-Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant.  If linkage disequilibrium is a concern, consider downgrading strength of segregation. 
-
-
-Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1.
-
-
-Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. 
-
-
-Caution is needed when distantly related (≥3
-rd
- degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).",Disease-specific
-MYBPC3 (HGNC:7551),PP1,Moderate,"Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at 
-≥5
- 
-segregations
- (LOD score of 1.5) for 
-MODERATE
-.
-
-
-Although rare for inherited cardiomyopathies, when the phenotype/presentation of a variant within and across families is highly specific (e.g., early-onset severe RCM in all affected individuals), the following thresholds as proposed by Jarvik and Browning (2016)
-16
- can be considered: 
-
-
-
-
-MODERATE evidence requires ≥4 segregations (LOD score of 1.2)
-
-
-
-
-Only genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance.
-
-
-Phenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis.  
-
-
-Important considerations include:
-
-
-
-
-Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant.  If linkage disequilibrium is a concern, consider downgrading strength of segregation. 
-
-
-Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1 (see below).
-
-
-Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. 
-
-
-Caution is needed when distantly related (≥3
-rd
- degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).",Disease-specific
-MYBPC3 (HGNC:7551),PP1,Supporting,"Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at 
-≥3
- 
-segregations
- (LOD score of 0.9) for 
-SUPPORTING
-. The thresholds as proposed by Jarvik and Browning (2016)
-16
- are the same at ≥3 segregations (LOD score of 0.9) for supporting.
-
-
-Only genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance.
-
-
-Phenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis.  
-
-
-Important considerations include:
-
-
-
-
-Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant.  If linkage disequilibrium is a concern, consider downgrading strength of segregation. 
-
-
-Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1 (see below).
-
-
-Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. 
-
-
-Caution is needed when distantly related (≥3
-rd
- degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).",Disease-specific
-MYBPC3 (HGNC:7551),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-MYBPC3 (HGNC:7551),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-MYBPC3 (HGNC:7551),PP3,Supporting,"As many 
-in silico
- algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. Meta-predictors, such as REVEL, are preferred over multiple individual predictors.
-
-
-Use of REVEL (Ioannidis 
-et al.
- 2016
-17
-) is recommended at thresholds of 
-≥0.70 for PP3
-.
-
-
-Clinical judgment is needed if any individual algorithms or conservation data are contradictory to REVEL data.
-
-
-Positive predictive value for benign/no impact predictions is generally higher than for pathogenic/impact predictions.
-
-
-SpliceAI
-2
- is recommended for evaluation of predicted splice impacts.",Disease-specific
-MYBPC3 (HGNC:7551),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-MYBPC3 (HGNC:7551),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MYBPC3 (HGNC:7551),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-MYBPC3 (HGNC:7551),BA1,Stand Alone,"Allele frequency is 
-≥0.001
- based on the 
-filtering allele frequency (FAF)
- in 
-gnomAD
- in the subpopulation with the highest frequency (popmax).
-
-
-The values used to calculate the BA1 threshold were derived from studies in Northern European populations that have been relatively well-characterized with regards to disease prevalence and variant spectrum. These thresholds can be applied to any population where disease prevalence is considered comparable (1/300 or lower).
-
-
-The threshold is applicable when assessing variants in the context of autosomal dominant cardiomyopathy. 
-
-
-gnomAD is the preferred database for this calculation. If a subpopulation specific FAF other than the popmax is needed, this value can be calculated using the AlleleFrequencyApp on the 
-CardioDB website
-.
-
-
-
-
-Using the Inverse AF tab, enter in the population size and the number of alleles identified and it will calculate the FAF.  
-
-
-Set confidence to 0.95 (95%).
-
-
-If the FAF is ≥0.001, this rule can be applied.
-
-
-
-
-The FAF by platform (e.g., exome vs. genome; v.2.1.1 vs. v.3.1.1) should be considered, the larger population is most likely to have the most accurate representation of “true” population allele frequency.
-
-
-Caution is needed when considering any population cohorts that are smaller than the smallest subpopulations within gnomAD v.2.1.1 (e.g., ~5000 individuals or ~10,000 alleles). Despite this conservative nature of this threshold and approach, in smaller cohorts, the observed allele frequency may less accurately reflect the true allele frequency. Traditionally, once a variant is classified as Benign, it is rarely re-evaluated and so the highest confidence is needed to establish that classification on an allele frequency alone.",Disease-specific
-MYBPC3 (HGNC:7551),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-MYBPC3 (HGNC:7551),BS1,Strong,"Allele frequency is 
-≥0.0002 for
- 
-MYBPC3
- based on the 
-filtering allele frequency (FAF)
- in 
-gnomAD
- in the subpopulation with the highest frequency (popmax).
-
-
-Criterion BS1 may only be used as standalone evidence to classify a variant as Likely Benign in the absence of conflicting data. See SVI guidance (Tavtigian 
-et al.
- 2018
-18
-; Tavtigian 
-et al.
- 2020
-19
-). 
-
-
-See BA1 for additional specifications that also apply to BS1.","Disease-specific,Gene-specific"
-MYBPC3 (HGNC:7551),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",NA
-MYBPC3 (HGNC:7551),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-MYBPC3 (HGNC:7551),BS3,Strong,See PS3 specifications.,Disease-specific
-MYBPC3 (HGNC:7551),BS3,Moderate,See PS3 specifications.,Disease-specific
-MYBPC3 (HGNC:7551),BS3,Supporting,See PS3 specifications.,Disease-specific
-MYBPC3 (HGNC:7551),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-MYBPC3 (HGNC:7551),BS4,Strong,"Any non-segregations should be carefully evaluated to rule out a phenocopy or the presence of a second disease-causing variant before considering it as conflicting or benign evidence. 
-
-
-
-
-The presence of “phenocopies” (e.g., athlete’s heart, hypertensive heart disease, ischemic cardiomyopathy, alcoholic cardiomyopathy, diabetic cardiomyopathy) can mimic non-segregation (i.e., lack of segregation) among affected individuals. 
-
-
-Families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent ‘non-segregation’.
-
-
-
-
-Because of these possibilities, 
-multiple (≥2) non-segregations
- that are highly unlikely to be phenocopies or due to alternate variants (e.g., those without a possible alternate cause) 
-are required to apply this rule
-.  A higher number of non-segregations is necessary for instances where alternative causes are possible (e.g., non-segregation in a sibling with childhood onset cardiomyopathy versus a grandparent with hypertension and HCM).
-
-
-Careful consideration of the above points is required when using this data as conflicting evidence, especially when overall evidence supports likely pathogenic or pathogenic.",Disease-specific
-MYBPC3 (HGNC:7551),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-MYBPC3 (HGNC:7551),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-MYBPC3 (HGNC:7551),BP2,Supporting,"Other variants must be pathogenic as defined by these specifications.
-
-
-Testing of parents or other informative relatives is often required to determine 
-cis
-/
-trans
- status.
-
-
-If a variant is seen in 
-trans
- (or as double heterozygous) with another pathogenic variant in ≥2 cases and the phenotype is not more severe than when either of the two variants are seen in isolation, this rule may be applied (i.e., high confidence this variant is NOT contributing to disease).
-
-
-
-
-<1% of cases of HCM have >1 pathogenic or likely pathogenic variant (0.6%; Alfares 
-et al.
- 2015
-20
-).
-
-
-
-
-This rule cannot be applied when the variant has only been observed in 
-cis
- with a pathogenic variant as its significance in isolation is unknown in this scenario. 
-
-
-Caution is needed if using this criterion as a primary piece of evidence for classifying a variant as likely benign/benign (i.e., only 2 SUPPORTING criteria are sufficient for a likely benign classification).",Disease-specific
-MYBPC3 (HGNC:7551),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-MYBPC3 (HGNC:7551),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-MYBPC3 (HGNC:7551),BP4,Supporting,"As many 
-in silico
- algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. Meta-predictors, such as REVEL, are preferred over multiple individual predictors.
-
-
-Use of REVEL (Ioannidis 
-et al.
- 2016
-17
-) is recommended at thresholds of 
-≤0.40 for BP4
-.
-
-
-Clinical judgment is needed if any individual algorithms or conservation data are contradictory to REVEL data.
-
-
-Positive predictive value for benign/no impact predictions is generally higher than for pathogenic/impact predictions.
-
-
-SpliceAI
-2
- is recommended for evaluation of predicted splice impacts.",Disease-specific
-MYBPC3 (HGNC:7551),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-MYBPC3 (HGNC:7551),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MYBPC3 (HGNC:7551),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-MYBPC3 (HGNC:7551),BP7,Supporting,"Also applicable to 
-intronic variants outside the splice consensus sequence (-4 and +7 outward)
- for which splicing prediction algorithms predict no impact to the splice consensus sequence NOR the creation of a new splice site AND the nucleotide is not highly conserved.
-
-
-Rule can be combined with BP4 to make a variant likely benign per Richards 
-et al.
- 2015
-6
-.",General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
deleted file mode 100644
index 1d062e8ed08f0df08bebbd2d772d12e9f6011ac6..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
+++ /dev/null
@@ -1,900 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-MYH7 (HGNC:7577),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-MYH7 (HGNC:7577),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MYH7 (HGNC:7577),PS1,Strong,"No cardiomyopathy specifications. Apply as outlined by Richards 
-et al
-. 2015
-1
-.
-
-
-Example of when rule should NOT be applied. NM_000256.3(
-MYBPC3
-): c.2308G>A (p.Asp770Asn) has an established impact on splicing leading to nonsense mediated decay (NMD) and should not be used to provide evidence for other variants observed to result in the same amino acid change.",No change
-MYH7 (HGNC:7577),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-MYH7 (HGNC:7577),PS2,Strong,"Refer to SVI guidance on number/combination of cases required based on phenotype specificity
-2
-).
-
-
-For most cardiomyopathies, it is recommended to default to 
-Phenotype consistency: “Phenotype consistent with gene but not highly specific”
-. Clinical judgment is required for shifting to a higher or lower category. 
-
-
-For use as a STRONG or VERY STRONG criterion, ideally parents have been thoroughly clinically evaluated without evidence of cardiomyopathy (ideally using a combination of ECG and echocardiogram or cardiac MRI for maximum sensitivity).
-
-
-A family history consistent with 
-de novo
- inheritance should not have any clinical signs or symptoms suggestive of cardiomyopathy in a 1
-st
- or 2
-nd
- degree relative, for example: 
-
-
-
-
-Sudden death under 60 years of age
-
-
-Heart transplant
-
-
-Implantable cardiac defibrillator (ICD) under 60 years of age
-
-
-Features of cardiomyopathy (e.g., systolic dysfunction, hypertrophy, left ventricular enlargement in an individual without risk factors).
-
-
-Other related/overlapping cardiomyopathies
-
-
-
-
-Examples of non-suspicious family history may include non-specific clinical features (e.g., palpitations, syncope, borderline/inconclusive echocardiogram findings, heart attack if age appropriate and suspected to result from coronary artery disease), but every attempt should be made to clarify features. 
-
-
-Generally, this criterion is only applicable in the ABSENCE of any other possible disease-causing variants.  If other pathogenic or likely pathogenic variants are present, consider decreasing points assigned or overall weight.",Disease-specific
-MYH7 (HGNC:7577),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-MYH7 (HGNC:7577),PS3,Strong,"In vitro splicing assays (e.g., RNA studies)
-
-
-In vitro
- splicing assays may be considered as 
-STRONG
- evidence, providing the following criteria are met.
-
-
-
-
-Prior knowledge of predominant transcripts in cardiac tissue
-
-
-
-
-Analysis undertaken using RNA extracted from cardiac tissue from the individual with the variant
-
-
-Analysis undertaken using RNA extracted from whole blood providing the relevant transcripts (isoforms) are expressed in blood and are at sufficient levels to assess splice disruption.
-
-
-Assay shows a clear, reproducible and convincing effect on splicing (i.e. a distinct splice product, present at a level comparable to the splice product from the wild-type allele), which is not observed in controls
-
-
-
-
-Confirmation of abnormal splice product by Sanger sequencing
-
-
-
-
-NOTE:
- Mini-gene assay in non-patient derived cell lines are NOT considered to provide STRONG evidence.
-
-
-NOTE:
-  Whether to activate this rule needs to be reconciled with the variant spectrum and disease mechanism for the gene at hand (i.e., consider whether the effect is likely to lead to LOF or an in-frame alteration and whether this type of effect is expected to be disease causing) (Abou Tayoun 
-et al.
- 2018
-3
-).",Disease-specific
-MYH7 (HGNC:7577),PS3,Moderate,"In vivo models (e.g., variant knock-in animal models)
-
-
-Mammalian variant-specific knock-in animal models that produce a phenotype consistent with the clinical phenotype in humans (e.g., structural and/or functional cardiac abnormalities, premature death, arrhythmia) may be considered as 
-MODERATE
- evidence
-
-
-NOTE:
- The following assays/models do NOT meet criteria
-
-
-
-
-Assays that are known to be associated with non-specific cardiac phenotypes (e.g., morpholino-induced pericardial edema in zebrafish)
-
-
-In vivo evidence that is not variant specific, such as whole gene alterations (i.e., cDNA or whole gene transgenic mice and whole or partial gene knock-out mice)",Disease-specific
-MYH7 (HGNC:7577),PS3,Supporting,"In vitro
- 
-assays (e.g., biochemical assays of myofilament function, motility assays, human iPSC-CM)
-
-
-While some 
-in vitro
- assays may provide evidence that a variant in a cardiomyopathy gene has an effect on protein and/or myofilament function, at present, there are no validated “gold-standard” assays that are considered to reliably predict the clinical phenotype.
-
-
-As such, in the cardiomyopathy genes listed in these guidelines, data from individual 
-in vitro
- studies are unlikely to meet the criteria required to assign this rule at more than SUPPORTING level.",Disease-specific
-MYH7 (HGNC:7577),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-MYH7 (HGNC:7577),PS4,Strong,"Currently few well-designed case-control studies have been performed for inherited cardiomyopathies.  Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). 
-
-
-Cohorts used in these analyses should meet the following criteria: 
-
-
-
-
-The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype*). 
-
-
-When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded.  This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).
-
-
-
-
-
-
-The controls should not be derived from study populations that might be enriched for the specified disorder.
-
-
-The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).
-
-
-The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).
-
-
-The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).
-
-
-The population diversity of the case and control cohorts are broadly similar.
-
-
-Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh 
-et al.
- 2017
-8
-, 
-DECIPHER
-).
-
-
-
-
-To account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:
-
-
-
-
-STRONG
- evidence requires the lower bound of the 95% confidence interval (CI) around the odds ratio (OR) estimate to be 
-≥20
-
-
-
-
-A PS4 calculator is available at 
-www.cardiodb.org
-.
-
-
-If multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered).  
-
-
-*RELEVANT PHENOTYPES:
-
-
-
-
-Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. 
-
-
-For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. 
-
-
-Additional considerations for LVNC and end-stage HCM: 
-
-
-Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson 
-et al.
- 2017
-9
-; Oechslin 
-et al.
- 2017
-6
-; Hershberger 
-et al.
- 2017
-5
-; Ross 
-et al.
- 2020
-7
-), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).
-
-
-
-
-
-
-
-
-HCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",Disease-specific
-MYH7 (HGNC:7577),PS4,Moderate,"Currently few well-designed case-control studies have been performed for inherited cardiomyopathies.  Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). 
-
-
-Cohorts used in these analyses should meet the following criteria: 
-
-
-
-
-The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype*). 
-
-
-When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded.  This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).
-
-
-
-
-
-
-The controls should not be derived from study populations that might be enriched for the specified disorder.
-
-
-The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).
-
-
-The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).
-
-
-The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).
-
-
-The population diversity of the case and control cohorts are broadly similar.
-
-
-Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh 
-et al.
- 2017
-8
-, 
-DECIPHER
-).
-
-
-
-
-To account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:
-
-
-
-
-MODERATE
- evidence requires the lower bound of the 95% CI around the OR to be 
-≥10
-
-
-
-
-A PS4 calculator is available at 
-www.cardiodb.org
-.
-
-
-If multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered).  
-
-
-*RELEVANT PHENOTYPES:
-
-
-
-
-Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. 
-
-
-For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. 
-
-
-Additional considerations for LVNC and end-stage HCM: 
-
-
-Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson 
-et al.
- 2017
-9
-; Oechslin 
-et al.
- 2017
-6
-; Hershberger 
-et al.
- 2017
-5
-; Ross 
-et al.
- 2020
-7
-), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).
-
-
-
-
-
-
-
-
-HCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",Disease-specific
-MYH7 (HGNC:7577),PS4,Supporting,"Currently few well-designed case-control studies have been performed for inherited cardiomyopathies.  Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). 
-
-
-Cohorts used in these analyses should meet the following criteria: 
-
-
-
-
-The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype*). 
-
-
-When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded.  This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).
-
-
-
-
-
-
-The controls should not be derived from study populations that might be enriched for the specified disorder.
-
-
-The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).
-
-
-The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).
-
-
-The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).
-
-
-The population diversity of the case and control cohorts are broadly similar.
-
-
-Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh 
-et al.
- 2017
-8
-, 
-DECIPHER
-).
-
-
-
-
-To account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:
-
-
-
-
-SUPPORTING
- evidence requires the lower bound of the 95% CI around the OR to be 
-≥5
-
-
-
-
-A PS4 calculator is available at 
-www.cardiodb.org
-.
-
-
-If multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered).  
-
-
-*RELEVANT PHENOTYPES:
-
-
-
-
-Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. 
-
-
-For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. 
-
-
-Additional considerations for LVNC and end-stage HCM: 
-
-
-Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson 
-et al.
- 2017
-9
-; Oechslin 
-et al.
- 2017
-6
-; Hershberger 
-et al.
- 2017
-5
-; Ross 
-et al.
- 2020
-7
-), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).
-
-
-
-
-
-
-
-
-HCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",Disease-specific
-MYH7 (HGNC:7577),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-MYH7 (HGNC:7577),PM1,Moderate,"Applicable to missense variants in 
-MYH7
- in the specific regions listed below (Walsh 
-et al.
- 2019
-10
-). 
-
-
-
-
-Transcripts ENST00000355349 & NM_000257.4
-
-
-Codons 167-931*
-
-
-
-
-Data from HCM case cohorts was used to derive these cluster regions. Therefore, this rule should NOT be applied when additional evidence for the variant supports that the variant causes a phenotype other than HCM (e.g., variant seen in multiple DCM cases).
-
-
-Enrichment was not observed for DCM in any genes.
-
-
-Rule should NOT be combined with PM5 because presence of pathogenic variants in the same codon/region were used to determine clustering and would be double-counting evidence.
-
-
-* This region is updated from v1.0 (Kelly et al. 2018
-11
-).","Disease-specific,Gene-specific"
-MYH7 (HGNC:7577),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-MYH7 (HGNC:7577),PM2,Supporting,"The values used to calculate the PM2 thresholds were derived from studies in Northern European populations that have been relatively well-characterized with regards to disease prevalence and variant spectrum. These thresholds can be applied to any population where disease prevalence is considered comparable (1/500 or lower), where the most frequent pathogenic variant accounts for no more than 2% of cases (e.g., has an allele frequency of ≤0.02 in cases based on the upper bound of 95% CI), and where the penetrance of a pathogenic variant is expected to be at least 50% (Kelly 
-et al.
- 2018
-11
-).
-
-
-A threshold of 
-≤0.00004
- in the subpopulation with the highest frequency when using the upper bound of the 95% CI activates this rule.
-
-
-
-
-Alternatively, this is equivalent to the variant NOT being observed more than once (≤1 allele) in gnomAD v.2.1.1 in one of the non-founder populations (e.g., absence required from the Other and Ashkenazi Jewish subpopulations).
-
-
-Applying a threshold of ≤0.00004 (upper bound of 95% CI of the allele frequency in gnomAD) is equivalent to the variant being seen in a single subpopulation and that subpopulation meets any of the following:
-
-
-Allele Count (AC) in Allele Number (AN)
-
-
-≤1 in ≥120,000
-
-
-≤2 in ≥160,000
-
-
-≤3 in ≥195,000
-
-
-≤4 in ≥230,000
-
-
-
-
-
-
-
-
-gnomAD is the preferred database for this calculation, but currently only displays the filtering allele frequency (FAF), which is equivalent to a lower bound estimate of the 95% CI, when the upper bound is what is needed.
-
-
-
-
-Confidence interval tools, such as 
-Confit-de-MAF
-, can be used to determine the upper bound of the 95% CI of the observed allele frequency.
-
-
-
-
-Due to current technical limitations of next generation sequencing technologies, minor allele frequencies for complex variants (e.g., large indels) may not be accurately represented in population databases.
-
-
-Caution should be used when a variant is only identified, or over-represented, in one of the smaller gnomAD populations, as the gnomAD allele frequencies may not accurately represent the true population frequency.
-
-
-Population databases may contain affected or pre-symptomatic individuals for diseases with reduced penetrance/variable onset.",Disease-specific
-MYH7 (HGNC:7577),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-MYH7 (HGNC:7577),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-MYH7 (HGNC:7577),PM4,Moderate,"Strength of rule should be carefully considered and may require downgrading to SUPPORTING based on the predicted impact of the variant, including the size of the deletion/insertion, its location, and conservation of the region. 
-
-
-For genes where PVS1 is not applicable (i.e., where there is no evidence that pLOF variants cause disease), consider using this rule at MODERATE or SUPPORTING strength for truncating variants that do NOT undergo nonsense mediated decay (NMD).",Disease-specific
-MYH7 (HGNC:7577),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MYH7 (HGNC:7577),PM5,Moderate,"This criterion can be used at MODERATE if a different missense variant at the same codon has been classified as 
-pathogenic
- using these modified guidelines without application of PM5.
-
-
-The impact of the amino acid change being evaluated needs to be compared to the impact of the amino acid change that is established as pathogenic (e.g., a change of Ala to His is less severe than Ala to Cys change). Consider reducing the strength of this rule to SUPPORTING if the predicted impact is not expected to be equivalent or more severe.
-
-
-PM5 should not be combined with PM1.  If both are applicable at MODERATE weight, use of PM5 is most appropriate since it is variant specific.",General recommendation
-MYH7 (HGNC:7577),PM5,Supporting,"This criterion can be considered at SUPPORTING if a different missense variant at the same codon has been classified as 
-likely pathogenic
- using these modified guidelines without application of PM5.
-
-
-The impact of the amino acid change being evaluated needs to be compared to the impact of the amino acid change that is established as likely pathogenic (e.g., a change of Ala to His is less severe than Ala to Cys change). Consider reducing the strength of this rule to NOT APPLICABLE if the predicted impact is not expected to be equivalent or more severe.
-
-
-PM5 should not be combined with PM1.  The one with the higher strength should be applied, but if both are applicable at SUPPORTING weight, use of PM5 is most appropriate since it is variant specific.",General recommendation
-MYH7 (HGNC:7577),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-MYH7 (HGNC:7577),PM6,Moderate,"Refer to SVI guidance on number/combination of cases required based on phenotype specificity
-2
-.
-
-
-For most cardiomyopathies, it is recommended to default to “phenotype consistent with gene but not highly specific”. Clinical judgment is required for shifting to a higher or lower phenotypic consistency. 
-
-
-See PS2 for additional considerations.",Disease-specific
-MYH7 (HGNC:7577),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-MYH7 (HGNC:7577),PP1,Strong,"Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at 
-≥7 segregations
- (LOD score of 2.1) for 
-STRONG
-.
-
-
-Although rare for inherited cardiomyopathies, when the phenotype/presentation of a variant within and across families is highly specific (e.g., early-onset severe RCM in all affected individuals), the following thresholds as proposed by Jarvik and Browning (2016)
-12
- can be considered: 
-
-
-
-
-STRONG evidence requires ≥5 segregations (LOD score of 1.5)
-
-
-
-
-Only genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance.
-
-
-Phenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis.  
-
-
-Important considerations include:
-
-
-
-
-Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant.  If linkage disequilibrium is a concern, consider downgrading strength of segregation. 
-
-
-Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1.
-
-
-Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. 
-
-
-Caution is needed when distantly related (≥3
-rd
- degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).",Disease-specific
-MYH7 (HGNC:7577),PP1,Moderate,"Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at 
-≥5
- 
-segregations
- (LOD score of 1.5) for 
-MODERATE
-.
-
-
-Although rare for inherited cardiomyopathies, when the phenotype/presentation of a variant within and across families is highly specific (e.g., early-onset severe RCM in all affected individuals), the following thresholds as proposed by Jarvik and Browning (2016)
-12
- can be considered: 
-
-
-
-
-MODERATE evidence requires ≥4 segregations (LOD score of 1.2)
-
-
-
-
-Only genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance.
-
-
-Phenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis.  
-
-
-Important considerations include:
-
-
-
-
-Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant.  If linkage disequilibrium is a concern, consider downgrading strength of segregation. 
-
-
-Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1 (see below).
-
-
-Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. 
-
-
-Caution is needed when distantly related (≥3
-rd
- degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).",Disease-specific
-MYH7 (HGNC:7577),PP1,Supporting,"Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at 
-≥3
- 
-segregations
- (LOD score of 0.9) for 
-SUPPORTING
-. The thresholds as proposed by Jarvik and Browning (2016)
-12
- are the same at ≥3 segregations (LOD score of 0.9) for supporting.
-
-
-Only genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance.
-
-
-Phenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis.  
-
-
-Important considerations include:
-
-
-
-
-Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant.  If linkage disequilibrium is a concern, consider downgrading strength of segregation. 
-
-
-Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1 (see below).
-
-
-Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. 
-
-
-Caution is needed when distantly related (≥3
-rd
- degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).",Disease-specific
-MYH7 (HGNC:7577),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-MYH7 (HGNC:7577),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-MYH7 (HGNC:7577),PP3,Supporting,"As many 
-in silico
- algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. Meta-predictors, such as REVEL, are preferred over multiple individual predictors.
-
-
-Use of REVEL (Ioannidis 
-et al.
- 2016
-14
-) is recommended at thresholds of 
-≥0.70 for PP3
-.
-
-
-Clinical judgment is needed if any individual algorithms or conservation data are contradictory to REVEL data.
-
-
-Positive predictive value for benign/no impact predictions is generally higher than for pathogenic/impact predictions.
-
-
-SpliceAI
-13
- is recommended for evaluation of predicted splice impacts.",Disease-specific
-MYH7 (HGNC:7577),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-MYH7 (HGNC:7577),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MYH7 (HGNC:7577),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-MYH7 (HGNC:7577),BA1,Stand Alone,"Allele frequency is 
-≥0.001
- based on the 
-filtering allele frequency (FAF)
- in 
-gnomAD
- in the subpopulation with the highest frequency (popmax).
-
-
-The values used to calculate the BA1 threshold were derived from studies in Northern European populations that have been relatively well-characterized with regards to disease prevalence and variant spectrum. These thresholds can be applied to any population where disease prevalence is considered comparable (1/300 or lower).
-
-
-The threshold is applicable when assessing variants in the context of autosomal dominant cardiomyopathy. 
-
-
-gnomAD is the preferred database for this calculation. If a subpopulation specific FAF other than the popmax is needed, this value can be calculated using the AlleleFrequencyApp on the 
-CardioDB website
-.
-
-
-
-
-Using the Inverse AF tab, enter in the population size and the number of alleles identified and it will calculate the FAF.  
-
-
-Set confidence to 0.95 (95%).
-
-
-If the FAF is ≥0.001, this rule can be applied.
-
-
-
-
-The FAF by platform (e.g., exome vs. genome; v.2.1.1 vs. v.3.1.1) should be considered, the larger population is most likely to have the most accurate representation of “true” population allele frequency.
-
-
-Caution is needed when considering any population cohorts that are smaller than the smallest subpopulations within gnomAD v.2.1.1 (e.g., ~5000 individuals or ~10,000 alleles). Despite this conservative nature of this threshold and approach, in smaller cohorts, the observed allele frequency may less accurately reflect the true allele frequency. Traditionally, once a variant is classified as Benign, it is rarely re-evaluated and so the highest confidence is needed to establish that classification on an allele frequency alone.",Disease-specific
-MYH7 (HGNC:7577),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-MYH7 (HGNC:7577),BS1,Strong,"Allele frequency is 
-≥0.0001 for
- 
-MYH7
- based on the 
-filtering allele frequency (FAF)
- in 
-gnomAD
- in the subpopulation with the highest frequency (popmax).
-
-
-Criterion BS1 may only be used as standalone evidence to classify a variant as Likely Benign in the absence of conflicting data. See SVI guidance (Tavtigian 
-et al.
- 2018
-16
-; Tavtigian 
-et al.
- 2020
-15
-). 
-
-
-See BA1 for additional specifications that also apply to BS1.","Disease-specific,Gene-specific"
-MYH7 (HGNC:7577),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",NA
-MYH7 (HGNC:7577),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-MYH7 (HGNC:7577),BS3,Strong,See PS3 specifications.,No change
-MYH7 (HGNC:7577),BS3,Moderate,See PS3 specifications.,Disease-specific
-MYH7 (HGNC:7577),BS3,Supporting,See PS3 specifications.,Disease-specific
-MYH7 (HGNC:7577),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-MYH7 (HGNC:7577),BS4,Strong,"Any non-segregations should be carefully evaluated to rule out a phenocopy or the presence of a second disease-causing variant before considering it as conflicting or benign evidence. 
-
-
-
-
-The presence of “phenocopies” (e.g., athlete’s heart, hypertensive heart disease, ischemic cardiomyopathy, alcoholic cardiomyopathy, diabetic cardiomyopathy) can mimic non-segregation (i.e., lack of segregation) among affected individuals. 
-
-
-Families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent ‘non-segregation’.
-
-
-
-
-Because of these possibilities, 
-multiple (≥2) non-segregations
- that are highly unlikely to be phenocopies or due to alternate variants (e.g., those without a possible alternate cause) 
-are required to apply this rule
-.  A higher number of non-segregations is necessary for instances where alternative causes are possible (e.g., non-segregation in a sibling with childhood onset cardiomyopathy versus a grandparent with hypertension and HCM).
-
-
-Careful consideration of the above points is required when using this data as conflicting evidence, especially when overall evidence supports likely pathogenic or pathogenic.",Disease-specific
-MYH7 (HGNC:7577),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-MYH7 (HGNC:7577),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-MYH7 (HGNC:7577),BP2,Supporting,"Other variants must be pathogenic as defined by these specifications.
-
-
-Testing of parents or other informative relatives is often required to determine 
-cis
-/
-trans
- status.
-
-
-If a variant is seen in 
-trans
- (or as double heterozygous) with another pathogenic variant in ≥2 cases and the phenotype is not more severe than when either of the two variants are seen in isolation, this rule may be applied (i.e., high confidence this variant is NOT contributing to disease).
-
-
-
-
-<1% of cases of HCM have >1 pathogenic or likely pathogenic variant (0.6%; Alfares 
-et al.
- 2015
-17
-).
-
-
-
-
-This rule cannot be applied when the variant has only been observed in 
-cis
- with a pathogenic variant as its significance in isolation is unknown in this scenario. 
-
-
-Caution is needed if using this criterion as a primary piece of evidence for classifying a variant as likely benign/benign (i.e., only 2 SUPPORTING criteria are sufficient for a likely benign classification).","Disease-specific,Gene-specific"
-MYH7 (HGNC:7577),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-MYH7 (HGNC:7577),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-MYH7 (HGNC:7577),BP4,Supporting,"As many 
-in silico
- algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. Meta-predictors, such as REVEL, are preferred over multiple individual predictors.
-
-
-Use of REVEL (Ioannidis et al. 2016
-14
-) is recommended at thresholds of 
-≤0.40 for BP4
-.
-
-
-Clinical judgment is needed if any individual algorithms or conservation data are contradictory to REVEL data.
-
-
-Positive predictive value for benign/no impact predictions is generally higher than for pathogenic/impact predictions.
-
-
-SpliceAI
-13
- is recommended for evaluation of predicted splice impacts.",No change
-MYH7 (HGNC:7577),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-MYH7 (HGNC:7577),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MYH7 (HGNC:7577),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-MYH7 (HGNC:7577),BP7,Supporting,"Also applicable to 
-intronic variants outside the splice consensus sequence (-4 and +7 outward)
- for which splicing prediction algorithms predict no impact to the splice consensus sequence NOR the creation of a new splice site AND the nucleotide is not highly conserved.
-
-
-Rule can be combined with BP4 to make a variant likely benign per Richards 
-et al.
- 2015
-1
-.",General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYL2Version1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYL2Version1.0.0_version=1.0.0.csv
deleted file mode 100644
index b8a87dea417f1ca152362dc4260d38d2694cceb8..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYL2Version1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,882 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-MYL2 (HGNC:7583),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-MYL2 (HGNC:7583),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MYL2 (HGNC:7583),PS1,Strong,"No cardiomyopathy specifications. Apply as outlined by Richards 
-et al
-. 2015
-1
-.
-
-
-Example of when rule should NOT be applied. NM_000256.3(
-MYBPC3
-): c.2308G>A (p.Asp770Asn) has an established impact on splicing leading to nonsense mediated decay (NMD) and should not be used to provide evidence for other variants observed to result in the same amino acid change.",No change
-MYL2 (HGNC:7583),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-MYL2 (HGNC:7583),PS2,Strong,"Refer to SVI guidance on number/combination of cases required based on phenotype specificity
-2
-.
-
-
-For most cardiomyopathies, it is recommended to default to 
-Phenotype consistency: “Phenotype consistent with gene but not highly specific”
-. Clinical judgment is required for shifting to a higher or lower category. 
-
-
-For use as a STRONG or VERY STRONG criterion, ideally parents have been thoroughly clinically evaluated without evidence of cardiomyopathy (ideally using a combination of ECG and echocardiogram or cardiac MRI for maximum sensitivity).
-
-
-A family history consistent with 
-de novo
- inheritance should not have any clinical signs or symptoms suggestive of cardiomyopathy in a 1
-st
- or 2
-nd
- degree relative, for example: 
-
-
-
-
-Sudden death under 60 years of age
-
-
-Heart transplant
-
-
-Implantable cardiac defibrillator (ICD) under 60 years of age
-
-
-Features of cardiomyopathy (e.g., systolic dysfunction, hypertrophy, left ventricular enlargement in an individual without risk factors).
-
-
-Other related/overlapping cardiomyopathies
-
-
-
-
-Examples of non-suspicious family history may include non-specific clinical features (e.g., palpitations, syncope, borderline/inconclusive echocardiogram findings, heart attack if age appropriate and suspected to result from coronary artery disease), but every attempt should be made to clarify features. 
-
-
-Generally, this criterion is only applicable in the ABSENCE of any other possible disease-causing variants.  If other pathogenic or likely pathogenic variants are present, consider decreasing points assigned or overall weight.",Disease-specific
-MYL2 (HGNC:7583),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-MYL2 (HGNC:7583),PS3,Strong,"In vitro splicing assays (e.g., RNA studies)
-
-
-In vitro
- splicing assays may be considered as 
-STRONG
- evidence, providing the following criteria are met.
-
-
-
-
-Prior knowledge of predominant transcripts in cardiac tissue
-
-
-
-
-Analysis undertaken using RNA extracted from cardiac tissue from the individual with the variant
-
-
-Analysis undertaken using RNA extracted from whole blood providing the relevant transcripts (isoforms) are expressed in blood and are at sufficient levels to assess splice disruption.
-
-
-Assay shows a clear, reproducible and convincing effect on splicing (i.e. a distinct splice product, present at a level comparable to the splice product from the wild-type allele), which is not observed in controls
-
-
-
-
-Confirmation of abnormal splice product by Sanger sequencing
-
-
-
-
-NOTE:
- Mini-gene assay in non-patient derived cell lines are NOT considered to provide STRONG evidence.
-
-
-NOTE:
-  Whether to activate this rule needs to be reconciled with the variant spectrum and disease mechanism for the gene at hand (i.e., consider whether the effect is likely to lead to LOF or an in-frame alteration and whether this type of effect is expected to be disease causing) (Abou Tayoun 
-et al.
- 2018
-3
-).",Disease-specific
-MYL2 (HGNC:7583),PS3,Moderate,"In vivo models (e.g., variant knock-in animal models)
-
-
-Mammalian variant-specific knock-in animal models that produce a phenotype consistent with the clinical phenotype in humans (e.g., structural and/or functional cardiac abnormalities, premature death, arrhythmia) may be considered as 
-MODERATE
- evidence
-
-
-NOTE:
- The following assays/models do NOT meet criteria
-
-
-
-
-Assays that are known to be associated with non-specific cardiac phenotypes (e.g., morpholino-induced pericardial edema in zebrafish)
-
-
-In vivo evidence that is not variant specific, such as whole gene alterations (i.e., cDNA or whole gene transgenic mice and whole or partial gene knock-out mice)",Disease-specific
-MYL2 (HGNC:7583),PS3,Supporting,"In vitro
- 
-assays (e.g., biochemical assays of myofilament function, motility assays, human iPSC-CM)
-
-
-While some 
-in vitro
- assays may provide evidence that a variant in a cardiomyopathy gene has an effect on protein and/or myofilament function, at present, there are no validated “gold-standard” assays that are considered to reliably predict the clinical phenotype.
-
-
-As such, in the cardiomyopathy genes listed in these guidelines, data from individual 
-in vitro
- studies are unlikely to meet the criteria required to assign this rule at more than SUPPORTING level.",Disease-specific
-MYL2 (HGNC:7583),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-MYL2 (HGNC:7583),PS4,Strong,"Currently few well-designed case-control studies have been performed for inherited cardiomyopathies.  Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). 
-
-
-Cohorts used in these analyses should meet the following criteria: 
-
-
-
-
-The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype*). 
-
-
-When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded.  This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).
-
-
-
-
-
-
-The controls should not be derived from study populations that might be enriched for the specified disorder.
-
-
-The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).
-
-
-The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).
-
-
-The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).
-
-
-The population diversity of the case and control cohorts are broadly similar.
-
-
-Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh 
-et al.
- 2017
-5
-, 
-DECIPHER
-).
-
-
-
-
-To account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:
-
-
-
-
-STRONG
- evidence requires the lower bound of the 95% confidence interval (CI) around the odds ratio (OR) estimate to be 
-≥20
-
-
-
-
-A PS4 calculator is available at 
-www.cardiodb.org
-.
-
-
-If multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered).  
-
-
-*RELEVANT PHENOTYPES:
-
-
-
-
-Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. 
-
-
-For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. 
-
-
-Additional considerations for LVNC and end-stage HCM: 
-
-
-Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson 
-et al.
- 2017
-6
-; Oechslin 
-et al.
- 2017
-7
-; Hershberger 
-et al.
- 2017
-8
-; Ross 
-et al.
- 2020
-9
-), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).
-
-
-
-
-
-
-
-
-HCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",Disease-specific
-MYL2 (HGNC:7583),PS4,Moderate,"Currently few well-designed case-control studies have been performed for inherited cardiomyopathies.  Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). 
-
-
-Cohorts used in these analyses should meet the following criteria: 
-
-
-
-
-The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype*). 
-
-
-When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded.  This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).
-
-
-
-
-
-
-The controls should not be derived from study populations that might be enriched for the specified disorder.
-
-
-The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).
-
-
-The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).
-
-
-The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).
-
-
-The population diversity of the case and control cohorts are broadly similar.
-
-
-Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh 
-et al.
- 2017
-5
-, 
-DECIPHER
-).
-
-
-
-
-To account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:
-
-
-
-
-MODERATE
- evidence requires the lower bound of the 95% CI around the OR to be 
-≥10
-
-
-
-
-A PS4 calculator is available at 
-www.cardiodb.org
-.
-
-
-If multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered).  
-
-
-*RELEVANT PHENOTYPES:
-
-
-
-
-Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. 
-
-
-For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. 
-
-
-Additional considerations for LVNC and end-stage HCM: 
-
-
-Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson 
-et al.
- 2017
-6
-; Oechslin 
-et al.
- 2017
-7
-; Hershberger 
-et al.
- 2017
-8
-; Ross 
-et al.
- 2020
-9
-), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).
-
-
-
-
-
-
-
-
-HCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",Disease-specific
-MYL2 (HGNC:7583),PS4,Supporting,"Currently few well-designed case-control studies have been performed for inherited cardiomyopathies.  Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). 
-
-
-Cohorts used in these analyses should meet the following criteria: 
-
-
-
-
-The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype*). 
-
-
-When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded.  This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).
-
-
-
-
-
-
-The controls should not be derived from study populations that might be enriched for the specified disorder.
-
-
-The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).
-
-
-The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).
-
-
-The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).
-
-
-The population diversity of the case and control cohorts are broadly similar.
-
-
-Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh 
-et al.
- 2017
-5
-, 
-DECIPHER
-).
-
-
-
-
-To account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:
-
-
-
-
-SUPPORTING
- evidence requires the lower bound of the 95% CI around the OR to be 
-≥5
-
-
-
-
-A PS4 calculator is available at 
-www.cardiodb.org
-.
-
-
-If multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered).  
-
-
-*RELEVANT PHENOTYPES:
-
-
-
-
-Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. 
-
-
-For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. 
-
-
-Additional considerations for LVNC and end-stage HCM: 
-
-
-Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson 
-et al.
- 2017
-6
-; Oechslin 
-et al.
- 2017
-7
-; Hershberger 
-et al.
- 2017
-8
-; Ross 
-et al.
- 2020
-9
-), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).
-
-
-
-
-
-
-
-
-HCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",Disease-specific
-MYL2 (HGNC:7583),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-MYL2 (HGNC:7583),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-MYL2 (HGNC:7583),PM2,Supporting,"The values used to calculate the PM2 thresholds were derived from studies in Northern European populations that have been relatively well-characterized with regards to disease prevalence and variant spectrum. These thresholds can be applied to any population where disease prevalence is considered comparable (1/500 or lower), where the most frequent pathogenic variant accounts for no more than 2% of cases (e.g., has an allele frequency of ≤0.02 in cases based on the upper bound of 95% CI), and where the penetrance of a pathogenic variant is expected to be at least 50% (Kelly 
-et al.
- 2018
-10
-).
-
-
-A threshold of 
-≤0.00004
- in the subpopulation with the highest frequency when using the upper bound of the 95% CI activates this rule.
-
-
-
-
-Alternatively, this is equivalent to the variant NOT being observed more than once (≤1 allele) in gnomAD v.2.1.1 in one of the non-founder populations (e.g., absence required from the Other and Ashkenazi Jewish subpopulations).
-
-
-Applying a threshold of ≤0.00004 (upper bound of 95% CI of the allele frequency in gnomAD) is equivalent to the variant being seen in a single subpopulation and that subpopulation meets any of the following:
-
-
-Allele Count (AC) in Allele Number (AN)
-
-
-≤1 in ≥120,000
-
-
-≤2 in ≥160,000
-
-
-≤3 in ≥195,000
-
-
-≤4 in ≥230,000
-
-
-
-
-
-
-
-
-gnomAD is the preferred database for this calculation, but currently only displays the filtering allele frequency (FAF), which is equivalent to a lower bound estimate of the 95% CI, when the upper bound is what is needed.
-
-
-
-
-Confidence interval tools, such as 
-Confit-de-MAF
-, can be used to determine the upper bound of the 95% CI of the observed allele frequency.
-
-
-
-
-Due to current technical limitations of next generation sequencing technologies, minor allele frequencies for complex variants (e.g., large indels) may not be accurately represented in population databases.
-
-
-Caution should be used when a variant is only identified, or over-represented, in one of the smaller gnomAD populations, as the gnomAD allele frequencies may not accurately represent the true population frequency.
-
-
-Population databases may contain affected or pre-symptomatic individuals for diseases with reduced penetrance/variable onset.",Disease-specific
-MYL2 (HGNC:7583),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-MYL2 (HGNC:7583),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-MYL2 (HGNC:7583),PM4,Moderate,"Strength of rule should be carefully considered and may require downgrading to SUPPORTING based on the predicted impact of the variant, including the size of the deletion/insertion, its location, and conservation of the region. 
-
-
-For genes where PVS1 is not applicable (i.e., where there is no evidence that pLOF variants cause disease), consider using this rule at MODERATE or SUPPORTING strength for truncating variants that do NOT undergo nonsense mediated decay (NMD).",General recommendation
-MYL2 (HGNC:7583),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MYL2 (HGNC:7583),PM5,Moderate,"This criterion can be used at MODERATE if a different missense variant at the same codon has been classified as 
-pathogenic
- using these modified guidelines without application of PM5.
-
-
-The impact of the amino acid change being evaluated needs to be compared to the impact of the amino acid change that is established as pathogenic (e.g., a change of Ala to His is less severe than Ala to Cys change). Consider reducing the strength of this rule to SUPPORTING if the predicted impact is not expected to be equivalent or more severe.
-
-
-PM5 should not be combined with PM1.  If both are applicable at MODERATE weight, use of PM5 is most appropriate since it is variant specific.",General recommendation
-MYL2 (HGNC:7583),PM5,Supporting,"This criterion can be considered at SUPPORTING if a different missense variant at the same codon has been classified as 
-likely pathogenic
- using these modified guidelines without application of PM5.
-
-
-The impact of the amino acid change being evaluated needs to be compared to the impact of the amino acid change that is established as likely pathogenic (e.g., a change of Ala to His is less severe than Ala to Cys change). Consider reducing the strength of this rule to NOT APPLICABLE if the predicted impact is not expected to be equivalent or more severe.
-
-
-PM5 should not be combined with PM1.  The one with the higher strength should be applied, but if both are applicable at SUPPORTING weight, use of PM5 is most appropriate since it is variant specific.",General recommendation
-MYL2 (HGNC:7583),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-MYL2 (HGNC:7583),PM6,Moderate,"Refer to SVI guidance on number/combination of cases required based on phenotype specificity
-2
-.
-
-
-For most cardiomyopathies, it is recommended to default to “phenotype consistent with gene but not highly specific”. Clinical judgment is required for shifting to a higher or lower phenotypic consistency. 
-
-
-See PS2 for additional considerations.",Disease-specific
-MYL2 (HGNC:7583),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-MYL2 (HGNC:7583),PP1,Strong,"Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at 
-≥7
- 
-segregations
- (LOD score of 2.1) for 
-STRONG
-.
-
-
-Although rare for inherited cardiomyopathies, when the phenotype/presentation of a variant within and across families is highly specific (e.g., early-onset severe RCM in all affected individuals), the following thresholds as proposed by Jarvik and Browning (2016)
-11
- can be considered: 
-
-
-
-
-STRONG evidence requires ≥5 segregations (LOD score of 1.5)
-
-
-
-
-Only genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance.
-
-
-Phenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis.  
-
-
-Important considerations include:
-
-
-
-
-Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant.  If linkage disequilibrium is a concern, consider downgrading strength of segregation. 
-
-
-Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1.
-
-
-Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. 
-
-
-Caution is needed when distantly related (≥3
-rd
- degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).",Disease-specific
-MYL2 (HGNC:7583),PP1,Moderate,"Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at 
-≥5
- 
-segregations
- (LOD score of 1.5) for 
-MODERATE
-.
-
-
-Although rare for inherited cardiomyopathies, when the phenotype/presentation of a variant within and across families is highly specific (e.g., early-onset severe RCM in all affected individuals), the following thresholds as proposed by Jarvik and Browning (2016)
-11
- can be considered: 
-
-
-
-
-MODERATE evidence requires ≥4 segregations (LOD score of 1.2)
-
-
-
-
-Only genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance.
-
-
-Phenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis.  
-
-
-Important considerations include:
-
-
-
-
-Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant.  If linkage disequilibrium is a concern, consider downgrading strength of segregation. 
-
-
-Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1 (see below).
-
-
-Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. 
-
-
-Caution is needed when distantly related (≥3
-rd
- degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).",Disease-specific
-MYL2 (HGNC:7583),PP1,Supporting,"Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at 
-≥3
- 
-segregations
- (LOD score of 0.9) for 
-SUPPORTING
-. The thresholds as proposed by Jarvik and Browning (2016)
-11
- are the same at ≥3 segregations (LOD score of 0.9) for supporting.
-
-
-Only genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance.
-
-
-Phenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis.  
-
-
-Important considerations include:
-
-
-
-
-Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant.  If linkage disequilibrium is a concern, consider downgrading strength of segregation. 
-
-
-Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1 (see below).
-
-
-Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. 
-
-
-Caution is needed when distantly related (≥3
-rd
- degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).",Disease-specific
-MYL2 (HGNC:7583),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-MYL2 (HGNC:7583),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-MYL2 (HGNC:7583),PP3,Supporting,"As many 
-in silico
- algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. Meta-predictors, such as REVEL, are preferred over multiple individual predictors.
-
-
-Use of REVEL (Ioannidis 
-et al.
- 2016
-12
-) is recommended at thresholds of 
-≥0.70 for PP3
-.
-
-
-Clinical judgment is needed if any individual algorithms or conservation data are contradictory to REVEL data.
-
-
-Positive predictive value for benign/no impact predictions is generally higher than for pathogenic/impact predictions.
-
-
-SpliceAI
-13
- is recommended for evaluation of predicted splice impacts.",Disease-specific
-MYL2 (HGNC:7583),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-MYL2 (HGNC:7583),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MYL2 (HGNC:7583),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-MYL2 (HGNC:7583),BA1,Stand Alone,"Allele frequency is 
-≥0.001
- based on the 
-filtering allele frequency (FAF)
- in 
-gnomAD
- in the subpopulation with the highest frequency (popmax).
-
-
-The values used to calculate the BA1 threshold were derived from studies in Northern European populations that have been relatively well-characterized with regards to disease prevalence and variant spectrum. These thresholds can be applied to any population where disease prevalence is considered comparable (1/300 or lower).
-
-
-The threshold is applicable when assessing variants in the context of autosomal dominant cardiomyopathy. 
-
-
-
-
-Caution should be applied when assessing variants in the 
-MYL2
- and 
-MYL3
- genes, as homozygous or compound heterozygous variants have been reported to cause a recessive HCM and heterozygous individuals show no sign of disease.
-
-
-
-
-gnomAD is the preferred database for this calculation. If a subpopulation specific FAF other than the popmax is needed, this value can be calculated using the AlleleFrequencyApp on the 
-CardioDB website
-.
-
-
-
-
-Using the Inverse AF tab, enter in the population size and the number of alleles identified and it will calculate the FAF.  
-
-
-Set confidence to 0.95 (95%).
-
-
-If the FAF is ≥0.001, this rule can be applied.
-
-
-
-
-The FAF by platform (e.g., exome vs. genome; v.2.1.1 vs. v.3.1.1) should be considered, the larger population is most likely to have the most accurate representation of “true” population allele frequency.
-
-
-Caution is needed when considering any population cohorts that are smaller than the smallest subpopulations within gnomAD v.2.1.1 (e.g., ~5000 individuals or ~10,000 alleles). Despite this conservative nature of this threshold and approach, in smaller cohorts, the observed allele frequency may less accurately reflect the true allele frequency. Traditionally, once a variant is classified as Benign, it is rarely re-evaluated and so the highest confidence is needed to establish that classification on an allele frequency alone.",Disease-specific
-MYL2 (HGNC:7583),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-MYL2 (HGNC:7583),BS1,Strong,"Allele frequency is 
-≥0.0001 for
- 
-MYL2
- based on the 
-filtering allele frequency (FAF)
- in 
-gnomAD
- in the subpopulation with the highest frequency (popmax).
-
-
-Criterion BS1 may only be used as standalone evidence to classify a variant as Likely Benign in the absence of conflicting data. See SVI guidance (Tavtigian 
-et al.
- 2018
-14
-; Tavtigian 
-et al.
- 2020
-15
-). 
-
-
-See BA1 for additional specifications that also apply to BS1.","Disease-specific,Gene-specific"
-MYL2 (HGNC:7583),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",NA
-MYL2 (HGNC:7583),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-MYL2 (HGNC:7583),BS3,Strong,See PS3 specifications.,Disease-specific
-MYL2 (HGNC:7583),BS3,Moderate,See PS3 specifications.,Disease-specific
-MYL2 (HGNC:7583),BS3,Supporting,See PS3 specifications.,Disease-specific
-MYL2 (HGNC:7583),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-MYL2 (HGNC:7583),BS4,Strong,"Any non-segregations should be carefully evaluated to rule out a phenocopy or the presence of a second disease-causing variant before considering it as conflicting or benign evidence. 
-
-
-
-
-The presence of “phenocopies” (e.g., athlete’s heart, hypertensive heart disease, ischemic cardiomyopathy, alcoholic cardiomyopathy, diabetic cardiomyopathy) can mimic non-segregation (i.e., lack of segregation) among affected individuals. 
-
-
-Families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent ‘non-segregation’.
-
-
-
-
-Because of these possibilities, 
-multiple (≥2) non-segregations
- that are highly unlikely to be phenocopies or due to alternate variants (e.g., those without a possible alternate cause) 
-are required to apply this rule
-.  A higher number of non-segregations is necessary for instances where alternative causes are possible (e.g., non-segregation in a sibling with childhood onset cardiomyopathy versus a grandparent with hypertension and HCM).
-
-
-Careful consideration of the above points is required when using this data as conflicting evidence, especially when overall evidence supports likely pathogenic or pathogenic.",Disease-specific
-MYL2 (HGNC:7583),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-MYL2 (HGNC:7583),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-MYL2 (HGNC:7583),BP2,Supporting,"Other variants must be pathogenic as defined by these specifications.
-
-
-Testing of parents or other informative relatives is often required to determine 
-cis
-/
-trans
- status.
-
-
-If a variant is seen in 
-trans
- (or as double heterozygous) with another pathogenic variant in ≥2 cases and the phenotype is not more severe than when either of the two variants are seen in isolation, this rule may be applied (i.e., high confidence this variant is NOT contributing to disease).
-
-
-
-
-<1% of cases of HCM have >1 pathogenic or likely pathogenic variant (0.6%; Alfares 
-et al.
- 2015
-16
-).
-
-
-
-
-This rule cannot be applied when the variant has only been observed in 
-cis
- with a pathogenic variant as its significance in isolation is unknown in this scenario. 
-
-
-Caution is needed if using this criterion as a primary piece of evidence for classifying a variant as likely benign/benign (i.e., only 2 SUPPORTING criteria are sufficient for a likely benign classification).",Disease-specific
-MYL2 (HGNC:7583),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-MYL2 (HGNC:7583),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-MYL2 (HGNC:7583),BP4,Supporting,"As many 
-in silico
- algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. Meta-predictors, such as REVEL, are preferred over multiple individual predictors.
-
-
-Use of REVEL (Ioannidis et al. 2016
-12
-) is recommended at thresholds of 
-≤0.40 for BP4
-.
-
-
-Clinical judgment is needed if any individual algorithms or conservation data are contradictory to REVEL data.
-
-
-Positive predictive value for benign/no impact predictions is generally higher than for pathogenic/impact predictions.
-
-
-SpliceAI
-13
- is recommended for evaluation of predicted splice impacts.",Disease-specific
-MYL2 (HGNC:7583),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-MYL2 (HGNC:7583),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MYL2 (HGNC:7583),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-MYL2 (HGNC:7583),BP7,Supporting,"Also applicable to 
-intronic variants outside the splice consensus sequence (-4 and +7 outward)
- for which splicing prediction algorithms predict no impact to the splice consensus sequence NOR the creation of a new splice site AND the nucleotide is not highly conserved.
-
-
-Rule can be combined with BP4 to make a variant likely benign per Richards 
-et al.
- 2015
-1
-.",General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYL3Version1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYL3Version1.0.0_version=1.0.0.csv
deleted file mode 100644
index a21b94af18fa12e4df6280c0f94ae7a7a4e41fee..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYL3Version1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,882 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-MYL3 (HGNC:7584),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-MYL3 (HGNC:7584),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MYL3 (HGNC:7584),PS1,Strong,"No cardiomyopathy specifications. Apply as outlined by Richards 
-et al
-. 2015
-1
-.
-
-
-Example of when rule should NOT be applied. NM_000256.3(
-MYBPC3
-): c.2308G>A (p.Asp770Asn) has an established impact on splicing leading to nonsense mediated decay (NMD) and should not be used to provide evidence for other variants observed to result in the same amino acid change.",No change
-MYL3 (HGNC:7584),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-MYL3 (HGNC:7584),PS2,Strong,"Refer to SVI guidance on number/combination of cases required based on phenotype specificity
-2
-.
-
-
-For most cardiomyopathies, it is recommended to default to 
-Phenotype consistency: “Phenotype consistent with gene but not highly specific”
-. Clinical judgment is required for shifting to a higher or lower category. 
-
-
-For use as a STRONG or VERY STRONG criterion, ideally parents have been thoroughly clinically evaluated without evidence of cardiomyopathy (ideally using a combination of ECG and echocardiogram or cardiac MRI for maximum sensitivity).
-
-
-A family history consistent with 
-de novo
- inheritance should not have any clinical signs or symptoms suggestive of cardiomyopathy in a 1
-st
- or 2
-nd
- degree relative, for example: 
-
-
-
-
-Sudden death under 60 years of age
-
-
-Heart transplant
-
-
-Implantable cardiac defibrillator (ICD) under 60 years of age
-
-
-Features of cardiomyopathy (e.g., systolic dysfunction, hypertrophy, left ventricular enlargement in an individual without risk factors).
-
-
-Other related/overlapping cardiomyopathies
-
-
-
-
-Examples of non-suspicious family history may include non-specific clinical features (e.g., palpitations, syncope, borderline/inconclusive echocardiogram findings, heart attack if age appropriate and suspected to result from coronary artery disease), but every attempt should be made to clarify features. 
-
-
-Generally, this criterion is only applicable in the ABSENCE of any other possible disease-causing variants.  If other pathogenic or likely pathogenic variants are present, consider decreasing points assigned or overall weight.",Disease-specific
-MYL3 (HGNC:7584),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-MYL3 (HGNC:7584),PS3,Strong,"In vitro splicing assays (e.g., RNA studies)
-
-
-In vitro
- splicing assays may be considered as 
-STRONG
- evidence, providing the following criteria are met.
-
-
-
-
-Prior knowledge of predominant transcripts in cardiac tissue
-
-
-
-
-Analysis undertaken using RNA extracted from cardiac tissue from the individual with the variant
-
-
-Analysis undertaken using RNA extracted from whole blood providing the relevant transcripts (isoforms) are expressed in blood and are at sufficient levels to assess splice disruption.
-
-
-Assay shows a clear, reproducible and convincing effect on splicing (i.e. a distinct splice product, present at a level comparable to the splice product from the wild-type allele), which is not observed in controls
-
-
-
-
-Confirmation of abnormal splice product by Sanger sequencing
-
-
-
-
-NOTE:
- Mini-gene assay in non-patient derived cell lines are NOT considered to provide STRONG evidence.
-
-
-NOTE:
-  Whether to activate this rule needs to be reconciled with the variant spectrum and disease mechanism for the gene at hand (i.e., consider whether the effect is likely to lead to LOF or an in-frame alteration and whether this type of effect is expected to be disease causing) (Abou Tayoun 
-et al.
- 2018
-3
-).",Disease-specific
-MYL3 (HGNC:7584),PS3,Moderate,"In vivo models (e.g., variant knock-in animal models)
-
-
-Mammalian variant-specific knock-in animal models that produce a phenotype consistent with the clinical phenotype in humans (e.g., structural and/or functional cardiac abnormalities, premature death, arrhythmia) may be considered as 
-MODERATE
- evidence
-
-
-NOTE:
- The following assays/models do NOT meet criteria
-
-
-
-
-Assays that are known to be associated with non-specific cardiac phenotypes (e.g., morpholino-induced pericardial edema in zebrafish)
-
-
-In vivo evidence that is not variant specific, such as whole gene alterations (i.e., cDNA or whole gene transgenic mice and whole or partial gene knock-out mice)",Disease-specific
-MYL3 (HGNC:7584),PS3,Supporting,"In vitro
- 
-assays (e.g., biochemical assays of myofilament function, motility assays, human iPSC-CM)
-
-
-While some 
-in vitro
- assays may provide evidence that a variant in a cardiomyopathy gene has an effect on protein and/or myofilament function, at present, there are no validated “gold-standard” assays that are considered to reliably predict the clinical phenotype.
-
-
-As such, in the cardiomyopathy genes listed in these guidelines, data from individual 
-in vitro
- studies are unlikely to meet the criteria required to assign this rule at more than SUPPORTING level.",Disease-specific
-MYL3 (HGNC:7584),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-MYL3 (HGNC:7584),PS4,Strong,"Currently few well-designed case-control studies have been performed for inherited cardiomyopathies.  Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). 
-
-
-Cohorts used in these analyses should meet the following criteria: 
-
-
-
-
-The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype*). 
-
-
-When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded.  This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).
-
-
-
-
-
-
-The controls should not be derived from study populations that might be enriched for the specified disorder.
-
-
-The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).
-
-
-The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).
-
-
-The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).
-
-
-The population diversity of the case and control cohorts are broadly similar.
-
-
-Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh 
-et al.
- 2017
-5
-, 
-DECIPHER
-).
-
-
-
-
-To account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:
-
-
-
-
-STRONG
- evidence requires the lower bound of the 95% confidence interval (CI) around the odds ratio (OR) estimate to be 
-≥20
-
-
-
-
-A PS4 calculator is available at 
-www.cardiodb.org
-.
-
-
-If multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered).  
-
-
-*RELEVANT PHENOTYPES:
-
-
-
-
-Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. 
-
-
-For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. 
-
-
-Additional considerations for LVNC and end-stage HCM: 
-
-
-Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson 
-et al.
- 2017
-6
-; Oechslin 
-et al.
- 2017
-7
-; Hershberger 
-et al.
- 2017
-8
-; Ross 
-et al.
- 2020
-9
-), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).
-
-
-
-
-
-
-
-
-HCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",Disease-specific
-MYL3 (HGNC:7584),PS4,Moderate,"Currently few well-designed case-control studies have been performed for inherited cardiomyopathies.  Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). 
-
-
-Cohorts used in these analyses should meet the following criteria: 
-
-
-
-
-The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype*). 
-
-
-When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded.  This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).
-
-
-
-
-
-
-The controls should not be derived from study populations that might be enriched for the specified disorder.
-
-
-The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).
-
-
-The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).
-
-
-The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).
-
-
-The population diversity of the case and control cohorts are broadly similar.
-
-
-Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh 
-et al.
- 2017
-5
-, 
-DECIPHER
-).
-
-
-
-
-To account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:
-
-
-
-
-MODERATE
- evidence requires the lower bound of the 95% CI around the OR to be 
-≥10
-
-
-
-
-A PS4 calculator is available at 
-www.cardiodb.org
-.
-
-
-If multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered).  
-
-
-*RELEVANT PHENOTYPES:
-
-
-
-
-Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. 
-
-
-For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. 
-
-
-Additional considerations for LVNC and end-stage HCM: 
-
-
-Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson 
-et al.
- 2017
-6
-; Oechslin 
-et al.
- 2017
-7
-; Hershberger 
-et al.
- 2017
-8
-; Ross 
-et al.
- 2020
-9
-), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).
-
-
-
-
-
-
-
-
-HCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",Disease-specific
-MYL3 (HGNC:7584),PS4,Supporting,"Currently few well-designed case-control studies have been performed for inherited cardiomyopathies.  Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). 
-
-
-Cohorts used in these analyses should meet the following criteria: 
-
-
-
-
-The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype*). 
-
-
-When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded.  This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).
-
-
-
-
-
-
-The controls should not be derived from study populations that might be enriched for the specified disorder.
-
-
-The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).
-
-
-The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).
-
-
-The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).
-
-
-The population diversity of the case and control cohorts are broadly similar.
-
-
-Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh 
-et al.
- 2017
-5
-, 
-DECIPHER
-).
-
-
-
-
-To account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:
-
-
-
-
-SUPPORTING
- evidence requires the lower bound of the 95% CI around the OR to be 
-≥5
-
-
-
-
-A PS4 calculator is available at 
-www.cardiodb.org
-.
-
-
-If multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered).  
-
-
-*RELEVANT PHENOTYPES:
-
-
-
-
-Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. 
-
-
-For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. 
-
-
-Additional considerations for LVNC and end-stage HCM: 
-
-
-Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson 
-et al.
- 2017
-6
-; Oechslin 
-et al.
- 2017
-7
-; Hershberger 
-et al.
- 2017
-8
-; Ross 
-et al.
- 2020
-9
-), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).
-
-
-
-
-
-
-
-
-HCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",Disease-specific
-MYL3 (HGNC:7584),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-MYL3 (HGNC:7584),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-MYL3 (HGNC:7584),PM2,Supporting,"The values used to calculate the PM2 thresholds were derived from studies in Northern European populations that have been relatively well-characterized with regards to disease prevalence and variant spectrum. These thresholds can be applied to any population where disease prevalence is considered comparable (1/500 or lower), where the most frequent pathogenic variant accounts for no more than 2% of cases (e.g., has an allele frequency of ≤0.02 in cases based on the upper bound of 95% CI), and where the penetrance of a pathogenic variant is expected to be at least 50% (Kelly 
-et al.
- 2018
-10
-).
-
-
-A threshold of 
-≤0.00004
- in the subpopulation with the highest frequency when using the upper bound of the 95% CI activates this rule.
-
-
-
-
-Alternatively, this is equivalent to the variant NOT being observed more than once (≤1 allele) in gnomAD v.2.1.1 in one of the non-founder populations (e.g., absence required from the Other and Ashkenazi Jewish subpopulations).
-
-
-Applying a threshold of ≤0.00004 (upper bound of 95% CI of the allele frequency in gnomAD) is equivalent to the variant being seen in a single subpopulation and that subpopulation meets any of the following:
-
-
-Allele Count (AC) in Allele Number (AN)
-
-
-≤1 in ≥120,000
-
-
-≤2 in ≥160,000
-
-
-≤3 in ≥195,000
-
-
-≤4 in ≥230,000
-
-
-
-
-
-
-
-
-gnomAD is the preferred database for this calculation, but currently only displays the filtering allele frequency (FAF), which is equivalent to a lower bound estimate of the 95% CI, when the upper bound is what is needed.
-
-
-
-
-Confidence interval tools, such as 
-Confit-de-MAF
-, can be used to determine the upper bound of the 95% CI of the observed allele frequency.
-
-
-
-
-Due to current technical limitations of next generation sequencing technologies, minor allele frequencies for complex variants (e.g., large indels) may not be accurately represented in population databases.
-
-
-Caution should be used when a variant is only identified, or over-represented, in one of the smaller gnomAD populations, as the gnomAD allele frequencies may not accurately represent the true population frequency.
-
-
-Population databases may contain affected or pre-symptomatic individuals for diseases with reduced penetrance/variable onset.",Disease-specific
-MYL3 (HGNC:7584),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-MYL3 (HGNC:7584),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-MYL3 (HGNC:7584),PM4,Moderate,"Strength of rule should be carefully considered and may require downgrading to SUPPORTING based on the predicted impact of the variant, including the size of the deletion/insertion, its location, and conservation of the region. 
-
-
-For genes where PVS1 is not applicable (i.e., where there is no evidence that pLOF variants cause disease), consider using this rule at MODERATE or SUPPORTING strength for truncating variants that do NOT undergo nonsense mediated decay (NMD).",General recommendation
-MYL3 (HGNC:7584),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MYL3 (HGNC:7584),PM5,Moderate,"This criterion can be used at MODERATE if a different missense variant at the same codon has been classified as 
-pathogenic
- using these modified guidelines without application of PM5.
-
-
-The impact of the amino acid change being evaluated needs to be compared to the impact of the amino acid change that is established as pathogenic (e.g., a change of Ala to His is less severe than Ala to Cys change). Consider reducing the strength of this rule to SUPPORTING if the predicted impact is not expected to be equivalent or more severe.
-
-
-PM5 should not be combined with PM1.  If both are applicable at MODERATE weight, use of PM5 is most appropriate since it is variant specific.",General recommendation
-MYL3 (HGNC:7584),PM5,Supporting,"This criterion can be considered at SUPPORTING if a different missense variant at the same codon has been classified as 
-likely pathogenic
- using these modified guidelines without application of PM5.
-
-
-The impact of the amino acid change being evaluated needs to be compared to the impact of the amino acid change that is established as likely pathogenic (e.g., a change of Ala to His is less severe than Ala to Cys change). Consider reducing the strength of this rule to NOT APPLICABLE if the predicted impact is not expected to be equivalent or more severe.
-
-
-PM5 should not be combined with PM1.  The one with the higher strength should be applied, but if both are applicable at SUPPORTING weight, use of PM5 is most appropriate since it is variant specific.",General recommendation
-MYL3 (HGNC:7584),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-MYL3 (HGNC:7584),PM6,Moderate,"Refer to SVI guidance on number/combination of cases required based on phenotype specificity
-2
-.
-
-
-For most cardiomyopathies, it is recommended to default to “phenotype consistent with gene but not highly specific”. Clinical judgment is required for shifting to a higher or lower phenotypic consistency. 
-
-
-See PS2 for additional considerations.",Disease-specific
-MYL3 (HGNC:7584),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-MYL3 (HGNC:7584),PP1,Strong,"Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at 
-≥7
- 
-segregations
- (LOD score of 2.1) for 
-STRONG
-.
-
-
-Although rare for inherited cardiomyopathies, when the phenotype/presentation of a variant within and across families is highly specific (e.g., early-onset severe RCM in all affected individuals), the following thresholds as proposed by Jarvik and Browning (2016)
-11
- can be considered: 
-
-
-
-
-STRONG evidence requires ≥5 segregations (LOD score of 1.5)
-
-
-
-
-Only genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance.
-
-
-Phenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis.  
-
-
-Important considerations include:
-
-
-
-
-Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant.  If linkage disequilibrium is a concern, consider downgrading strength of segregation. 
-
-
-Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1.
-
-
-Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. 
-
-
-Caution is needed when distantly related (≥3
-rd
- degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).",Disease-specific
-MYL3 (HGNC:7584),PP1,Moderate,"Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at 
-≥5
- 
-segregations
- (LOD score of 1.5) for 
-MODERATE
-.
-
-
-Although rare for inherited cardiomyopathies, when the phenotype/presentation of a variant within and across families is highly specific (e.g., early-onset severe RCM in all affected individuals), the following thresholds as proposed by Jarvik and Browning (2016)
-11
- can be considered: 
-
-
-
-
-MODERATE evidence requires ≥4 segregations (LOD score of 1.2)
-
-
-
-
-Only genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance.
-
-
-Phenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis.  
-
-
-Important considerations include:
-
-
-
-
-Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant.  If linkage disequilibrium is a concern, consider downgrading strength of segregation. 
-
-
-Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1 (see below).
-
-
-Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. 
-
-
-Caution is needed when distantly related (≥3
-rd
- degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).",Disease-specific
-MYL3 (HGNC:7584),PP1,Supporting,"Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at 
-≥3
- 
-segregations
- (LOD score of 0.9) for 
-SUPPORTING
-. The thresholds as proposed by Jarvik and Browning (2016)
-11
- are the same at ≥3 segregations (LOD score of 0.9) for supporting.
-
-
-Only genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance.
-
-
-Phenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis.  
-
-
-Important considerations include:
-
-
-
-
-Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant.  If linkage disequilibrium is a concern, consider downgrading strength of segregation. 
-
-
-Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1 (see below).
-
-
-Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. 
-
-
-Caution is needed when distantly related (≥3
-rd
- degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).",Disease-specific
-MYL3 (HGNC:7584),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-MYL3 (HGNC:7584),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-MYL3 (HGNC:7584),PP3,Supporting,"As many 
-in silico
- algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. Meta-predictors, such as REVEL, are preferred over multiple individual predictors.
-
-
-Use of REVEL (Ioannidis 
-et al.
- 2016
-12
-) is recommended at thresholds of 
-≥0.70 for PP3
-.
-
-
-Clinical judgment is needed if any individual algorithms or conservation data are contradictory to REVEL data.
-
-
-Positive predictive value for benign/no impact predictions is generally higher than for pathogenic/impact predictions.
-
-
-SpliceAI
-13
- is recommended for evaluation of predicted splice impacts.",Disease-specific
-MYL3 (HGNC:7584),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-MYL3 (HGNC:7584),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MYL3 (HGNC:7584),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-MYL3 (HGNC:7584),BA1,Stand Alone,"Allele frequency is 
-≥0.001
- based on the 
-filtering allele frequency (FAF)
- in 
-gnomAD
- in the subpopulation with the highest frequency (popmax).
-
-
-The values used to calculate the BA1 threshold were derived from studies in Northern European populations that have been relatively well-characterized with regards to disease prevalence and variant spectrum. These thresholds can be applied to any population where disease prevalence is considered comparable (1/300 or lower).
-
-
-The threshold is applicable when assessing variants in the context of autosomal dominant cardiomyopathy. 
-
-
-
-
-Caution should be applied when assessing variants in the 
-MYL2
- and 
-MYL3
- genes, as homozygous or compound heterozygous variants have been reported to cause a recessive HCM and heterozygous individuals show no sign of disease.
-
-
-
-
-gnomAD is the preferred database for this calculation. If a subpopulation specific FAF other than the popmax is needed, this value can be calculated using the AlleleFrequencyApp on the 
-CardioDB website
-.
-
-
-
-
-Using the Inverse AF tab, enter in the population size and the number of alleles identified and it will calculate the FAF.  
-
-
-Set confidence to 0.95 (95%).
-
-
-If the FAF is ≥0.001, this rule can be applied.
-
-
-
-
-The FAF by platform (e.g., exome vs. genome; v.2.1.1 vs. v.3.1.1) should be considered, the larger population is most likely to have the most accurate representation of “true” population allele frequency.
-
-
-Caution is needed when considering any population cohorts that are smaller than the smallest subpopulations within gnomAD v.2.1.1 (e.g., ~5000 individuals or ~10,000 alleles). Despite this conservative nature of this threshold and approach, in smaller cohorts, the observed allele frequency may less accurately reflect the true allele frequency. Traditionally, once a variant is classified as Benign, it is rarely re-evaluated and so the highest confidence is needed to establish that classification on an allele frequency alone.",Disease-specific
-MYL3 (HGNC:7584),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-MYL3 (HGNC:7584),BS1,Strong,"Allele frequency is 
-≥0.0001 for
- 
-MYL3
- based on the 
-filtering allele frequency (FAF)
- in 
-gnomAD
- in the subpopulation with the highest frequency (popmax).
-
-
-Criterion BS1 may only be used as standalone evidence to classify a variant as Likely Benign in the absence of conflicting data. See SVI guidance (Tavtigian 
-et al.
- 2018
-14
-; Tavtigian 
-et al.
- 2020
-15
-). 
-
-
-See BA1 for additional specifications that also apply to BS1.","Disease-specific,Gene-specific"
-MYL3 (HGNC:7584),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",NA
-MYL3 (HGNC:7584),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-MYL3 (HGNC:7584),BS3,Strong,See PS3 specifications.,Disease-specific
-MYL3 (HGNC:7584),BS3,Moderate,See PS3 specifications.,Disease-specific
-MYL3 (HGNC:7584),BS3,Supporting,See PS3 specifications.,Disease-specific
-MYL3 (HGNC:7584),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-MYL3 (HGNC:7584),BS4,Strong,"Any non-segregations should be carefully evaluated to rule out a phenocopy or the presence of a second disease-causing variant before considering it as conflicting or benign evidence. 
-
-
-
-
-The presence of “phenocopies” (e.g., athlete’s heart, hypertensive heart disease, ischemic cardiomyopathy, alcoholic cardiomyopathy, diabetic cardiomyopathy) can mimic non-segregation (i.e., lack of segregation) among affected individuals. 
-
-
-Families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent ‘non-segregation’.
-
-
-
-
-Because of these possibilities, 
-multiple (≥2) non-segregations
- that are highly unlikely to be phenocopies or due to alternate variants (e.g., those without a possible alternate cause) 
-are required to apply this rule
-.  A higher number of non-segregations is necessary for instances where alternative causes are possible (e.g., non-segregation in a sibling with childhood onset cardiomyopathy versus a grandparent with hypertension and HCM).
-
-
-Careful consideration of the above points is required when using this data as conflicting evidence, especially when overall evidence supports likely pathogenic or pathogenic.",Disease-specific
-MYL3 (HGNC:7584),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-MYL3 (HGNC:7584),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-MYL3 (HGNC:7584),BP2,Supporting,"Other variants must be pathogenic as defined by these specifications.
-
-
-Testing of parents or other informative relatives is often required to determine 
-cis
-/
-trans
- status.
-
-
-If a variant is seen in 
-trans
- (or as double heterozygous) with another pathogenic variant in ≥2 cases and the phenotype is not more severe than when either of the two variants are seen in isolation, this rule may be applied (i.e., high confidence this variant is NOT contributing to disease).
-
-
-
-
-<1% of cases of HCM have >1 pathogenic or likely pathogenic variant (0.6%; Alfares 
-et al.
- 2015
-16
-).
-
-
-
-
-This rule cannot be applied when the variant has only been observed in 
-cis
- with a pathogenic variant as its significance in isolation is unknown in this scenario. 
-
-
-Caution is needed if using this criterion as a primary piece of evidence for classifying a variant as likely benign/benign (i.e., only 2 SUPPORTING criteria are sufficient for a likely benign classification).",Disease-specific
-MYL3 (HGNC:7584),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-MYL3 (HGNC:7584),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-MYL3 (HGNC:7584),BP4,Supporting,"As many 
-in silico
- algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. Meta-predictors, such as REVEL, are preferred over multiple individual predictors.
-
-
-Use of REVEL (Ioannidis et al. 2016
-12
-) is recommended at thresholds of 
-≤0.40 for BP4
-.
-
-
-Clinical judgment is needed if any individual algorithms or conservation data are contradictory to REVEL data.
-
-
-Positive predictive value for benign/no impact predictions is generally higher than for pathogenic/impact predictions.
-
-
-SpliceAI
-13
- is recommended for evaluation of predicted splice impacts.",Disease-specific
-MYL3 (HGNC:7584),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-MYL3 (HGNC:7584),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MYL3 (HGNC:7584),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-MYL3 (HGNC:7584),BP7,Supporting,"Also applicable to 
-intronic variants outside the splice consensus sequence (-4 and +7 outward)
- for which splicing prediction algorithms predict no impact to the splice consensus sequence NOR the creation of a new splice site AND the nucleotide is not highly conserved.
-
-
-Rule can be combined with BP4 to make a variant likely benign per Richards 
-et al.
- 2015
-1
-.",General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTNNI3Version1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTNNI3Version1.0.0_version=1.0.0.csv
deleted file mode 100644
index 9c51a722a34412428eaaa010713ab0472ceb3498..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTNNI3Version1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,897 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-TNNI3 (HGNC:11947),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-TNNI3 (HGNC:11947),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-TNNI3 (HGNC:11947),PS1,Strong,"No cardiomyopathy specifications. Apply as outlined by Richards 
-et al
-. 2015
-1
-.
-
-
-Example of when rule should NOT be applied. NM_000256.3(
-MYBPC3
-): c.2308G>A (p.Asp770Asn) has an established impact on splicing leading to nonsense mediated decay (NMD) and should not be used to provide evidence for other variants observed to result in the same amino acid change.",No change
-TNNI3 (HGNC:11947),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-TNNI3 (HGNC:11947),PS2,Strong,"Refer to SVI guidance on number/combination of cases required based on phenotype specificity
-2
-.
-
-
-For most cardiomyopathies, it is recommended to default to 
-Phenotype consistency: “Phenotype consistent with gene but not highly specific”
-. Clinical judgment is required for shifting to a higher or lower category. 
-
-
-For use as a STRONG or VERY STRONG criterion, ideally parents have been thoroughly clinically evaluated without evidence of cardiomyopathy (ideally using a combination of ECG and echocardiogram or cardiac MRI for maximum sensitivity).
-
-
-A family history consistent with 
-de novo
- inheritance should not have any clinical signs or symptoms suggestive of cardiomyopathy in a 1
-st
- or 2
-nd
- degree relative, for example: 
-
-
-
-
-Sudden death under 60 years of age
-
-
-Heart transplant
-
-
-Implantable cardiac defibrillator (ICD) under 60 years of age
-
-
-Features of cardiomyopathy (e.g., systolic dysfunction, hypertrophy, left ventricular enlargement in an individual without risk factors).
-
-
-Other related/overlapping cardiomyopathies
-
-
-
-
-Examples of non-suspicious family history may include non-specific clinical features (e.g., palpitations, syncope, borderline/inconclusive echocardiogram findings, heart attack if age appropriate and suspected to result from coronary artery disease), but every attempt should be made to clarify features. 
-
-
-Generally, this criterion is only applicable in the ABSENCE of any other possible disease-causing variants.  If other pathogenic or likely pathogenic variants are present, consider decreasing points assigned or overall weight.",Disease-specific
-TNNI3 (HGNC:11947),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-TNNI3 (HGNC:11947),PS3,Strong,"In vitro splicing assays (e.g., RNA studies)
-
-
-In vitro
- splicing assays may be considered as 
-STRONG
- evidence, providing the following criteria are met.
-
-
-
-
-Prior knowledge of predominant transcripts in cardiac tissue
-
-
-
-
-Analysis undertaken using RNA extracted from cardiac tissue from the individual with the variant
-
-
-Analysis undertaken using RNA extracted from whole blood providing the relevant transcripts (isoforms) are expressed in blood and are at sufficient levels to assess splice disruption.
-
-
-Assay shows a clear, reproducible and convincing effect on splicing (i.e. a distinct splice product, present at a level comparable to the splice product from the wild-type allele), which is not observed in controls
-
-
-
-
-Confirmation of abnormal splice product by Sanger sequencing
-
-
-
-
-NOTE:
- Mini-gene assay in non-patient derived cell lines are NOT considered to provide STRONG evidence.
-
-
-NOTE:
-  Whether to activate this rule needs to be reconciled with the variant spectrum and disease mechanism for the gene at hand (i.e., consider whether the effect is likely to lead to LOF or an in-frame alteration and whether this type of effect is expected to be disease causing) (Abou Tayoun 
-et al.
- 2018
-3
-).",Disease-specific
-TNNI3 (HGNC:11947),PS3,Moderate,"In vivo models (e.g., variant knock-in animal models)
-
-
-Mammalian variant-specific knock-in animal models that produce a phenotype consistent with the clinical phenotype in humans (e.g., structural and/or functional cardiac abnormalities, premature death, arrhythmia) may be considered as 
-MODERATE
- evidence
-
-
-NOTE:
- The following assays/models do NOT meet criteria
-
-
-
-
-Assays that are known to be associated with non-specific cardiac phenotypes (e.g., morpholino-induced pericardial edema in zebrafish)
-
-
-In vivo evidence that is not variant specific, such as whole gene alterations (i.e., cDNA or whole gene transgenic mice and whole or partial gene knock-out mice)",Disease-specific
-TNNI3 (HGNC:11947),PS3,Supporting,"In vitro
- 
-assays (e.g., biochemical assays of myofilament function, motility assays, human iPSC-CM)
-
-
-While some 
-in vitro
- assays may provide evidence that a variant in a cardiomyopathy gene has an effect on protein and/or myofilament function, at present, there are no validated “gold-standard” assays that are considered to reliably predict the clinical phenotype.
-
-
-As such, in the cardiomyopathy genes listed in these guidelines, data from individual 
-in vitro
- studies are unlikely to meet the criteria required to assign this rule at more than SUPPORTING level.",Disease-specific
-TNNI3 (HGNC:11947),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-TNNI3 (HGNC:11947),PS4,Strong,"Currently few well-designed case-control studies have been performed for inherited cardiomyopathies.  Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). 
-
-
-Cohorts used in these analyses should meet the following criteria: 
-
-
-
-
-The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype*). 
-
-
-When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded.  This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).
-
-
-
-
-
-
-The controls should not be derived from study populations that might be enriched for the specified disorder.
-
-
-The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).
-
-
-The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).
-
-
-The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).
-
-
-The population diversity of the case and control cohorts are broadly similar.
-
-
-Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh 
-et al.
- 2017
-5
-, 
-DECIPHER
-).
-
-
-
-
-To account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:
-
-
-
-
-STRONG
- evidence requires the lower bound of the 95% confidence interval (CI) around the odds ratio (OR) estimate to be 
-≥20
-
-
-
-
-A PS4 calculator is available at 
-www.cardiodb.org
-.
-
-
-If multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered).  
-
-
-*RELEVANT PHENOTYPES:
-
-
-
-
-Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. 
-
-
-For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. 
-
-
-Additional considerations for LVNC and end-stage HCM: 
-
-
-Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson 
-et al.
- 2017
-6
-; Oechslin 
-et al.
- 2017
-7
-; Hershberger 
-et al.
- 2017
-8
-; Ross 
-et al.
- 2020
-9
-), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).
-
-
-
-
-
-
-
-
-HCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",Disease-specific
-TNNI3 (HGNC:11947),PS4,Moderate,"Currently few well-designed case-control studies have been performed for inherited cardiomyopathies.  Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). 
-
-
-Cohorts used in these analyses should meet the following criteria: 
-
-
-
-
-The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype*). 
-
-
-When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded.  This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).
-
-
-
-
-
-
-The controls should not be derived from study populations that might be enriched for the specified disorder.
-
-
-The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).
-
-
-The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).
-
-
-The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).
-
-
-The population diversity of the case and control cohorts are broadly similar.
-
-
-Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh 
-et al.
- 2017
-5
-, 
-DECIPHER
-).
-
-
-
-
-To account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:
-
-
-
-
-MODERATE
- evidence requires the lower bound of the 95% CI around the OR to be 
-≥10
-
-
-
-
-A PS4 calculator is available at 
-www.cardiodb.org
-.
-
-
-If multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered).  
-
-
-*RELEVANT PHENOTYPES:
-
-
-
-
-Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. 
-
-
-For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. 
-
-
-Additional considerations for LVNC and end-stage HCM: 
-
-
-Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson 
-et al.
- 2017
-6
-; Oechslin 
-et al.
- 2017
-7
-; Hershberger 
-et al.
- 2017
-8
-; Ross 
-et al.
- 2020
-9
-), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).
-
-
-
-
-
-
-
-
-HCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",Disease-specific
-TNNI3 (HGNC:11947),PS4,Supporting,"Currently few well-designed case-control studies have been performed for inherited cardiomyopathies.  Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). 
-
-
-Cohorts used in these analyses should meet the following criteria: 
-
-
-
-
-The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype*). 
-
-
-When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded.  This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).
-
-
-
-
-
-
-The controls should not be derived from study populations that might be enriched for the specified disorder.
-
-
-The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).
-
-
-The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).
-
-
-The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).
-
-
-The population diversity of the case and control cohorts are broadly similar.
-
-
-Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh 
-et al.
- 2017
-5
-, 
-DECIPHER
-).
-
-
-
-
-To account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:
-
-
-
-
-SUPPORTING
- evidence requires the lower bound of the 95% CI around the OR to be 
-≥5
-
-
-
-
-A PS4 calculator is available at 
-www.cardiodb.org
-.
-
-
-If multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered).  
-
-
-*RELEVANT PHENOTYPES:
-
-
-
-
-Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. 
-
-
-For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. 
-
-
-Additional considerations for LVNC and end-stage HCM: 
-
-
-Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson 
-et al.
- 2017
-6
-; Oechslin 
-et al.
- 2017
-7
-; Hershberger 
-et al.
- 2017
-8
-; Ross 
-et al.
- 2020
-9
-), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).
-
-
-
-
-
-
-
-
-HCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",Disease-specific
-TNNI3 (HGNC:11947),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-TNNI3 (HGNC:11947),PM1,Moderate,"Applicable to missense variants in 
-TNNI3
- in the specific regions listed below (Walsh 
-et al.
- 2019
-10
-). 
-
-
-
-
-Transcripts ENST00000344887 and NM_000363.5
-
-
-Codons 141-209
-
-
-
-
-Data from HCM case cohorts was used to derive these cluster regions. Therefore, this rule should NOT be applied when additional evidence for the variant supports that the variant causes a phenotype other than HCM (e.g., variant seen in multiple DCM cases).
-
-
-Enrichment was not observed for DCM in any genes.
-
-
-Rule should NOT be combined with PM5 because presence of pathogenic variants in the same codon/region were used to determine clustering and would be double-counting evidence.","Disease-specific,Gene-specific"
-TNNI3 (HGNC:11947),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-TNNI3 (HGNC:11947),PM2,Supporting,"The values used to calculate the PM2 thresholds were derived from studies in Northern European populations that have been relatively well-characterized with regards to disease prevalence and variant spectrum. These thresholds can be applied to any population where disease prevalence is considered comparable (1/500 or lower), where the most frequent pathogenic variant accounts for no more than 2% of cases (e.g., has an allele frequency of ≤0.02 in cases based on the upper bound of 95% CI), and where the penetrance of a pathogenic variant is expected to be at least 50% (Kelly 
-et al.
- 2018
-11
-).
-
-
-A threshold of 
-≤0.00004
- in the subpopulation with the highest frequency when using the upper bound of the 95% CI activates this rule.
-
-
-
-
-Alternatively, this is equivalent to the variant NOT being observed more than once (≤1 allele) in gnomAD v.2.1.1 in one of the non-founder populations (e.g., absence required from the Other and Ashkenazi Jewish subpopulations).
-
-
-Applying a threshold of ≤0.00004 (upper bound of 95% CI of the allele frequency in gnomAD) is equivalent to the variant being seen in a single subpopulation and that subpopulation meets any of the following:
-
-
-Allele Count (AC) in Allele Number (AN)
-
-
-≤1 in ≥120,000
-
-
-≤2 in ≥160,000
-
-
-≤3 in ≥195,000
-
-
-≤4 in ≥230,000
-
-
-
-
-
-
-
-
-gnomAD is the preferred database for this calculation, but currently only displays the filtering allele frequency (FAF), which is equivalent to a lower bound estimate of the 95% CI, when the upper bound is what is needed.
-
-
-
-
-Confidence interval tools, such as 
-Confit-de-MAF
-, can be used to determine the upper bound of the 95% CI of the observed allele frequency.
-
-
-
-
-Due to current technical limitations of next generation sequencing technologies, minor allele frequencies for complex variants (e.g., large indels) may not be accurately represented in population databases.
-
-
-Caution should be used when a variant is only identified, or over-represented, in one of the smaller gnomAD populations, as the gnomAD allele frequencies may not accurately represent the true population frequency.
-
-
-Population databases may contain affected or pre-symptomatic individuals for diseases with reduced penetrance/variable onset.",Disease-specific
-TNNI3 (HGNC:11947),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-TNNI3 (HGNC:11947),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-TNNI3 (HGNC:11947),PM4,Moderate,"Strength of rule should be carefully considered and may require downgrading to SUPPORTING based on the predicted impact of the variant, including the size of the deletion/insertion, its location, and conservation of the region. 
-
-
-For genes where PVS1 is not applicable (i.e., where there is no evidence that pLOF variants cause disease), consider using this rule at MODERATE or SUPPORTING strength for truncating variants that do NOT undergo nonsense mediated decay (NMD).",General recommendation
-TNNI3 (HGNC:11947),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-TNNI3 (HGNC:11947),PM5,Moderate,"This criterion can be used at MODERATE if a different missense variant at the same codon has been classified as 
-pathogenic
- using these modified guidelines without application of PM5.
-
-
-The impact of the amino acid change being evaluated needs to be compared to the impact of the amino acid change that is established as pathogenic (e.g., a change of Ala to His is less severe than Ala to Cys change). Consider reducing the strength of this rule to SUPPORTING if the predicted impact is not expected to be equivalent or more severe.
-
-
-PM5 should not be combined with PM1.  If both are applicable at MODERATE weight, use of PM5 is most appropriate since it is variant specific.",General recommendation
-TNNI3 (HGNC:11947),PM5,Supporting,"This criterion can be considered at SUPPORTING if a different missense variant at the same codon has been classified as 
-likely pathogenic
- using these modified guidelines without application of PM5.
-
-
-The impact of the amino acid change being evaluated needs to be compared to the impact of the amino acid change that is established as likely pathogenic (e.g., a change of Ala to His is less severe than Ala to Cys change). Consider reducing the strength of this rule to NOT APPLICABLE if the predicted impact is not expected to be equivalent or more severe.
-
-
-PM5 should not be combined with PM1.  The one with the higher strength should be applied, but if both are applicable at SUPPORTING weight, use of PM5 is most appropriate since it is variant specific.",General recommendation
-TNNI3 (HGNC:11947),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-TNNI3 (HGNC:11947),PM6,Moderate,"Refer to SVI guidance on number/combination of cases required based on phenotype specificity
-2
-.
-
-
-For most cardiomyopathies, it is recommended to default to “phenotype consistent with gene but not highly specific”. Clinical judgment is required for shifting to a higher or lower phenotypic consistency. 
-
-
-See PS2 for additional considerations.",Disease-specific
-TNNI3 (HGNC:11947),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-TNNI3 (HGNC:11947),PP1,Strong,"Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at 
-≥7
- 
-segregations
- (LOD score of 2.1) for 
-STRONG
-.
-
-
-Although rare for inherited cardiomyopathies, when the phenotype/presentation of a variant within and across families is highly specific (e.g., early-onset severe RCM in all affected individuals), the following thresholds as proposed by Jarvik and Browning (2016)
-12
- can be considered: 
-
-
-
-
-STRONG evidence requires ≥5 segregations (LOD score of 1.5)
-
-
-
-
-Only genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance.
-
-
-Phenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis.  
-
-
-Important considerations include:
-
-
-
-
-Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant.  If linkage disequilibrium is a concern, consider downgrading strength of segregation. 
-
-
-Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1.
-
-
-Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. 
-
-
-Caution is needed when distantly related (≥3
-rd
- degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).",Disease-specific
-TNNI3 (HGNC:11947),PP1,Moderate,"Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at 
-≥5
- 
-segregations
- (LOD score of 1.5) for 
-MODERATE
-.
-
-
-Although rare for inherited cardiomyopathies, when the phenotype/presentation of a variant within and across families is highly specific (e.g., early-onset severe RCM in all affected individuals), the following thresholds as proposed by Jarvik and Browning (2016)
-12
- can be considered: 
-
-
-
-
-MODERATE evidence requires ≥4 segregations (LOD score of 1.2)
-
-
-
-
-Only genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance.
-
-
-Phenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis.  
-
-
-Important considerations include:
-
-
-
-
-Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant.  If linkage disequilibrium is a concern, consider downgrading strength of segregation. 
-
-
-Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1 (see below).
-
-
-Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. 
-
-
-Caution is needed when distantly related (≥3
-rd
- degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).",Disease-specific
-TNNI3 (HGNC:11947),PP1,Supporting,"Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at 
-≥3
- 
-segregations
- (LOD score of 0.9) for 
-SUPPORTING
-. The thresholds as proposed by Jarvik and Browning (2016)
-12
- are the same at ≥3 segregations (LOD score of 0.9) for supporting.
-
-
-Only genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance.
-
-
-Phenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis.  
-
-
-Important considerations include:
-
-
-
-
-Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant.  If linkage disequilibrium is a concern, consider downgrading strength of segregation. 
-
-
-Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1 (see below).
-
-
-Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. 
-
-
-Caution is needed when distantly related (≥3
-rd
- degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).",Disease-specific
-TNNI3 (HGNC:11947),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-TNNI3 (HGNC:11947),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-TNNI3 (HGNC:11947),PP3,Supporting,"As many 
-in silico
- algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. Meta-predictors, such as REVEL, are preferred over multiple individual predictors.
-
-
-Use of REVEL (Ioannidis 
-et al.
- 2016
-13
-) is recommended at thresholds of 
-≥0.70 for PP3
-.
-
-
-Clinical judgment is needed if any individual algorithms or conservation data are contradictory to REVEL data.
-
-
-Positive predictive value for benign/no impact predictions is generally higher than for pathogenic/impact predictions.
-
-
-SpliceAI
-14
- is recommended for evaluation of predicted splice impacts.",Disease-specific
-TNNI3 (HGNC:11947),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-TNNI3 (HGNC:11947),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-TNNI3 (HGNC:11947),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-TNNI3 (HGNC:11947),BA1,Stand Alone,"Allele frequency is 
-≥0.001
- based on the 
-filtering allele frequency (FAF)
- in 
-gnomAD
- in the subpopulation with the highest frequency (popmax).
-
-
-The values used to calculate the BA1 threshold were derived from studies in Northern European populations that have been relatively well-characterized with regards to disease prevalence and variant spectrum. These thresholds can be applied to any population where disease prevalence is considered comparable (1/300 or lower).
-
-
-The threshold is applicable when assessing variants in the context of autosomal dominant cardiomyopathy. 
-
-
-gnomAD is the preferred database for this calculation. If a subpopulation specific FAF other than the popmax is needed, this value can be calculated using the AlleleFrequencyApp on the 
-CardioDB website
-.
-
-
-
-
-Using the Inverse AF tab, enter in the population size and the number of alleles identified and it will calculate the FAF.  
-
-
-Set confidence to 0.95 (95%).
-
-
-If the FAF is ≥0.001, this rule can be applied.
-
-
-
-
-The FAF by platform (e.g., exome vs. genome; v.2.1.1 vs. v.3.1.1) should be considered, the larger population is most likely to have the most accurate representation of “true” population allele frequency.
-
-
-Caution is needed when considering any population cohorts that are smaller than the smallest subpopulations within gnomAD v.2.1.1 (e.g., ~5000 individuals or ~10,000 alleles). Despite this conservative nature of this threshold and approach, in smaller cohorts, the observed allele frequency may less accurately reflect the true allele frequency. Traditionally, once a variant is classified as Benign, it is rarely re-evaluated and so the highest confidence is needed to establish that classification on an allele frequency alone.",Disease-specific
-TNNI3 (HGNC:11947),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-TNNI3 (HGNC:11947),BS1,Strong,"Allele frequency is 
-≥0.0001 for
- 
-TNNI3
- based on the 
-filtering allele frequency (FAF)
- in 
-gnomAD
- in the subpopulation with the highest frequency (popmax).
-
-
-Criterion BS1 may only be used as standalone evidence to classify a variant as Likely Benign in the absence of conflicting data. See SVI guidance (Tavtigian 
-et al.
- 2018
-15
-; Tavtigian 
-et al.
- 2020
-16
-). 
-
-
-See BA1 for additional specifications that also apply to BS1.","Disease-specific,Gene-specific"
-TNNI3 (HGNC:11947),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",NA
-TNNI3 (HGNC:11947),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-TNNI3 (HGNC:11947),BS3,Strong,See PS3 specifications.,Disease-specific
-TNNI3 (HGNC:11947),BS3,Moderate,See PS3 specifications.,Disease-specific
-TNNI3 (HGNC:11947),BS3,Supporting,See PS3 specifications.,Disease-specific
-TNNI3 (HGNC:11947),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-TNNI3 (HGNC:11947),BS4,Strong,"Any non-segregations should be carefully evaluated to rule out a phenocopy or the presence of a second disease-causing variant before considering it as conflicting or benign evidence. 
-
-
-
-
-The presence of “phenocopies” (e.g., athlete’s heart, hypertensive heart disease, ischemic cardiomyopathy, alcoholic cardiomyopathy, diabetic cardiomyopathy) can mimic non-segregation (i.e., lack of segregation) among affected individuals. 
-
-
-Families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent ‘non-segregation’.
-
-
-
-
-Because of these possibilities, 
-multiple (≥2) non-segregations
- that are highly unlikely to be phenocopies or due to alternate variants (e.g., those without a possible alternate cause) 
-are required to apply this rule
-.  A higher number of non-segregations is necessary for instances where alternative causes are possible (e.g., non-segregation in a sibling with childhood onset cardiomyopathy versus a grandparent with hypertension and HCM).
-
-
-Careful consideration of the above points is required when using this data as conflicting evidence, especially when overall evidence supports likely pathogenic or pathogenic.",Disease-specific
-TNNI3 (HGNC:11947),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-TNNI3 (HGNC:11947),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-TNNI3 (HGNC:11947),BP2,Supporting,"Other variants must be pathogenic as defined by these specifications.
-
-
-Testing of parents or other informative relatives is often required to determine 
-cis
-/
-trans
- status.
-
-
-If a variant is seen in 
-trans
- (or as double heterozygous) with another pathogenic variant in ≥2 cases and the phenotype is not more severe than when either of the two variants are seen in isolation, this rule may be applied (i.e., high confidence this variant is NOT contributing to disease).
-
-
-
-
-<1% of cases of HCM have >1 pathogenic or likely pathogenic variant (0.6%; Alfares 
-et al.
- 2015
-17
-).
-
-
-
-
-This rule cannot be applied when the variant has only been observed in 
-cis
- with a pathogenic variant as its significance in isolation is unknown in this scenario. 
-
-
-Caution is needed if using this criterion as a primary piece of evidence for classifying a variant as likely benign/benign (i.e., only 2 SUPPORTING criteria are sufficient for a likely benign classification).",Disease-specific
-TNNI3 (HGNC:11947),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-TNNI3 (HGNC:11947),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-TNNI3 (HGNC:11947),BP4,Supporting,"As many 
-in silico
- algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. Meta-predictors, such as REVEL, are preferred over multiple individual predictors.
-
-
-Use of REVEL (Ioannidis et al. 2016
-13
-) is recommended at thresholds of 
-≤0.40 for BP4
-.
-
-
-Clinical judgment is needed if any individual algorithms or conservation data are contradictory to REVEL data.
-
-
-Positive predictive value for benign/no impact predictions is generally higher than for pathogenic/impact predictions.
-
-
-SpliceAI
-14
- is recommended for evaluation of predicted splice impacts.",Disease-specific
-TNNI3 (HGNC:11947),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-TNNI3 (HGNC:11947),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-TNNI3 (HGNC:11947),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-TNNI3 (HGNC:11947),BP7,Supporting,"Also applicable to 
-intronic variants outside the splice consensus sequence (-4 and +7 outward)
- for which splicing prediction algorithms predict no impact to the splice consensus sequence NOR the creation of a new splice site AND the nucleotide is not highly conserved.
-
-
-Rule can be combined with BP4 to make a variant likely benign per Richards 
-et al.
- 2015
-1
-.",General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTNNT2Version1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTNNT2Version1.0.0_version=1.0.0.csv
deleted file mode 100644
index 919d24eb1b19ee29f843355574385a5ea16ab9df..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTNNT2Version1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,897 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-TNNT2 (HGNC:11949),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-TNNT2 (HGNC:11949),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-TNNT2 (HGNC:11949),PS1,Strong,"No cardiomyopathy specifications. Apply as outlined by Richards 
-et al
-. 2015
-1
-.
-
-
-Example of when rule should NOT be applied. NM_000256.3(
-MYBPC3
-): c.2308G>A (p.Asp770Asn) has an established impact on splicing leading to nonsense mediated decay (NMD) and should not be used to provide evidence for other variants observed to result in the same amino acid change.",No change
-TNNT2 (HGNC:11949),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-TNNT2 (HGNC:11949),PS2,Strong,"Refer to SVI guidance on number/combination of cases required based on phenotype specificity
-2
-.
-
-
-For most cardiomyopathies, it is recommended to default to 
-Phenotype consistency: “Phenotype consistent with gene but not highly specific”
-. Clinical judgment is required for shifting to a higher or lower category. 
-
-
-For use as a STRONG or VERY STRONG criterion, ideally parents have been thoroughly clinically evaluated without evidence of cardiomyopathy (ideally using a combination of ECG and echocardiogram or cardiac MRI for maximum sensitivity).
-
-
-A family history consistent with 
-de novo
- inheritance should not have any clinical signs or symptoms suggestive of cardiomyopathy in a 1
-st
- or 2
-nd
- degree relative, for example: 
-
-
-
-
-Sudden death under 60 years of age
-
-
-Heart transplant
-
-
-Implantable cardiac defibrillator (ICD) under 60 years of age
-
-
-Features of cardiomyopathy (e.g., systolic dysfunction, hypertrophy, left ventricular enlargement in an individual without risk factors).
-
-
-Other related/overlapping cardiomyopathies
-
-
-
-
-Examples of non-suspicious family history may include non-specific clinical features (e.g., palpitations, syncope, borderline/inconclusive echocardiogram findings, heart attack if age appropriate and suspected to result from coronary artery disease), but every attempt should be made to clarify features. 
-
-
-Generally, this criterion is only applicable in the ABSENCE of any other possible disease-causing variants.  If other pathogenic or likely pathogenic variants are present, consider decreasing points assigned or overall weight.",Disease-specific
-TNNT2 (HGNC:11949),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-TNNT2 (HGNC:11949),PS3,Strong,"In vitro splicing assays (e.g., RNA studies)
-
-
-In vitro
- splicing assays may be considered as 
-STRONG
- evidence, providing the following criteria are met.
-
-
-
-
-Prior knowledge of predominant transcripts in cardiac tissue
-
-
-
-
-Analysis undertaken using RNA extracted from cardiac tissue from the individual with the variant
-
-
-Analysis undertaken using RNA extracted from whole blood providing the relevant transcripts (isoforms) are expressed in blood and are at sufficient levels to assess splice disruption.
-
-
-Assay shows a clear, reproducible and convincing effect on splicing (i.e. a distinct splice product, present at a level comparable to the splice product from the wild-type allele), which is not observed in controls
-
-
-
-
-Confirmation of abnormal splice product by Sanger sequencing
-
-
-
-
-NOTE:
- Mini-gene assay in non-patient derived cell lines are NOT considered to provide STRONG evidence.
-
-
-NOTE:
-  Whether to activate this rule needs to be reconciled with the variant spectrum and disease mechanism for the gene at hand (i.e., consider whether the effect is likely to lead to LOF or an in-frame alteration and whether this type of effect is expected to be disease causing) (Abou Tayoun 
-et al.
- 2018
-3
-).",Disease-specific
-TNNT2 (HGNC:11949),PS3,Moderate,"In vivo models (e.g., variant knock-in animal models)
-
-
-Mammalian variant-specific knock-in animal models that produce a phenotype consistent with the clinical phenotype in humans (e.g., structural and/or functional cardiac abnormalities, premature death, arrhythmia) may be considered as 
-MODERATE
- evidence
-
-
-NOTE:
- The following assays/models do NOT meet criteria
-
-
-
-
-Assays that are known to be associated with non-specific cardiac phenotypes (e.g., morpholino-induced pericardial edema in zebrafish)
-
-
-In vivo evidence that is not variant specific, such as whole gene alterations (i.e., cDNA or whole gene transgenic mice and whole or partial gene knock-out mice)",Disease-specific
-TNNT2 (HGNC:11949),PS3,Supporting,"In vitro
- 
-assays (e.g., biochemical assays of myofilament function, motility assays, human iPSC-CM)
-
-
-While some 
-in vitro
- assays may provide evidence that a variant in a cardiomyopathy gene has an effect on protein and/or myofilament function, at present, there are no validated “gold-standard” assays that are considered to reliably predict the clinical phenotype.
-
-
-As such, in the cardiomyopathy genes listed in these guidelines, data from individual 
-in vitro
- studies are unlikely to meet the criteria required to assign this rule at more than SUPPORTING level.",Disease-specific
-TNNT2 (HGNC:11949),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-TNNT2 (HGNC:11949),PS4,Strong,"Currently few well-designed case-control studies have been performed for inherited cardiomyopathies.  Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). 
-
-
-Cohorts used in these analyses should meet the following criteria: 
-
-
-
-
-The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype*). 
-
-
-When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded.  This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).
-
-
-
-
-
-
-The controls should not be derived from study populations that might be enriched for the specified disorder.
-
-
-The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).
-
-
-The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).
-
-
-The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).
-
-
-The population diversity of the case and control cohorts are broadly similar.
-
-
-Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh 
-et al.
- 2017
-5
-, 
-DECIPHER
-).
-
-
-
-
-To account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:
-
-
-
-
-STRONG
- evidence requires the lower bound of the 95% confidence interval (CI) around the odds ratio (OR) estimate to be 
-≥20
-
-
-
-
-A PS4 calculator is available at 
-www.cardiodb.org
-.
-
-
-If multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered).  
-
-
-*RELEVANT PHENOTYPES:
-
-
-
-
-Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. 
-
-
-For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. 
-
-
-Additional considerations for LVNC and end-stage HCM: 
-
-
-Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson 
-et al.
- 2017
-6
-; Oechslin 
-et al.
- 2017
-7
-; Hershberger 
-et al.
- 2017
-8
-; Ross 
-et al.
- 2020
-9
-), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).
-
-
-
-
-
-
-
-
-HCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",Disease-specific
-TNNT2 (HGNC:11949),PS4,Moderate,"Currently few well-designed case-control studies have been performed for inherited cardiomyopathies.  Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). 
-
-
-Cohorts used in these analyses should meet the following criteria: 
-
-
-
-
-The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype*). 
-
-
-When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded.  This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).
-
-
-
-
-
-
-The controls should not be derived from study populations that might be enriched for the specified disorder.
-
-
-The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).
-
-
-The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).
-
-
-The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).
-
-
-The population diversity of the case and control cohorts are broadly similar.
-
-
-Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh 
-et al.
- 2017
-5
-, 
-DECIPHER
-).
-
-
-
-
-To account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:
-
-
-
-
-MODERATE
- evidence requires the lower bound of the 95% CI around the OR to be 
-≥10
-
-
-
-
-A PS4 calculator is available at 
-www.cardiodb.org
-.
-
-
-If multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered).  
-
-
-*RELEVANT PHENOTYPES:
-
-
-
-
-Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. 
-
-
-For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. 
-
-
-Additional considerations for LVNC and end-stage HCM: 
-
-
-Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson 
-et al.
- 2017
-6
-; Oechslin 
-et al.
- 2017
-7
-; Hershberger 
-et al.
- 2017
-8
-; Ross 
-et al.
- 2020
-9
-), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).
-
-
-
-
-
-
-
-
-HCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",Disease-specific
-TNNT2 (HGNC:11949),PS4,Supporting,"Currently few well-designed case-control studies have been performed for inherited cardiomyopathies.  Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). 
-
-
-Cohorts used in these analyses should meet the following criteria: 
-
-
-
-
-The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype*). 
-
-
-When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded.  This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).
-
-
-
-
-
-
-The controls should not be derived from study populations that might be enriched for the specified disorder.
-
-
-The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).
-
-
-The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).
-
-
-The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).
-
-
-The population diversity of the case and control cohorts are broadly similar.
-
-
-Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh 
-et al.
- 2017
-5
-, 
-DECIPHER
-).
-
-
-
-
-To account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:
-
-
-
-
-SUPPORTING
- evidence requires the lower bound of the 95% CI around the OR to be 
-≥5
-
-
-
-
-A PS4 calculator is available at 
-www.cardiodb.org
-.
-
-
-If multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered).  
-
-
-*RELEVANT PHENOTYPES:
-
-
-
-
-Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. 
-
-
-For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. 
-
-
-Additional considerations for LVNC and end-stage HCM: 
-
-
-Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson 
-et al.
- 2017
-6
-; Oechslin 
-et al.
- 2017
-7
-; Hershberger 
-et al.
- 2017
-8
-; Ross 
-et al.
- 2020
-9
-), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).
-
-
-
-
-
-
-
-
-HCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",Disease-specific
-TNNT2 (HGNC:11949),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-TNNT2 (HGNC:11949),PM1,Supporting,"Applicable to missense variants in 
-TNNT2
- in the specific regions listed below (Walsh 
-et al.
- 2019
-10
-). 
-
-
-
-
-Transcripts ENST00000367318 with codons 79-179
-
-
-ENST00000656932.1 and NM_001276345.2 with codons 89-189
-
-
-
-
-Data from HCM case cohorts was used to derive these cluster regions. Therefore, this rule should NOT be applied when additional evidence for the variant supports that the variant causes a phenotype other than HCM (e.g., variant seen in multiple DCM cases).
-
-
-Enrichment was not observed for DCM in any genes.
-
-
-Rule should NOT be combined with PM5 because presence of pathogenic variants in the same codon/region were used to determine clustering and would be double-counting evidence.","Disease-specific,Gene-specific"
-TNNT2 (HGNC:11949),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-TNNT2 (HGNC:11949),PM2,Supporting,"The values used to calculate the PM2 thresholds were derived from studies in Northern European populations that have been relatively well-characterized with regards to disease prevalence and variant spectrum. These thresholds can be applied to any population where disease prevalence is considered comparable (1/500 or lower), where the most frequent pathogenic variant accounts for no more than 2% of cases (e.g., has an allele frequency of ≤0.02 in cases based on the upper bound of 95% CI), and where the penetrance of a pathogenic variant is expected to be at least 50% (Kelly 
-et al.
- 2018
-11
-).
-
-
-A threshold of 
-≤0.00004
- in the subpopulation with the highest frequency when using the upper bound of the 95% CI activates this rule.
-
-
-
-
-Alternatively, this is equivalent to the variant NOT being observed more than once (≤1 allele) in gnomAD v.2.1.1 in one of the non-founder populations (e.g., absence required from the Other and Ashkenazi Jewish subpopulations).
-
-
-Applying a threshold of ≤0.00004 (upper bound of 95% CI of the allele frequency in gnomAD) is equivalent to the variant being seen in a single subpopulation and that subpopulation meets any of the following:
-
-
-Allele Count (AC) in Allele Number (AN)
-
-
-≤1 in ≥120,000
-
-
-≤2 in ≥160,000
-
-
-≤3 in ≥195,000
-
-
-≤4 in ≥230,000
-
-
-
-
-
-
-
-
-gnomAD is the preferred database for this calculation, but currently only displays the filtering allele frequency (FAF), which is equivalent to a lower bound estimate of the 95% CI, when the upper bound is what is needed.
-
-
-
-
-Confidence interval tools, such as 
-Confit-de-MAF
-, can be used to determine the upper bound of the 95% CI of the observed allele frequency.
-
-
-
-
-Due to current technical limitations of next generation sequencing technologies, minor allele frequencies for complex variants (e.g., large indels) may not be accurately represented in population databases.
-
-
-Caution should be used when a variant is only identified, or over-represented, in one of the smaller gnomAD populations, as the gnomAD allele frequencies may not accurately represent the true population frequency.
-
-
-Population databases may contain affected or pre-symptomatic individuals for diseases with reduced penetrance/variable onset.",Disease-specific
-TNNT2 (HGNC:11949),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-TNNT2 (HGNC:11949),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-TNNT2 (HGNC:11949),PM4,Moderate,"Strength of rule should be carefully considered and may require downgrading to SUPPORTING based on the predicted impact of the variant, including the size of the deletion/insertion, its location, and conservation of the region. 
-
-
-For genes where PVS1 is not applicable (i.e., where there is no evidence that pLOF variants cause disease), consider using this rule at MODERATE or SUPPORTING strength for truncating variants that do NOT undergo nonsense mediated decay (NMD).",General recommendation
-TNNT2 (HGNC:11949),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-TNNT2 (HGNC:11949),PM5,Moderate,"This criterion can be used at MODERATE if a different missense variant at the same codon has been classified as 
-pathogenic
- using these modified guidelines without application of PM5.
-
-
-The impact of the amino acid change being evaluated needs to be compared to the impact of the amino acid change that is established as pathogenic (e.g., a change of Ala to His is less severe than Ala to Cys change). Consider reducing the strength of this rule to SUPPORTING if the predicted impact is not expected to be equivalent or more severe.
-
-
-PM5 should not be combined with PM1.  If both are applicable at MODERATE weight, use of PM5 is most appropriate since it is variant specific.",General recommendation
-TNNT2 (HGNC:11949),PM5,Supporting,"This criterion can be considered at SUPPORTING if a different missense variant at the same codon has been classified as 
-likely pathogenic
- using these modified guidelines without application of PM5.
-
-
-The impact of the amino acid change being evaluated needs to be compared to the impact of the amino acid change that is established as likely pathogenic (e.g., a change of Ala to His is less severe than Ala to Cys change). Consider reducing the strength of this rule to NOT APPLICABLE if the predicted impact is not expected to be equivalent or more severe.
-
-
-PM5 should not be combined with PM1.  The one with the higher strength should be applied, but if both are applicable at SUPPORTING weight, use of PM5 is most appropriate since it is variant specific.",General recommendation
-TNNT2 (HGNC:11949),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-TNNT2 (HGNC:11949),PM6,Moderate,"Refer to SVI guidance on number/combination of cases required based on phenotype specificity
-2
-.
-
-
-For most cardiomyopathies, it is recommended to default to “phenotype consistent with gene but not highly specific”. Clinical judgment is required for shifting to a higher or lower phenotypic consistency. 
-
-
-See PS2 for additional considerations.",Disease-specific
-TNNT2 (HGNC:11949),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-TNNT2 (HGNC:11949),PP1,Strong,"Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at 
-≥7
- 
-segregations
- (LOD score of 2.1) for 
-STRONG
-.
-
-
-Although rare for inherited cardiomyopathies, when the phenotype/presentation of a variant within and across families is highly specific (e.g., early-onset severe RCM in all affected individuals), the following thresholds as proposed by Jarvik and Browning (2016)
-12
- can be considered: 
-
-
-
-
-STRONG evidence requires ≥5 segregations (LOD score of 1.5)
-
-
-
-
-Only genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance.
-
-
-Phenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis.  
-
-
-Important considerations include:
-
-
-
-
-Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant.  If linkage disequilibrium is a concern, consider downgrading strength of segregation. 
-
-
-Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1.
-
-
-Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. 
-
-
-Caution is needed when distantly related (≥3
-rd
- degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).",Disease-specific
-TNNT2 (HGNC:11949),PP1,Moderate,"Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at 
-≥5
- 
-segregations
- (LOD score of 1.5) for 
-MODERATE
-.
-
-
-Although rare for inherited cardiomyopathies, when the phenotype/presentation of a variant within and across families is highly specific (e.g., early-onset severe RCM in all affected individuals), the following thresholds as proposed by Jarvik and Browning (2016)
-12
- can be considered: 
-
-
-
-
-MODERATE evidence requires ≥4 segregations (LOD score of 1.2)
-
-
-
-
-Only genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance.
-
-
-Phenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis.  
-
-
-Important considerations include:
-
-
-
-
-Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant.  If linkage disequilibrium is a concern, consider downgrading strength of segregation. 
-
-
-Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1 (see below).
-
-
-Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. 
-
-
-Caution is needed when distantly related (≥3
-rd
- degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).",Disease-specific
-TNNT2 (HGNC:11949),PP1,Supporting,"Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at 
-≥3
- 
-segregations
- (LOD score of 0.9) for 
-SUPPORTING
-. The thresholds as proposed by Jarvik and Browning (2016)
-12
- are the same at ≥3 segregations (LOD score of 0.9) for supporting.
-
-
-Only genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance.
-
-
-Phenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis.  
-
-
-Important considerations include:
-
-
-
-
-Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant.  If linkage disequilibrium is a concern, consider downgrading strength of segregation. 
-
-
-Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1 (see below).
-
-
-Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. 
-
-
-Caution is needed when distantly related (≥3
-rd
- degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).",Disease-specific
-TNNT2 (HGNC:11949),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-TNNT2 (HGNC:11949),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-TNNT2 (HGNC:11949),PP3,Supporting,"As many 
-in silico
- algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. Meta-predictors, such as REVEL, are preferred over multiple individual predictors.
-
-
-Use of REVEL (Ioannidis 
-et al.
- 2016
-13
-) is recommended at thresholds of 
-≥0.70 for PP3
-.
-
-
-Clinical judgment is needed if any individual algorithms or conservation data are contradictory to REVEL data.
-
-
-Positive predictive value for benign/no impact predictions is generally higher than for pathogenic/impact predictions.
-
-
-SpliceAI
-14
- is recommended for evaluation of predicted splice impacts.",Disease-specific
-TNNT2 (HGNC:11949),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-TNNT2 (HGNC:11949),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-TNNT2 (HGNC:11949),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-TNNT2 (HGNC:11949),BA1,Stand Alone,"Allele frequency is 
-≥0.001
- based on the 
-filtering allele frequency (FAF)
- in 
-gnomAD
- in the subpopulation with the highest frequency (popmax).
-
-
-The values used to calculate the BA1 threshold were derived from studies in Northern European populations that have been relatively well-characterized with regards to disease prevalence and variant spectrum. These thresholds can be applied to any population where disease prevalence is considered comparable (1/300 or lower).
-
-
-The threshold is applicable when assessing variants in the context of autosomal dominant cardiomyopathy. 
-
-
-gnomAD is the preferred database for this calculation. If a subpopulation specific FAF other than the popmax is needed, this value can be calculated using the AlleleFrequencyApp on the 
-CardioDB website
-.
-
-
-
-
-Using the Inverse AF tab, enter in the population size and the number of alleles identified and it will calculate the FAF.  
-
-
-Set confidence to 0.95 (95%).
-
-
-If the FAF is ≥0.001, this rule can be applied.
-
-
-
-
-The FAF by platform (e.g., exome vs. genome; v.2.1.1 vs. v.3.1.1) should be considered, the larger population is most likely to have the most accurate representation of “true” population allele frequency.
-
-
-Caution is needed when considering any population cohorts that are smaller than the smallest subpopulations within gnomAD v.2.1.1 (e.g., ~5000 individuals or ~10,000 alleles). Despite this conservative nature of this threshold and approach, in smaller cohorts, the observed allele frequency may less accurately reflect the true allele frequency. Traditionally, once a variant is classified as Benign, it is rarely re-evaluated and so the highest confidence is needed to establish that classification on an allele frequency alone.",Disease-specific
-TNNT2 (HGNC:11949),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-TNNT2 (HGNC:11949),BS1,Strong,"Allele frequency is 
-≥0.0001 for
- 
-TNNT2
- based on the 
-filtering allele frequency (FAF)
- in 
-gnomAD
- in the subpopulation with the highest frequency (popmax).
-
-
-Criterion BS1 may only be used as standalone evidence to classify a variant as Likely Benign in the absence of conflicting data. See SVI guidance (Tavtigian 
-et al.
- 2018
-15
-; Tavtigian 
-et al.
- 2020
-16
-). 
-
-
-See BA1 for additional specifications that also apply to BS1.","Disease-specific,Gene-specific"
-TNNT2 (HGNC:11949),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",NA
-TNNT2 (HGNC:11949),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-TNNT2 (HGNC:11949),BS3,Strong,See PS3 specifications.,Disease-specific
-TNNT2 (HGNC:11949),BS3,Moderate,See PS3 specifications.,Disease-specific
-TNNT2 (HGNC:11949),BS3,Supporting,See PS3 specifications.,Disease-specific
-TNNT2 (HGNC:11949),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-TNNT2 (HGNC:11949),BS4,Strong,"Any non-segregations should be carefully evaluated to rule out a phenocopy or the presence of a second disease-causing variant before considering it as conflicting or benign evidence. 
-
-
-
-
-The presence of “phenocopies” (e.g., athlete’s heart, hypertensive heart disease, ischemic cardiomyopathy, alcoholic cardiomyopathy, diabetic cardiomyopathy) can mimic non-segregation (i.e., lack of segregation) among affected individuals. 
-
-
-Families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent ‘non-segregation’.
-
-
-
-
-Because of these possibilities, 
-multiple (≥2) non-segregations
- that are highly unlikely to be phenocopies or due to alternate variants (e.g., those without a possible alternate cause) 
-are required to apply this rule
-.  A higher number of non-segregations is necessary for instances where alternative causes are possible (e.g., non-segregation in a sibling with childhood onset cardiomyopathy versus a grandparent with hypertension and HCM).
-
-
-Careful consideration of the above points is required when using this data as conflicting evidence, especially when overall evidence supports likely pathogenic or pathogenic.",Disease-specific
-TNNT2 (HGNC:11949),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-TNNT2 (HGNC:11949),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-TNNT2 (HGNC:11949),BP2,Supporting,"Other variants must be pathogenic as defined by these specifications.
-
-
-Testing of parents or other informative relatives is often required to determine 
-cis
-/
-trans
- status.
-
-
-If a variant is seen in 
-trans
- (or as double heterozygous) with another pathogenic variant in ≥2 cases and the phenotype is not more severe than when either of the two variants are seen in isolation, this rule may be applied (i.e., high confidence this variant is NOT contributing to disease).
-
-
-
-
-<1% of cases of HCM have >1 pathogenic or likely pathogenic variant (0.6%; Alfares 
-et al.
- 2015
-17
-).
-
-
-
-
-This rule cannot be applied when the variant has only been observed in 
-cis
- with a pathogenic variant as its significance in isolation is unknown in this scenario. 
-
-
-Caution is needed if using this criterion as a primary piece of evidence for classifying a variant as likely benign/benign (i.e., only 2 SUPPORTING criteria are sufficient for a likely benign classification).",Disease-specific
-TNNT2 (HGNC:11949),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-TNNT2 (HGNC:11949),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-TNNT2 (HGNC:11949),BP4,Supporting,"As many 
-in silico
- algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. Meta-predictors, such as REVEL, are preferred over multiple individual predictors.
-
-
-Use of REVEL (Ioannidis et al. 2016
-13
-) is recommended at thresholds of 
-≤0.40 for BP4
-.
-
-
-Clinical judgment is needed if any individual algorithms or conservation data are contradictory to REVEL data.
-
-
-Positive predictive value for benign/no impact predictions is generally higher than for pathogenic/impact predictions.
-
-
-SpliceAI
-14
- is recommended for evaluation of predicted splice impacts.",Disease-specific
-TNNT2 (HGNC:11949),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-TNNT2 (HGNC:11949),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-TNNT2 (HGNC:11949),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-TNNT2 (HGNC:11949),BP7,Supporting,"Also applicable to 
-intronic variants outside the splice consensus sequence (-4 and +7 outward)
- for which splicing prediction algorithms predict no impact to the splice consensus sequence NOR the creation of a new splice site AND the nucleotide is not highly conserved.
-
-
-Rule can be combined with BP4 to make a variant likely benign per Richards 
-et al.
- 2015
-1
-.",General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTPM1Version1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTPM1Version1.0.0_version=1.0.0.csv
deleted file mode 100644
index a30377cc0d01023e9b065e0dea0931d59e04e32e..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTPM1Version1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,898 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-TPM1 (HGNC:12010),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-TPM1 (HGNC:12010),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-TPM1 (HGNC:12010),PS1,Strong,"No cardiomyopathy specifications. Apply as outlined by Richards 
-et al
-. 2015
-1
-.
-
-
-Example of when rule should NOT be applied. NM_000256.3(
-MYBPC3
-): c.2308G>A (p.Asp770Asn) has an established impact on splicing leading to nonsense mediated decay (NMD) and should not be used to provide evidence for other variants observed to result in the same amino acid change.",No change
-TPM1 (HGNC:12010),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-TPM1 (HGNC:12010),PS2,Strong,"Refer to SVI guidance on number/combination of cases required based on phenotype specificity
-2
-.
-
-
-For most cardiomyopathies, it is recommended to default to 
-Phenotype consistency: “Phenotype consistent with gene but not highly specific”
-. Clinical judgment is required for shifting to a higher or lower category. 
-
-
-For use as a STRONG or VERY STRONG criterion, ideally parents have been thoroughly clinically evaluated without evidence of cardiomyopathy (ideally using a combination of ECG and echocardiogram or cardiac MRI for maximum sensitivity).
-
-
-A family history consistent with 
-de novo
- inheritance should not have any clinical signs or symptoms suggestive of cardiomyopathy in a 1
-st
- or 2
-nd
- degree relative, for example: 
-
-
-
-
-Sudden death under 60 years of age
-
-
-Heart transplant
-
-
-Implantable cardiac defibrillator (ICD) under 60 years of age
-
-
-Features of cardiomyopathy (e.g., systolic dysfunction, hypertrophy, left ventricular enlargement in an individual without risk factors).
-
-
-Other related/overlapping cardiomyopathies
-
-
-
-
-Examples of non-suspicious family history may include non-specific clinical features (e.g., palpitations, syncope, borderline/inconclusive echocardiogram findings, heart attack if age appropriate and suspected to result from coronary artery disease), but every attempt should be made to clarify features. 
-
-
-Generally, this criterion is only applicable in the ABSENCE of any other possible disease-causing variants.  If other pathogenic or likely pathogenic variants are present, consider decreasing points assigned or overall weight.",Disease-specific
-TPM1 (HGNC:12010),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-TPM1 (HGNC:12010),PS3,Strong,"In vitro splicing assays (e.g., RNA studies)
-
-
-In vitro
- splicing assays may be considered as 
-STRONG
- evidence, providing the following criteria are met.
-
-
-
-
-Prior knowledge of predominant transcripts in cardiac tissue
-
-
-
-
-Analysis undertaken using RNA extracted from cardiac tissue from the individual with the variant
-
-
-Analysis undertaken using RNA extracted from whole blood providing the relevant transcripts (isoforms) are expressed in blood and are at sufficient levels to assess splice disruption.
-
-
-Assay shows a clear, reproducible and convincing effect on splicing (i.e. a distinct splice product, present at a level comparable to the splice product from the wild-type allele), which is not observed in controls
-
-
-
-
-Confirmation of abnormal splice product by Sanger sequencing
-
-
-
-
-NOTE:
- Mini-gene assay in non-patient derived cell lines are NOT considered to provide STRONG evidence.
-
-
-NOTE:
-  Whether to activate this rule needs to be reconciled with the variant spectrum and disease mechanism for the gene at hand (i.e., consider whether the effect is likely to lead to LOF or an in-frame alteration and whether this type of effect is expected to be disease causing) (Abou Tayoun 
-et al.
- 2018
-3
-).",Disease-specific
-TPM1 (HGNC:12010),PS3,Moderate,"In vivo models (e.g., variant knock-in animal models)
-
-
-Mammalian variant-specific knock-in animal models that produce a phenotype consistent with the clinical phenotype in humans (e.g., structural and/or functional cardiac abnormalities, premature death, arrhythmia) may be considered as 
-MODERATE
- evidence
-
-
-NOTE:
- The following assays/models do NOT meet criteria
-
-
-
-
-Assays that are known to be associated with non-specific cardiac phenotypes (e.g., morpholino-induced pericardial edema in zebrafish)
-
-
-In vivo evidence that is not variant specific, such as whole gene alterations (i.e., cDNA or whole gene transgenic mice and whole or partial gene knock-out mice)",Disease-specific
-TPM1 (HGNC:12010),PS3,Supporting,"In vitro
- 
-assays (e.g., biochemical assays of myofilament function, motility assays, human iPSC-CM)
-
-
-While some 
-in vitro
- assays may provide evidence that a variant in a cardiomyopathy gene has an effect on protein and/or myofilament function, at present, there are no validated “gold-standard” assays that are considered to reliably predict the clinical phenotype.
-
-
-As such, in the cardiomyopathy genes listed in these guidelines, data from individual 
-in vitro
- studies are unlikely to meet the criteria required to assign this rule at more than SUPPORTING level.",Disease-specific
-TPM1 (HGNC:12010),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-TPM1 (HGNC:12010),PS4,Strong,"Currently few well-designed case-control studies have been performed for inherited cardiomyopathies.  Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). 
-
-
-Cohorts used in these analyses should meet the following criteria: 
-
-
-
-
-The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype*). 
-
-
-When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded.  This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).
-
-
-
-
-
-
-The controls should not be derived from study populations that might be enriched for the specified disorder.
-
-
-The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).
-
-
-The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).
-
-
-The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).
-
-
-The population diversity of the case and control cohorts are broadly similar.
-
-
-Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh 
-et al.
- 2017
-5
-, 
-DECIPHER
-).
-
-
-
-
-To account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:
-
-
-
-
-STRONG
- evidence requires the lower bound of the 95% confidence interval (CI) around the odds ratio (OR) estimate to be 
-≥20
-
-
-
-
-A PS4 calculator is available at 
-www.cardiodb.org
-.
-
-
-If multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered).  
-
-
-*RELEVANT PHENOTYPES:
-
-
-
-
-Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. 
-
-
-For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. 
-
-
-Additional considerations for LVNC and end-stage HCM: 
-
-
-Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson 
-et al.
- 2017
-6
-; Oechslin 
-et al.
- 2017
-7
-; Hershberger 
-et al.
- 2017
-8
-; Ross 
-et al.
- 2020
-9
-), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).
-
-
-
-
-
-
-
-
-HCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",Disease-specific
-TPM1 (HGNC:12010),PS4,Moderate,"Currently few well-designed case-control studies have been performed for inherited cardiomyopathies.  Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). 
-
-
-Cohorts used in these analyses should meet the following criteria: 
-
-
-
-
-The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype*). 
-
-
-When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded.  This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).
-
-
-
-
-
-
-The controls should not be derived from study populations that might be enriched for the specified disorder.
-
-
-The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).
-
-
-The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).
-
-
-The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).
-
-
-The population diversity of the case and control cohorts are broadly similar.
-
-
-Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh 
-et al.
- 2017
-5
-, 
-DECIPHER
-).
-
-
-
-
-To account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:
-
-
-
-
-MODERATE
- evidence requires the lower bound of the 95% CI around the OR to be 
-≥10
-
-
-
-
-A PS4 calculator is available at 
-www.cardiodb.org
-.
-
-
-If multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered).  
-
-
-*RELEVANT PHENOTYPES:
-
-
-
-
-Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. 
-
-
-For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. 
-
-
-Additional considerations for LVNC and end-stage HCM: 
-
-
-Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson 
-et al.
- 2017
-6
-; Oechslin 
-et al.
- 2017
-7
-; Hershberger 
-et al.
- 2017
-8
-; Ross 
-et al.
- 2020
-9
-), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).
-
-
-
-
-
-
-
-
-HCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",Disease-specific
-TPM1 (HGNC:12010),PS4,Supporting,"Currently few well-designed case-control studies have been performed for inherited cardiomyopathies.  Until such studies become available, comparative analyses can be undertaken using case data (e.g., internal and/or published cohorts) and control data from population-level cohorts (e.g., gnomAD). 
-
-
-Cohorts used in these analyses should meet the following criteria: 
-
-
-
-
-The cases have a clinical diagnosis of the specified disorder or related phenotype (e.g., all cases have HCM or another relevant phenotype*). 
-
-
-When assessing cases, it's important to consider how likely another potential cause of the phenotype has been excluded.  This includes considering the presence of other variants in relevant genes (particularly those likely to be contributing to phenotype) and the extent of testing performed (i.e., single gene sequencing, panel testing, whole exome/genome sequencing).
-
-
-
-
-
-
-The controls should not be derived from study populations that might be enriched for the specified disorder.
-
-
-The denominator of the cohorts must be available (e.g., variant detected in 5 out of 3,500 cases and 1 out of 60,000 controls).
-
-
-The cohorts do not include closely related individuals (i.e., family members are not included in the case counts).
-
-
-The cohorts do not overlap with other cohorts being used in the analysis (i.e., cases are not being counted more than once).
-
-
-The population diversity of the case and control cohorts are broadly similar.
-
-
-Consider the size of the case cohort — larger cohorts are likely to provide more accurate estimates of variant frequency; therefore, it may be preferable to use data from the largest available case series for case-control analyses (e.g., Walsh 
-et al.
- 2017
-5
-, 
-DECIPHER
-).
-
-
-
-
-To account for limitations that arise when performing unmatched case-control analyses, the following stringent OR threshold is recommended:
-
-
-
-
-SUPPORTING
- evidence requires the lower bound of the 95% CI around the OR to be 
-≥5
-
-
-
-
-A PS4 calculator is available at 
-www.cardiodb.org
-.
-
-
-If multiple cohorts are available, the final ORs and associated CIs need to be harmonized across all cohorts to determine the final level (e.g., if 2 large cohorts have an OR of ~6 and a third small cohort has an OR of 11, application at a SUPPORTING level should be considered).  
-
-
-*RELEVANT PHENOTYPES:
-
-
-
-
-Cases of HCM and RCM may be combined as they are considered part of the same disease spectrum. 
-
-
-For the eight genes covered by these guidelines, the combination of probands with other phenotypes should be reviewed by a clinical expert to determine if grouping is appropriate. 
-
-
-Additional considerations for LVNC and end-stage HCM: 
-
-
-Due to the current debate about whether isolated LVNC represents a true disease entity or variation of typical cardiac morphology (Anderson 
-et al.
- 2017
-6
-; Oechslin 
-et al.
- 2017
-7
-; Hershberger 
-et al.
- 2017
-8
-; Ross 
-et al.
- 2020
-9
-), individuals with isolated LVNC should NOT be added to proband or segregation counts (including individuals with isolated LVNC in a family with other cardiomyopathies).
-
-
-
-
-
-
-
-
-HCM and DCM have distinct mechanisms of disease and therefore pathogenetic variants are not anticipated to cause both primary phenotypes. While occurrence in both phenotypes may initially be considered as evidence against pathogenicity, end-stage HCM can present similarly to DCM. Careful consideration is needed before including DCM or related phenotypes in case or segregation data for primarily HCM variants.",Disease-specific
-TPM1 (HGNC:12010),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-TPM1 (HGNC:12010),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-TPM1 (HGNC:12010),PM2,Supporting,"The values used to calculate the PM2 thresholds were derived from studies in Northern European populations that have been relatively well-characterized with regards to disease prevalence and variant spectrum. These thresholds can be applied to any population where disease prevalence is considered comparable (1/500 or lower), where the most frequent pathogenic variant accounts for no more than 2% of cases (e.g., has an allele frequency of ≤0.02 in cases based on the upper bound of 95% CI), and where the penetrance of a pathogenic variant is expected to be at least 50% (Kelly 
-et al.
- 2018
-10
-).
-
-
-A threshold of 
-≤0.00004
- in the subpopulation with the highest frequency when using the upper bound of the 95% CI activates this rule.
-
-
-
-
-Alternatively, this is equivalent to the variant NOT being observed more than once (≤1 allele) in gnomAD v.2.1.1 in one of the non-founder populations (e.g., absence required from the Other and Ashkenazi Jewish subpopulations).
-
-
-Applying a threshold of ≤0.00004 (upper bound of 95% CI of the allele frequency in gnomAD) is equivalent to the variant being seen in a single subpopulation and that subpopulation meets any of the following:
-
-
-Allele Count (AC) in Allele Number (AN)
-
-
-≤1 in ≥120,000
-
-
-≤2 in ≥160,000
-
-
-≤3 in ≥195,000
-
-
-≤4 in ≥230,000
-
-
-
-
-
-
-
-
-gnomAD is the preferred database for this calculation, but currently only displays the filtering allele frequency (FAF), which is equivalent to a lower bound estimate of the 95% CI, when the upper bound is what is needed.
-
-
-
-
-Confidence interval tools, such as 
-Confit-de-MAF
-, can be used to determine the upper bound of the 95% CI of the observed allele frequency.
-
-
-
-
-Due to current technical limitations of next generation sequencing technologies, minor allele frequencies for complex variants (e.g., large indels) may not be accurately represented in population databases.
-
-
-Caution should be used when a variant is only identified, or over-represented, in one of the smaller gnomAD populations, as the gnomAD allele frequencies may not accurately represent the true population frequency.
-
-
-Population databases may contain affected or pre-symptomatic individuals for diseases with reduced penetrance/variable onset.",Disease-specific
-TPM1 (HGNC:12010),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-TPM1 (HGNC:12010),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-TPM1 (HGNC:12010),PM4,Moderate,"Strength of rule should be carefully considered and may require downgrading to SUPPORTING based on the predicted impact of the variant, including the size of the deletion/insertion, its location, and conservation of the region. 
-
-
-For genes where PVS1 is not applicable (i.e., where there is no evidence that pLOF variants cause disease), consider using this rule at MODERATE or SUPPORTING strength for truncating variants that do NOT undergo nonsense mediated decay (NMD).",General recommendation
-TPM1 (HGNC:12010),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-TPM1 (HGNC:12010),PM5,Moderate,"This criterion can be used at MODERATE if a different missense variant at the same codon has been classified as 
-pathogenic
- using these modified guidelines without application of PM5.
-
-
-The impact of the amino acid change being evaluated needs to be compared to the impact of the amino acid change that is established as pathogenic (e.g., a change of Ala to His is less severe than Ala to Cys change). Consider reducing the strength of this rule to SUPPORTING if the predicted impact is not expected to be equivalent or more severe.
-
-
-PM5 should not be combined with PM1.  If both are applicable at MODERATE weight, use of PM5 is most appropriate since it is variant specific.",General recommendation
-TPM1 (HGNC:12010),PM5,Supporting,"This criterion can be considered at SUPPORTING if a different missense variant at the same codon has been classified as 
-likely pathogenic
- using these modified guidelines without application of PM5.
-
-
-The impact of the amino acid change being evaluated needs to be compared to the impact of the amino acid change that is established as likely pathogenic (e.g., a change of Ala to His is less severe than Ala to Cys change). Consider reducing the strength of this rule to NOT APPLICABLE if the predicted impact is not expected to be equivalent or more severe.
-
-
-PM5 should not be combined with PM1.  The one with the higher strength should be applied, but if both are applicable at SUPPORTING weight, use of PM5 is most appropriate since it is variant specific.",General recommendation
-TPM1 (HGNC:12010),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-TPM1 (HGNC:12010),PM6,Moderate,"Refer to SVI guidance on number/combination of cases required based on phenotype specificity
-2
-.
-
-
-For most cardiomyopathies, it is recommended to default to “phenotype consistent with gene but not highly specific”. Clinical judgment is required for shifting to a higher or lower phenotypic consistency. 
-
-
-See PS2 for additional considerations.",Disease-specific
-TPM1 (HGNC:12010),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-TPM1 (HGNC:12010),PP1,Strong,"Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at 
-≥7
- 
-segregations
- (LOD score of 2.1) for 
-STRONG
-.
-
-
-Although rare for inherited cardiomyopathies, when the phenotype/presentation of a variant within and across families is highly specific (e.g., early-onset severe RCM in all affected individuals), the following thresholds as proposed by Jarvik and Browning (2016)
-11
- can be considered: 
-
-
-
-
-STRONG evidence requires ≥5 segregations (LOD score of 1.5)
-
-
-
-
-Only genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance.
-
-
-Phenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis.  
-
-
-Important considerations include:
-
-
-
-
-Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant.  If linkage disequilibrium is a concern, consider downgrading strength of segregation. 
-
-
-Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1.
-
-
-Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. 
-
-
-Caution is needed when distantly related (≥3
-rd
- degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).",Disease-specific
-TPM1 (HGNC:12010),PP1,Moderate,"Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at 
-≥5
- 
-segregations
- (LOD score of 1.5) for 
-MODERATE
-.
-
-
-Although rare for inherited cardiomyopathies, when the phenotype/presentation of a variant within and across families is highly specific (e.g., early-onset severe RCM in all affected individuals), the following thresholds as proposed by Jarvik and Browning (2016)
-11
- can be considered: 
-
-
-
-
-MODERATE evidence requires ≥4 segregations (LOD score of 1.2)
-
-
-
-
-Only genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance.
-
-
-Phenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis.  
-
-
-Important considerations include:
-
-
-
-
-Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant.  If linkage disequilibrium is a concern, consider downgrading strength of segregation. 
-
-
-Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1 (see below).
-
-
-Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. 
-
-
-Caution is needed when distantly related (≥3
-rd
- degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).",Disease-specific
-TPM1 (HGNC:12010),PP1,Supporting,"Due to the genotypic and phenotypic heterogeneity of inherited cardiomyopathies, segregation thresholds have been conservatively set at 
-≥3
- 
-segregations
- (LOD score of 0.9) for 
-SUPPORTING
-. The thresholds as proposed by Jarvik and Browning (2016)
-11
- are the same at ≥3 segregations (LOD score of 0.9) for supporting.
-
-
-Only genotype positive/phenotype positive individuals are counted as segregations, which can include affected obligate carriers. Genotype positive/phenotype negative individuals are generally less informative for cardiomyopathy genes due to variable age at onset and reduced penetrance.
-
-
-Phenotypes should be clinically confirmed, whenever possible, and should not include individuals with a suspected diagnosis.  
-
-
-Important considerations include:
-
-
-
-
-Segregation of a variant within a single family or haplotype has the potential to represent linkage disequilibrium with another undetected variant.  If linkage disequilibrium is a concern, consider downgrading strength of segregation. 
-
-
-Use of segregation criteria should be carefully evaluated if variant frequency meets criteria for BS1 (see below).
-
-
-Caution is needed when counting segregations in presence of other possible disease-causing variants, as both variants may be contributing to the phenotype. 
-
-
-Caution is needed when distantly related (≥3
-rd
- degree) affected individuals are connected by unknown or unaffected relatives (raises possibility of multiple causes of disease).",Disease-specific
-TPM1 (HGNC:12010),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,
-TPM1 (HGNC:12010),PP2,Supporting,"Application of this rule takes into consideration empirical data quantifying levels of rare missense variant enrichment in HCM referral cohorts compared to population-based cohorts (Walsh 
-et al.
- 2019
-12
-) rather than the missense constraint score in gnomAD. 
-
-
-On the basis of data from Walsh 
-et al.
- 2019
-12
-, 
-PP2 is currently
- 
-only applicable to
- 
-TPM1
- 
-for HCM
- (transcripts ENST00000403994 and NM_001018005.2)
-.
-
-
-Data from HCM case cohorts was used to derive these cluster regions. Therefore, this rule should NOT be applied when additional evidence for the variant supports that the variant causes a phenotype other than HCM (e.g., variant seen in multiple DCM cases).
-
-
-Enrichment was not observed for DCM in any genes.","Disease-specific,Gene-specific"
-TPM1 (HGNC:12010),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-TPM1 (HGNC:12010),PP3,Supporting,"As many 
-in silico
- algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. Meta-predictors, such as REVEL, are preferred over multiple individual predictors.
-
-
-Use of REVEL (Ioannidis 
-et al.
- 2016
-13
-) is recommended at thresholds of 
-≥0.70 for PP3
-.
-
-
-Clinical judgment is needed if any individual algorithms or conservation data are contradictory to REVEL data.
-
-
-Positive predictive value for benign/no impact predictions is generally higher than for pathogenic/impact predictions.
-
-
-SpliceAI
-14
- is recommended for evaluation of predicted splice impacts.",Disease-specific
-TPM1 (HGNC:12010),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-TPM1 (HGNC:12010),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-TPM1 (HGNC:12010),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-TPM1 (HGNC:12010),BA1,Stand Alone,"Allele frequency is 
-≥0.001
- based on the 
-filtering allele frequency (FAF)
- in 
-gnomAD
- in the subpopulation with the highest frequency (popmax).
-
-
-The values used to calculate the BA1 threshold were derived from studies in Northern European populations that have been relatively well-characterized with regards to disease prevalence and variant spectrum. These thresholds can be applied to any population where disease prevalence is considered comparable (1/300 or lower).
-
-
-The threshold is applicable when assessing variants in the context of autosomal dominant cardiomyopathy. 
-
-
-gnomAD is the preferred database for this calculation. If a subpopulation specific FAF other than the popmax is needed, this value can be calculated using the AlleleFrequencyApp on the 
-CardioDB website
-.
-
-
-
-
-Using the Inverse AF tab, enter in the population size and the number of alleles identified and it will calculate the FAF.  
-
-
-Set confidence to 0.95 (95%).
-
-
-If the FAF is ≥0.001, this rule can be applied.
-
-
-
-
-The FAF by platform (e.g., exome vs. genome; v.2.1.1 vs. v.3.1.1) should be considered, the larger population is most likely to have the most accurate representation of “true” population allele frequency.
-
-
-Caution is needed when considering any population cohorts that are smaller than the smallest subpopulations within gnomAD v.2.1.1 (e.g., ~5000 individuals or ~10,000 alleles). Despite this conservative nature of this threshold and approach, in smaller cohorts, the observed allele frequency may less accurately reflect the true allele frequency. Traditionally, once a variant is classified as Benign, it is rarely re-evaluated and so the highest confidence is needed to establish that classification on an allele frequency alone.",Disease-specific
-TPM1 (HGNC:12010),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-TPM1 (HGNC:12010),BS1,Strong,"Allele frequency is 
-≥0.0001 for
- 
-TPM1
- based on the 
-filtering allele frequency (FAF)
- in 
-gnomAD
- in the subpopulation with the highest frequency (popmax).
-
-
-Criterion BS1 may only be used as standalone evidence to classify a variant as Likely Benign in the absence of conflicting data. See SVI guidance (Tavtigian 
-et al.
- 2018
-15
-; Tavtigian 
-et al.
- 2020
-16
-). 
-
-
-See BA1 for additional specifications that also apply to BS1.","Disease-specific,Gene-specific"
-TPM1 (HGNC:12010),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",NA
-TPM1 (HGNC:12010),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-TPM1 (HGNC:12010),BS3,Strong,See PS3 specifications.,Disease-specific
-TPM1 (HGNC:12010),BS3,Moderate,See PS3 specifications.,Disease-specific
-TPM1 (HGNC:12010),BS3,Supporting,See PS3 specifications.,Disease-specific
-TPM1 (HGNC:12010),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-TPM1 (HGNC:12010),BS4,Strong,"Any non-segregations should be carefully evaluated to rule out a phenocopy or the presence of a second disease-causing variant before considering it as conflicting or benign evidence. 
-
-
-
-
-The presence of “phenocopies” (e.g., athlete’s heart, hypertensive heart disease, ischemic cardiomyopathy, alcoholic cardiomyopathy, diabetic cardiomyopathy) can mimic non-segregation (i.e., lack of segregation) among affected individuals. 
-
-
-Families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent ‘non-segregation’.
-
-
-
-
-Because of these possibilities, 
-multiple (≥2) non-segregations
- that are highly unlikely to be phenocopies or due to alternate variants (e.g., those without a possible alternate cause) 
-are required to apply this rule
-.  A higher number of non-segregations is necessary for instances where alternative causes are possible (e.g., non-segregation in a sibling with childhood onset cardiomyopathy versus a grandparent with hypertension and HCM).
-
-
-Careful consideration of the above points is required when using this data as conflicting evidence, especially when overall evidence supports likely pathogenic or pathogenic.",Disease-specific
-TPM1 (HGNC:12010),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-TPM1 (HGNC:12010),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-TPM1 (HGNC:12010),BP2,Supporting,"Other variants must be pathogenic as defined by these specifications.
-
-
-Testing of parents or other informative relatives is often required to determine 
-cis
-/
-trans
- status.
-
-
-If a variant is seen in 
-trans
- (or as double heterozygous) with another pathogenic variant in ≥2 cases and the phenotype is not more severe than when either of the two variants are seen in isolation, this rule may be applied (i.e., high confidence this variant is NOT contributing to disease).
-
-
-
-
-<1% of cases of HCM have >1 pathogenic or likely pathogenic variant (0.6%; Alfares 
-et al.
- 2015
-17
-).
-
-
-
-
-This rule cannot be applied when the variant has only been observed in 
-cis
- with a pathogenic variant as its significance in isolation is unknown in this scenario. 
-
-
-Caution is needed if using this criterion as a primary piece of evidence for classifying a variant as likely benign/benign (i.e., only 2 SUPPORTING criteria are sufficient for a likely benign classification).",Disease-specific
-TPM1 (HGNC:12010),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-TPM1 (HGNC:12010),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-TPM1 (HGNC:12010),BP4,Supporting,"As many 
-in silico
- algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. Meta-predictors, such as REVEL, are preferred over multiple individual predictors.
-
-
-Use of REVEL (Ioannidis et al. 2016
-13
-) is recommended at thresholds of 
-≤0.40 for BP4
-.
-
-
-Clinical judgment is needed if any individual algorithms or conservation data are contradictory to REVEL data.
-
-
-Positive predictive value for benign/no impact predictions is generally higher than for pathogenic/impact predictions.
-
-
-SpliceAI
-14
- is recommended for evaluation of predicted splice impacts.",Disease-specific
-TPM1 (HGNC:12010),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-TPM1 (HGNC:12010),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-TPM1 (HGNC:12010),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-TPM1 (HGNC:12010),BP7,Supporting,"Also applicable to 
-intronic variants outside the splice consensus sequence (-4 and +7 outward)
- for which splicing prediction algorithms predict no impact to the splice consensus sequence NOR the creation of a new splice site AND the nucleotide is not highly conserved.
-
-
-Rule can be combined with BP4 to make a variant likely benign per Richards 
-et al.
- 2015
-1
-.",General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGAMTVersion1.1.0_version=1.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGAMTVersion1.1.0_version=1.1.0.csv
deleted file mode 100644
index 9bc61a1079599a7ff529e0b0867236fe11877a0b..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGAMTVersion1.1.0_version=1.1.0.csv
+++ /dev/null
@@ -1,324 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-GAMT (HGNC:4136),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-GAMT (HGNC:4136),PVS1,Very Strong,"Nonsense-mediated decay predicted
-
-
-CCDS VCEP notes:
-Loss of function (LOF) of GAMT is a known mechanism of disease for guanidinoacetate methyltransferase deficiency (GAMT-D). There are examples of various LOF variants, including nonsense and frameshift, in GAMT in individuals with GAMT-D (
-https://databases.lovd.nl/shared/variants/GAMT/unique
-). The specifications below are based on the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042).
-
-
-Nonsense and frameshift variants
-* All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 6) or the last 50 bases of the penultimate exon of the gene (exon 5, c.520). In that case, PVS1_Strong or PVS1_Moderate will be applied, depending on whether >10% or <10% of the protein is lost.
-
-
-Splice site variants (+1, +2, -1, -2)
-* All canonical splice site pairs in GAMT are GT-AG.
-* For any canonical splice site variant (+1, +2, -1, -2), the exon immediately adjacent to the variant is predicted to be skipped i.e. upstream exon skipped for canonical donor splice site variants and downstream exon skipped for canonical acceptor splice site variants.
-* For the predicted in frame/out of frame consequences of exon skipping and assigned strength of PVS1, see 
-Appendix 1
-.
-* If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used.
-* To apply PVS1, splice site variants must have no detectable nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing. Otherwise, the PVS1 strength should be reduced accordingly.
-* Non-canonical splice variants, such as +3 or -3, will not meet PVS1, but could meet PS3 and/or PP3 criteria.
-
-
-Deletions (single or multi exon)
-* If a single or multi-exon deletion results in an out of frame consequence, use PVS1 unless not predicted to undergo NMD. If not predicted to undergo NMD, use PVS1_Strong if >10% of the protein is predicted to be removed, and use PVS1_Moderate if <10% of the protein is predicted to be removed.
-* If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. Use PVS1_Strong if more than 10% of the protein is removed and PVS1_Moderate if <10% of the protein is removed.
-* If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4.
-* 
-Appendix 1
- can be used to predict the consequences of single exon deletions.
-
-
-Duplications
-* Use the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042) to assess the impact of duplications.",None
-GAMT (HGNC:4136),PVS1,Strong,"In frame loss of >10% of the protein.
-
-
-CCDS VCEP notes:
-Loss of function (LOF) of GAMT is a known mechanism of disease for guanidinoacetate methyltransferase deficiency (GAMT-D). There are examples of various LOF variants, including nonsense and frameshift, in GAMT in individuals with GAMT-D (
-https://databases.lovd.nl/shared/variants/GAMT/unique
-). The specifications below are based on the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042).
-
-
-Nonsense and frameshift variants
-* All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 6) or the last 50 bases of the penultimate exon of the gene (exon 5, c.520). In that case, PVS1_Strong will be applied if >10% of the protein is lost.
-
-
-Splice site variants (+1, +2, -1, -2)
-* All canonical splice site pairs in GAMT are GT-AG.
-* For any canonical splice site variant (+1, +2, -1, -2), the exon immediately adjacent to the variant is predicted to be skipped i.e. upstream exon skipped for canonical donor splice site variants and downstream exon skipped for canonical acceptor splice site variants.
-* Use SpliceAI and varSEAK to look for nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing. 
-* For considerations for strength at which PVS1 may be applied see 
-Appendix 1
-.
-* If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used.
-* Non-canonical splice variants, such as +3 or -3, will not meet PVS1, but could meet PS3 and/or PP3 criteria.
-
-
-Deletions (single or multi exon)
-* If a single or multi-exon deletion results in an out of frame consequence, use PVS1 unless not predicted to undergo NMD. If not predicted to undergo NMD, use PVS1_Strong if >10% of the protein is predicted to be removed, and use PVS1_Moderate if <10% of the protein is predicted to be removed.
-* If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. Use PVS1_Strong if more than 10% of the protein is removed and PVS1_Moderate if <10% of the protein is removed.
-* If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4.
-* 
-Appendix 1
- can be used to predict the consequences of single exon deletions.
-
-
-Duplications
-* Use the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042) to assess the impact of duplications.",Strength
-GAMT (HGNC:4136),PVS1,Moderate,"Single exon or larger deletion resulting in loss of <10% of the protein.
-
-
-Initiator codon variant.
-  
-
-
-CCDS VCEP notes:
-Loss of function (LOF) of GAMT is a known mechanism of disease for guanidinoacetate methyltransferase deficiency (GAMT-D). There are examples of various LOF variants, including nonsense and frameshift, in GAMT in individuals with GAMT-D (
-https://databases.lovd.nl/shared/variants/GAMT/unique
-). The specifications below are based on the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042).
-
-
-Nonsense and frameshift variants
-* All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 6) or the last 50 bases of the penultimate exon of the gene (exon 5, c.520). In that case, PVS1_Moderate will be applied if <10% of the protein is lost.
-
-
-Splice site variants (+1, +2, -1, -2)
-* All canonical splice site pairs in GAMT are GT-AG.
-* Use SpliceAI and varSEAK to look for nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing. 
-* For any canonical splice site variant (+1, +2, -1, -2), if RT-PCR data predicts in-frame loss of <10% of the protein, apply PVS1_Moderate.
-* If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used.
-* Non-canonical splice variants, such as +3 or -3, will not meet PVS1, but could meet PS3 and/or PP3 criteria.
-
-
-Initiator codon variants
-* To our knowledge, initiator codon variants have not been reported in GAMT (01/2019) but may occur.
-* All initiator codon variants will meet PVS1_Moderate. The next in-frame methionine is at amino acid position 42 (based on NP_000147.1).
-
-
-Deletions (single or multi exon)
-* If a single or multi-exon deletion results in an out of frame consequence, use PVS1 unless not predicted to undergo NMD. If not predicted to undergo NMD, use PVS1_Strong if >10% of the protein is predicted to be removed, and use PVS1_Moderate if <10% of the protein is predicted to be removed.
-* If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. Use PVS1_Strong if more than 10% of the protein is removed and PVS1_Moderate if <10% of the protein is removed.
-* If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4.
-* 
-Appendix 1
- can be used to predict the consequences of single exon deletions.
-
-
-Duplications
-* Use the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042) to assess the impact of duplications.",Strength
-GAMT (HGNC:4136),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-GAMT (HGNC:4136),PS1,Strong,"This criterion is applicable as described.
-
-
-If the variant is in the last 3 nucleotides of an exon, further analysis using splicing site prediction algorithms (see PP3) and data from the literature (if available) is required to investigate the impact on splicing.",None
-GAMT (HGNC:4136),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",NA
-GAMT (HGNC:4136),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-GAMT (HGNC:4136),PS3,Strong,"RT-PCR evidence of mis-splicing for non-canonical +1, +2, -2, -1 intronic variants with no evidence of normal splice products.
-  
-
-
-GAMT specifications:
-Any variant meeting the description for splicing assays below can meet PS3 or PS3_Supporting, and variants meeting the description for in vitro activity assays can meet PS3_Supporting. If a variant meets the description for both e.g., a splice site variant with evidence of abnormal splicing and deficient GAMT activity in vitro, PS3 must only be counted once.
-
-
-Splicing assays
-For non-canonical splicing variants, use PS3 if there is RT-PCR and/or RNA sequencing evidence demonstrating only abnormal splice products, with no evidence of normal splicing.
-* Evidence of abnormal splicing includes transcripts of alternative length or with specific intron or exon inclusion/exclusion. These studies can be performed on mRNA extracted from patient-derived cells, or by inserting the mutant genomic DNA into plasmid vectors and introducing these into human or other mammalian host cells.
-* Note that in patients who are compound heterozygotes for a splicing variant and another variants type that does not disrupt splicing, such as a missense variant, evidence of normal splicing is expected. However, the presence of normal splice products could complicate the assessment of the impact of the splice variant. Therefore, if there is any evidence of normal splice products, either when using RNA from patient cells or in an in vitro expression system, use PS3_Supporting.
-* PP3 may also be used for non-canonical splice variants meeting PS3 or PS3_Supporting.",Disease-specific
-GAMT (HGNC:4136),PS3,Supporting,"<15% control activity when variant is expressed in GAMT-deficient fibroblasts or HeLa cells.
-* RT-PCR evidence of mis-splicing for non-canonical intronic variants with evidence of normal splice products.
-  
-
-
-GAMT specifications:
-Any variant meeting the description for splicing assays below can meet PS3 or PS3_Supporting, and variants meeting the description for in vitro activity assays can meet PS3_Supporting. If a variant meets the description for both e.g., a splice site variant with evidence of abnormal splicing and deficient GAMT activity in vitro, PS3 must only be counted once.
-
-
-In vitro expression
-PS3_Supporting can be assigned if a variant is expressed in GAMT-deficient fibroblasts or HeLa cells and has <15% of the control value, for values published in Mercimek-Mahmutoglu et al, 2014, PMID 24415674; Mercimek-Mahmutoglu et al, 2016, PMID 26319512; or DesRoches et al, 2016, PMID 26003046. See 
-Appendix 2
- for further details on GAMT functional assays.  
-
-
-Splicing assays
-For non-canonical splicing variants, use PS3 if there is RT-PCR and/or RNA sequencing evidence demonstrating only abnormal splice products, with no evidence of normal splicing.
-* Evidence of abnormal splicing includes transcripts of alternative length or with specific intron or exon inclusion/exclusion. These studies can be performed on mRNA extracted from patient-derived cells, or by inserting the mutant genomic DNA into plasmid vectors and introducing these into human or other mammalian host cells.
-* Note that in patients who are compound heterozygotes for a splicing variant and another variants type that does not disrupt splicing, such as a missense variant, evidence of normal splicing is expected. However, the presence of normal splice products could complicate the assessment of the impact of the splice variant. Therefore, if there is any evidence of normal splice products, either when using RNA from patient cells or in an in vitro expression system, use PS3_Supporting.
-* PP3 may also be used for non-canonical splice variants meeting PS3 or PS3_Supporting.",Disease-specific
-GAMT (HGNC:4136),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",NA
-GAMT (HGNC:4136),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-GAMT (HGNC:4136),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-GAMT (HGNC:4136),PM2,Supporting,"Allele frequency <0.0004 (<0.04%) in all populations in gnomAD.
-
-
-CCDS VCEP notes: It is acceptable for a GAMT variant to be present in controls, if heterozygous, because GAMT-D is a recessive disorder. Homozygotes should not be seen in a population database, such as gnomAD, because the penetrance of this condition in individuals with biallelic pathogenic variants is expected to be 100%.
-
-
-GAMT specifications:
-
-
-
-
-All subpopulations in gnomAD must have a maximum allele frequency less than 0.0004 (the highest population minor allele frequency of the most common pathogenic GAMT variant, c.327G>A, in gnomAD). Any variant with a frequency below this cutoff will meet PM2_Supporting (See Appendix 3). Note – PM2 will NOT be used at moderate strength; PM2 will only be applied as a Supporting criterion.
-
-
-If homozygotes are observed, the variant will meet BS2 (assuming 100% penetrance for an individual with 2 pathogenic variants in trans).","Disease-specific,Strength"
-GAMT (HGNC:4136),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-GAMT (HGNC:4136),PM3,Very Strong,"Follow SVI guidance for PM3 (
-https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf
-).
-
-
-Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",Strength
-GAMT (HGNC:4136),PM3,Strong,"Follow SVI guidance for PM3 (
-https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf
-).
-
-
-Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",Strength
-GAMT (HGNC:4136),PM3,Moderate,"Follow SVI guidance for PM3 (
-https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf
-).
-
-
-Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",None
-GAMT (HGNC:4136),PM3,Supporting,"Follow SVI guidance for PM3 (
-https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf
-).
-
-
-Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",Strength
-GAMT (HGNC:4136),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-GAMT (HGNC:4136),PM4,Moderate,"Stop loss variants in GAMT have not been reported, as far as we are aware.
-
-
-GAMT specifications: Use this rule “as is” for in frame deletions and insertions of 2 or more amino acids, but downgrade to PM4_Supporting for single amino acid deletions and insertions.",None
-GAMT (HGNC:4136),PM4,Supporting,Downgrade to PM4_Supporting for single amino acid deletions and insertions.,Strength
-GAMT (HGNC:4136),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-GAMT (HGNC:4136),PM5,Moderate,"If the pathogenicity of another missense change at the same amino acid residue is unknown, determine its pathogenicity using these specifications in order to determine if this criterion can be used. If the variant is pathogenic, use PM5. If the variant is likely pathogenic, use PM5_Supporting.",None
-GAMT (HGNC:4136),PM5,Supporting,"If the pathogenicity of another missense change at the same amino acid residue is unknown, determine its pathogenicity using these specifications in order to determine if this criterion can be used. If the variant is pathogenic, use PM5. If the variant is likely pathogenic, use PM5_Supporting.",Strength
-GAMT (HGNC:4136),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-GAMT (HGNC:4136),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",NA
-GAMT (HGNC:4136),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-GAMT (HGNC:4136),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-GAMT (HGNC:4136),PP3,Moderate,"Non-canonical splice site variant predicted to be more deleterious, by SpliceAI and varSEAK, than a previously observed pathogenic variant at the same nucleotide.",Strength
-GAMT (HGNC:4136),PP3,Supporting,"For missense changes, those with a REVEL score more than 0.75 will meet PP3.
-
-
-For in frame insertions and deletions, use PROVEAN and Mutation Taster. Results must be consistent to count.
-
-
-For non-canonical splice site variants (e.g., +3, -3), use SpliceAI (
-https://spliceailookup.broadinstitute.org/
- ) and varSEAK (
-https://varseak.bio/
-). Results must be consistent to apply this criterion.
-
-
-For SpliceAI, any donor loss or acceptor loss with a score >0.5. For varSEAK, any variant with splicing class 4 or 5. Evidence for creation of a cryptic splice site should also be assessed.
-
-
-Do not apply this rule for canonical splice site changes meeting PVS1.",None
-GAMT (HGNC:4136),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-GAMT (HGNC:4136),PP4,Strong,"4 points based on any combination of the following. Two or more data types are required to apply PP4_Strong:
-• Elevated urine guanidinoacetate with or without low or low normal creatine (1 point)
-• Elevated plasma guanidinoacetate with or without low or low normal creatine (2 points)
-• Significantly decreased creatine peak in brain magnetic resonance spectroscopy with or without visible guanidinoacetate peak (3 points)
-• GAMT enzyme activity <5% of normal (3 points)
-
-
-* Variant must meet PM2_Supporting for PP4 to apply at any strength.
-* For PP4 to be applied at strong, full GAMT gene sequencing, including all coding exons and intron/exon boundaries, must have been carried out. If not, consider downgrading.",Disease-specific
-GAMT (HGNC:4136),PP4,Moderate,"3 points based on any combination of the following. Two or more data types are recommended to apply PP4_Moderate:
-• Elevated urine guanidinoacetate with or without low or low normal creatine (1 point)
-• Elevated plasma guanidinoacetate with or without low or low normal creatine (2 points)
-• Significantly decreased creatine peak in brain magnetic resonance spectroscopy with or without visible guanidinoacetate peak (3 points)
-• GAMT enzyme activity <5% of normal (3 points)
-
-
-* Variant must meet PM2_Supporting for PP4 to apply at any strength.",Strength
-GAMT (HGNC:4136),PP4,Supporting,"1-2 points based on: 
-• Elevated urine guanidinoacetate with or without low or low normal creatine (1 point)
-• Elevated plasma guanidinoacetate with or without low or low normal creatine (2 points)
-
-
-* Variant must meet PM2_Supporting for PP4 to apply at any strength",Disease-specific
-GAMT (HGNC:4136),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-GAMT (HGNC:4136),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-GAMT (HGNC:4136),BA1,Stand Alone,"Allele frequency >0.003 (0.3%) in gnomAD in any continental population in gnomAD with >2000 alleles.
-
-
-GAMT specifications:
-
-
-
-
-Any variant with a frequency >0.003 (based on the estimated prevalence 1 in 114,000, PMID 24071436) in gnomAD (max allelic contribution = 100%; max genetic contribution = 100%).
-
-
-Use the highest population minor allele frequency (MAF) in any given continental population with >2,000 alleles (European non-Finnish, African, East Asian, South Asian, Latino) (PMID 30311383).",Disease-specific
-GAMT (HGNC:4136),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-GAMT (HGNC:4136),BS1,Strong,"Allele frequency >0.001 (0.1%) in gnomAD in any continental population in gnomAD with >2000 alleles. 
-
-
-GAMT specifications:
-
-
-
-
-Any variant with a frequency >0.001 (based on the estimated prevalence 1 in 114,000 (PMID: 24071436) in gnomAD (max allelic contribution = 40%; max genetic contribution = 100%).
-
-
-Use the highest population minor allele frequency (MAF) in any given continental population with >2,000 alleles (European non-Finnish, African, East Asian, South Asian, Latino) (PMID 30311383).",Disease-specific
-GAMT (HGNC:4136),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-GAMT (HGNC:4136),BS2,Strong,Observed in the homozygous state in a healthy adult.,None
-GAMT (HGNC:4136),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-GAMT (HGNC:4136),BS3,Supporting,">30% normal GAA activity when the variant is expressed in a heterologous cell type.
-GAMT specifications:
-In vitro assays in which a variant is expressed in GAMT-deficient cultured cells (e.g. GAMT-deficient fibroblasts) or in-fusion High-Fidelity cloning of GAMT transcript and site directed mutagenesis to generate missense variant overexpressed in HeLa cells and measurement of GAMT activity in cells for wild-type and missense variant. Any variant with enzyme activity at or above 30% of normal in the following publications meets BS3_Supporting (Mercimek-Mahmutoglu et al, 2014; PMID 24415674; Mercimek-Mahmutoglu et al, 2016, PMID 26319512; DesRoches et al, 2016, PMID 26003046).","Disease-specific,Strength"
-GAMT (HGNC:4136),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",NA
-GAMT (HGNC:4136),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-GAMT (HGNC:4136),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-GAMT (HGNC:4136),BP2,Supporting,Observed in cis with a pathogenic variant (to take AR inheritance into account).,None
-GAMT (HGNC:4136),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-GAMT (HGNC:4136),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-GAMT (HGNC:4136),BP4,Supporting,"For missense changes, REVEL score <0.5.
-
-
-For in frame insertions and deletions, use PROVEAN and Mutation Taster. Results must be consistent to count.
-
-
-For non-canonical splice site variants, use SpliceAI (
-https://spliceailookup.broadinstitute.org/
- ) and varSEAK (
-https://varseak.bio/
-) to assess the impact of variants that are not +/-1 or 2 canonical splice site variants. For SpliceAI, this criterion can be applied for scores <0.2, and for varSEAK class 1 and 2. If there is any evidence for possible creation of a cryptic splice site, this criterion should not be applied.",None
-GAMT (HGNC:4136),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-GAMT (HGNC:4136),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-GAMT (HGNC:4136),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-GAMT (HGNC:4136),BP7,Supporting,Apply this criterion as described.,None
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGAMTVersion1_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGAMTVersion1_version=1.0.0.csv
deleted file mode 100644
index 27761ccabdd22f83c0ff01d8a285dc639282415f..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGAMTVersion1_version=1.0.0.csv
+++ /dev/null
@@ -1,610 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-GAMT (HGNC:4136),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-GAMT (HGNC:4136),PVS1,Very Strong,"Nonsense-mediated decay predicted.
-
-
-
-
-CCDS VCEP notes:
-Loss of function (LOF) of GAMT is a known mechanism of disease for guanidinoacetate methyltransferase deficiency (GAMT-D). There are examples of various LOF variants, including nonsense and frameshift, in GAMT in individuals with GAMT-D (
-https://databases.lovd.nl/shared/variants/GAMT?search_var_status=%3D%22Marked%22%7C%3D%22Public%22
- ). The specifications below are based on the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042).
-
-
-Nonsense and frameshift variants
-
-
-
-
-All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 6) or the last 50 bases of the penultimate exon of the gene (exon 5, c.520). In that case, PVS1_Moderate will be applied.
-
-
-
-
-Splice site variants (+1, +2, -1, -2)
-
-
-
-
-All canonical splice site pairs in GAMT are GT-AG.
-
-
-For any canonical splice site variant (+1, +2, -1, -2), the exon immediately adjacent to the variant is predicted to be skipped i.e. upstream exon skipped for canonical donor splice site variants and downstream exon skipped for canonical acceptor splice site variants.
-
-
-For the predicted in frame/out of frame consequences of exon skipping and assigned strength of PVS1, see Appendix 1.
-
-
-If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used.
-
-
-To apply PVS1, splice site variants must have no detectable nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing. Otherwise, the PVS1 strength should be reduced accordingly.
-
-
-Non-canonical splice variants, such as +3 or -3, will not meet PVS1, but could meet PS3 and/or PP3 criteria.
-
-
-
-
-Initiator codon variants
-
-
-
-
-To our knowledge, initiator codon variants have not been reported in GAMT (01/2019) but may occur.
-
-
-All initiator codon variants will meet PVS1_Moderate. The next in-frame methionine is at amino acid position 42 (based on NP_000147.1).
-
-
-
-
-Deletions (single or multi exon)
-
-
-
-
-If a single or multi-exon deletion results in an out of frame consequence, use PVS1 unless not predicted to undergo NMD. If not predicted to undergo NMD, use PVS1_Strong if >10% of the protein is predicted to be removed, and use PVS1_Moderate if <10% of the protein is predicted to be removed.
-
-
-If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. Use PVS1_Strong if more than 10% of the protein is removed and PVS1_Moderate if <10% of the protein is removed.
-
-
-If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4.
-
-
-Appendix 1 can be used to predict the consequences of single exon deletions.
-
-
-
-
-Duplications 
-
-
-
-
-Use the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042) to assess the impact of duplications.",None
-GAMT (HGNC:4136),PVS1,Strong,"In frame loss of >10% of the protein.
-
-
-
-
-CCDS VCEP notes:
-Loss of function (LOF) of GAMT is a known mechanism of disease for guanidinoacetate methyltransferase deficiency (GAMT-D). There are examples of various LOF variants, including nonsense and frameshift, in GAMT in individuals with GAMT-D (
-https://databases.lovd.nl/shared/variants/GAMT?search_var_status=%3D%22Marked%22%7C%3D%22Public%22
- ). The specifications below are based on the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042).
-
-
-Nonsense and frameshift variants
-
-
-
-
-All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 6) or the last 50 bases of the penultimate exon of the gene (exon 5, c.520). In that case, PVS1_Moderate will be applied.
-
-
-
-
-Splice site variants (+1, +2, -1, -2)
-
-
-
-
-All canonical splice site pairs in GAMT are GT-AG.
-
-
-For any canonical splice site variant (+1, +2, -1, -2), the exon immediately adjacent to the variant is predicted to be skipped i.e. upstream exon skipped for canonical donor splice site variants and downstream exon skipped for canonical acceptor splice site variants.
-
-
-For the predicted in frame/out of frame consequences of exon skipping and assigned strength of PVS1, see Appendix 1.
-
-
-If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used.
-
-
-To apply PVS1, splice site variants must have no detectable nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing. Otherwise, the PVS1 strength should be reduced accordingly.
-
-
-Non-canonical splice variants, such as +3 or -3, will not meet PVS1, but could meet PS3 and/or PP3 criteria.
-
-
-
-
-Initiator codon variants
-
-
-
-
-To our knowledge, initiator codon variants have not been reported in GAMT (01/2019) but may occur.
-
-
-All initiator codon variants will meet PVS1_Moderate. The next in-frame methionine is at amino acid position 42 (based on NP_000147.1).
-
-
-
-
-Deletions (single or multi exon)
-
-
-
-
-If a single or multi-exon deletion results in an out of frame consequence, use PVS1 unless not predicted to undergo NMD. If not predicted to undergo NMD, use PVS1_Strong if >10% of the protein is predicted to be removed, and use PVS1_Moderate if <10% of the protein is predicted to be removed.
-
-
-If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. Use PVS1_Strong if more than 10% of the protein is removed and PVS1_Moderate if <10% of the protein is removed.
-
-
-If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4.
-
-
-Appendix 1 can be used to predict the consequences of single exon deletions.
-
-
-
-
-Duplications 
-
-
-
-
-Use the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042) to assess the impact of duplications.",Strength
-GAMT (HGNC:4136),PVS1,Moderate,"Initiator codon variant.
-
-
-Single exon or larger deletion resulting in loss of <10% of the protein.
-
-
-
-
-CCDS VCEP notes:
-Loss of function (LOF) of GAMT is a known mechanism of disease for guanidinoacetate methyltransferase deficiency (GAMT-D). There are examples of various LOF variants, including nonsense and frameshift, in GAMT in individuals with GAMT-D (
-https://databases.lovd.nl/shared/variants/GAMT?search_var_status=%3D%22Marked%22%7C%3D%22Public%22
- ). The specifications below are based on the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042).
-
-
-Nonsense and frameshift variants
-
-
-
-
-All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 6) or the last 50 bases of the penultimate exon of the gene (exon 5, c.520). In that case, PVS1_Moderate will be applied.
-
-
-
-
-Splice site variants (+1, +2, -1, -2)
-
-
-
-
-All canonical splice site pairs in GAMT are GT-AG.
-
-
-For any canonical splice site variant (+1, +2, -1, -2), the exon immediately adjacent to the variant is predicted to be skipped i.e. upstream exon skipped for canonical donor splice site variants and downstream exon skipped for canonical acceptor splice site variants.
-
-
-For the predicted in frame/out of frame consequences of exon skipping and assigned strength of PVS1, see Appendix 1.
-
-
-If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used.
-
-
-To apply PVS1, splice site variants must have no detectable nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing. Otherwise, the PVS1 strength should be reduced accordingly.
-
-
-Non-canonical splice variants, such as +3 or -3, will not meet PVS1, but could meet PS3 and/or PP3 criteria.
-
-
-
-
-Initiator codon variants
-
-
-
-
-To our knowledge, initiator codon variants have not been reported in GAMT (01/2019) but may occur.
-
-
-All initiator codon variants will meet PVS1_Moderate. The next in-frame methionine is at amino acid position 42 (based on NP_000147.1).
-
-
-
-
-Deletions (single or multi exon)
-
-
-
-
-If a single or multi-exon deletion results in an out of frame consequence, use PVS1 unless not predicted to undergo NMD. If not predicted to undergo NMD, use PVS1_Strong if >10% of the protein is predicted to be removed, and use PVS1_Moderate if <10% of the protein is predicted to be removed.
-
-
-If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. Use PVS1_Strong if more than 10% of the protein is removed and PVS1_Moderate if <10% of the protein is removed.
-
-
-If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4.
-
-
-Appendix 1 can be used to predict the consequences of single exon deletions.
-
-
-
-
-Duplications 
-
-
-
-
-Use the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042) to assess the impact of duplications.",Strength
-GAMT (HGNC:4136),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-GAMT (HGNC:4136),PS1,Strong,"CCDS VCEP notes:
-
-
-
-
-This criterion is applicable as described.
-
-
-If the variant is in the last 3 nucleotides of an exon, further analysis using splicing site prediction algorithms (see PP3) and data from the literature (if available) is required to investigate the impact on splicing.",None
-GAMT (HGNC:4136),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",NA
-GAMT (HGNC:4136),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-GAMT (HGNC:4136),PS3,Strong,"RT-PCR evidence of mis-splicing for non-canonical +1, +2, -2, -1 intronic variants with no evidence of normal splice products.
-GAMT specifications:
-Any variant meeting the description for splicing assays below can meet PS3 or PS3_Supporting, and variants meeting the description for in vitro activity assays can meet PS3_Supporting. If a variant meets the description for both e.g., a splice site variant with evidence of abnormal splicing and deficient GAMT activity in vitro, PS3 must only be counted once.
-In vitro expression
-PS3_Supporting can be assigned if a variant is expressed in GAMT-deficient fibroblasts or HeLa cells and has <15% of the control value, for values published in Mercimek-Mahmutoglu et al, 2014, PMID 24415674; Mercimek-Mahmutoglu et al, 2016, PMID 26319512; or DesRoches et al, 2016, PMID 26003046. See Appendix 2 for further details on GAMT functional assays.
-Splicing assays
-For non-canonical splicing variants, use PS3 if there is RT-PCR and/or RNA sequencing evidence demonstrating only abnormal splice products, with no evidence of normal splicing.
-
-
-Evidence of abnormal splicing includes transcripts of alternative length or with specific intron or exon inclusion/exclusion. These studies can be performed on mRNA extracted from patient-derived cells, or by inserting the mutant genomic DNA into plasmid vectors and introducing these into human or other mammalian host cells.
-
-
-Note that in patients who are compound heterozygotes for a splicing variant and another variants type that does not disrupt splicing, such as a missense variant, evidence of normal splicing is expected. However, the presence of normal splice products could complicate the assessment of the impact of the splice variant. Therefore, if there is any evidence of normal splice products, either when using RNA from patient cells or in an in vitro expression system, use PS3_Supporting.
-
-
-PP3 may also be used for non-canonical splice variants meeting PS3 or PS3_Supporting.",Disease-specific
-GAMT (HGNC:4136),PS3,Supporting,"<15% control activity when variant is expressed in GAMT-deficient fibroblasts or HeLa cells, as reported in PMID 24415674, 26003046, and 26319512.
-
-
-RT-PCR evidence of mis-splicing for non-canonical intronic variants with evidence of normal splice products.
-GAMT specifications:
-Any variant meeting the description for splicing assays below can meet PS3 or PS3_Supporting, and variants meeting the description for in vitro activity assays can meet PS3_Supporting. If a variant meets the description for both e.g., a splice site variant with evidence of abnormal splicing and deficient GAMT activity in vitro, PS3 must only be counted once.
-In vitro expression
-PS3_Supporting can be assigned if a variant is expressed in GAMT-deficient fibroblasts or HeLa cells and has <15% of the control value, for values published in Mercimek-Mahmutoglu et al, 2014, PMID 24415674; Mercimek-Mahmutoglu et al, 2016, PMID 26319512; or DesRoches et al, 2016, PMID 26003046. See Appendix 2 for further details on GAMT functional assays.
-Splicing assays
-For non-canonical splicing variants, use PS3 if there is RT-PCR and/or RNA sequencing evidence demonstrating only abnormal splice products, with no evidence of normal splicing.
-
-
-Evidence of abnormal splicing includes transcripts of alternative length or with specific intron or exon inclusion/exclusion. These studies can be performed on mRNA extracted from patient-derived cells, or by inserting the mutant genomic DNA into plasmid vectors and introducing these into human or other mammalian host cells.
-
-
-Note that in patients who are compound heterozygotes for a splicing variant and another variants type that does not disrupt splicing, such as a missense variant, evidence of normal splicing is expected. However, the presence of normal splice products could complicate the assessment of the impact of the splice variant. Therefore, if there is any evidence of normal splice products, either when using RNA from patient cells or in an in vitro expression system, use PS3_Supporting.
-
-
-PP3 may also be used for non-canonical splice variants meeting PS3 or PS3_Supporting.",Disease-specific
-GAMT (HGNC:4136),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",NA
-GAMT (HGNC:4136),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-GAMT (HGNC:4136),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-GAMT (HGNC:4136),PM2,Supporting,"Allele frequency <0.0004 (<0.04%) in all populations in gnomAD.
-
-
-
-
-CCDS VCEP notes:
-It is acceptable for a GAMT variant to be present in controls, if heterozygous, because GAMT-D is a recessive disorder. Homozygotes should not be seen in a population database, such as gnomAD, because the penetrance of this condition in individuals with biallelic pathogenic variants is expected to be 100%.
-
-
-GAMT specifications:
-
-
-
-
-All subpopulations in gnomAD must have a maximum allele frequency less than 0.0004 (the highest population minor allele frequency of the most common pathogenic GAMT variant, c.327G>A, in gnomAD). Any variant with a frequency below this cutoff will meet PM2_Supporting (See Appendix 3).
-Note – PM2 will NOT be used at moderate strength; PM2 will only be applied as a Supporting criterion.
-
-
-If homozygotes are observed, the variant will meet BS2 (assuming 100% penetrance for an individual with 2 pathogenic variants in trans).","Strength,Disease-specific"
-GAMT (HGNC:4136),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-GAMT (HGNC:4136),PM3,Very Strong,"Consult specifications for assigning strength of evidence for PM3.
-
-
-GAMT specifications:
-
-
-
-
-Following SVI guidance for PM3 (
-https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf
-), use the scoring system below.
-
-
-Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",Strength
-GAMT (HGNC:4136),PM3,Strong,"Consult specifications for assigning strength of evidence for PM3.
-
-
-GAMT specifications:
-
-
-
-
-Following SVI guidance for PM3 (
-https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf
-), use the scoring system below.
-
-
-Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",Strength
-GAMT (HGNC:4136),PM3,Moderate,"Consult specifications for assigning strength of evidence for PM3.
-
-
-GAMT specifications:
-
-
-
-
-Following SVI guidance for PM3 (
-https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf
-), use the scoring system below.
-
-
-Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",None
-GAMT (HGNC:4136),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-GAMT (HGNC:4136),PM4,Moderate,"CCDS VCEP notes:
-
-
-
-
-Stop loss variants in GAMT have not been reported, as far as we are aware.
-
-
-
-
-GAMT specifications:
-Use this rule “as is” for in frame deletions and insertions of 2 or more amino acids, but downgrade to PM4_Supporting for single amino acid deletions and insertions.",None
-GAMT (HGNC:4136),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-GAMT (HGNC:4136),PM5,Moderate,"GAMT specifications:
-
-
-
-
-If the pathogenicity of another missense change at the same amino acid residue is unknown, determine its pathogenicity using these specifications in order to determine if this criterion can be used. If the variant is pathogenic, use PM5. If the variant is likely pathogenic, use PM5_Supporting.",None
-GAMT (HGNC:4136),PM5,Supporting,"GAMT specifications:
-
-
-
-
-If the pathogenicity of another missense change at the same amino acid residue is unknown, determine its pathogenicity using these specifications in order to determine if this criterion can be used. If the variant is pathogenic, use PM5. If the variant is likely pathogenic, use PM5_Supporting.",Strength
-GAMT (HGNC:4136),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-GAMT (HGNC:4136),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",NA
-GAMT (HGNC:4136),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-GAMT (HGNC:4136),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-GAMT (HGNC:4136),PP3,Moderate,"Non-canonical splice site variant predicted to be more deleterious than a previously observed pathogenic variant at the same nucleotide.
-
-
-
-
-GAMT specifications:
-
-
-
-
-For missense changes, those with a REVEL score more than 0.75 will meet PP3.
-
-
-For in frame insertions and deletions, use PROVEAN and Mutation Taster. Results must be consistent to count.
-
-
-For non-canonical splice site variants (e.g., +3, -3), use SpliceAI ((
-https://spliceailookup.broadinstitute.org/
- ) and varSEAK (
-https://varseak.bio/
-). Results must be consistent to apply this criterion.
-
-
-For SpliceAI, any donor loss or acceptor loss with a score >0.5. For varSEAK, any variant with splicing class 4 or 5. Evidence for creation of a cryptic splice site should also be assessed.
-
-
-Do not apply this rule for canonical splice site changes meeting PVS1.
-
-
-Upgrade to PP3_Moderate if a different non-canonical splice site variant at the same position is known to be pathogenic AND the newly observed variant is at least as deleterious as the previously observed variant, based on in silico prediction (Human Splicing Finder, MaxEntScan) e.g. variant being interpreted is +3C>G, previously reported variant is +3C>T and +3C>G is predicted to be more deleterious than +3C>T.",Strength
-GAMT (HGNC:4136),PP3,Supporting,"REVEL score >0.75 for missense variants.
-
-
-In frame deletion or insertion predicted deleterious by PROVEAN and MutationTaster.
-
-
-Predicted impact on splicing by SpliceAI and varSEAK.
-
-
-
-
-GAMT specifications:
-
-
-
-
-For missense changes, those with a REVEL score more than 0.75 will meet PP3.
-
-
-For in frame insertions and deletions, use PROVEAN and Mutation Taster. Results must be consistent to count.
-
-
-For non-canonical splice site variants (e.g., +3, -3), use SpliceAI ((
-https://spliceailookup.broadinstitute.org/
- ) and varSEAK (
-https://varseak.bio/
-). Results must be consistent to apply this criterion.
-
-
-For SpliceAI, any donor loss or acceptor loss with a score >0.5. For varSEAK, any variant with splicing class 4 or 5. Evidence for creation of a cryptic splice site should also be assessed.
-
-
-Do not apply this rule for canonical splice site changes meeting PVS1.
-
-
-Upgrade to PP3_Moderate if a different non-canonical splice site variant at the same position is known to be pathogenic AND the newly observed variant is at least as deleterious as the previously observed variant, based on in silico prediction (Human Splicing Finder, MaxEntScan) e.g. variant being interpreted is +3C>G, previously reported variant is +3C>T and +3C>G is predicted to be more deleterious than +3C>T.",None
-GAMT (HGNC:4136),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-GAMT (HGNC:4136),PP4,Strong,"Any combination of two or more of the data types listed for PP4_Moderate and PP4 OR significantly decreased creatine peak and visible GAA peak on 1H-MRS (see points scheme in main document)
-Note: Do not apply this rule if the variant meets BA1, or otherwise meets criteria for benign or likely benign status.
-
-
-GAMT specifications:
-The following table shows the weight used for PP4 depending upon the data that is available. Assign points for each type of data present, and then add up the points.
-PP4 = 1-2 points
-PP4_Moderate = 3 points
-PP4_Strong = 4 points
-Two or more data types are recommended to reach moderate and required to reach strong.
-
-
-
-
-Variant must meet PM2_Supporting for PP4 to apply at any strength.
-
-
-For PP4 to be applied at strong, full GAMT gene sequencing, including all coding exons and intron/exon boundaries, must have been carried out. If not, consider downgrading.",Disease-specific
-GAMT (HGNC:4136),PP4,Moderate,"Elevated GAA and low or low normal creatine in urine, OR elevated GAA and low creatine in plasma OR
-
-
-Significantly decreased creatine peak on 1H-MRS (GAA not measured/not reported) OR
-
-
-GAMT activity <5% normal in fibroblasts.
-Note: Do not apply this rule if the variant meets BA1, or otherwise meets criteria for benign or likely benign status.
-
-
-
-
-GAMT specifications:
-The following table shows the weight used for PP4 depending upon the data that is available. Assign points for each type of data present, and then add up the points.
-PP4 = 1-2 points
-PP4_Moderate = 3 points
-PP4_Strong = 4 points
-Two or more data types are recommended to reach moderate and required to reach strong.
-
-
-
-
-Variant must meet PM2_Supporting for PP4 to apply at any strength.
-
-
-For PP4 to be applied at strong, full GAMT gene sequencing, including all coding exons and intron/exon boundaries, must have been carried out. If not, consider downgrading.",Strength
-GAMT (HGNC:4136),PP4,Supporting,"Elevated GAA in plasma or urine (with no creatine measurement)
-Note: Do not apply this rule if the variant meets BA1, or otherwise meets criteria for benign or likely benign status.
-
-
-
-
-GAMT specifications:
-The following table shows the weight used for PP4 depending upon the data that is available. Assign points for each type of data present, and then add up the points.
-PP4 = 1-2 points
-PP4_Moderate = 3 points
-PP4_Strong = 4 points
-Two or more data types are recommended to reach moderate and required to reach strong.
-
-
-
-
-Variant must meet PM2_Supporting for PP4 to apply at any strength.
-
-
-For PP4 to be applied at strong, full GAMT gene sequencing, including all coding exons and intron/exon boundaries, must have been carried out. If not, consider downgrading.",Disease-specific
-GAMT (HGNC:4136),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-GAMT (HGNC:4136),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-GAMT (HGNC:4136),BA1,Stand Alone,"Allele frequency >0.003 (0.3%) in gnomAD in any continental population in gnomAD with >2000 alleles.
-
-
-GAMT specifications:
-
-
-
-
-Any variant with a frequency >0.003 (based on the estimated prevalence 1 in 114,000, PMID 24071436) in gnomAD (max allelic contribution = 100%; max genetic contribution = 100%)(See Appendix 3).
-
-
-Use the highest population minor allele frequency (MAF) in any given continental population with >2,000 alleles (European non-Finnish, African, East Asian, South Asian, Latino) (PMID 30311383).",Disease-specific
-GAMT (HGNC:4136),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-GAMT (HGNC:4136),BS1,Strong,"Allele frequency >0.001 (0.1%) in gnomAD in any continental population in gnomAD with >2000 alleles.
-GAMT specifications:
-
-
-
-
-Any variant with a frequency >0.001 (based on the estimated prevalence 1 in 114,000 (PMID: 24071436) in gnomAD (max allelic contribution = 40%; max genetic contribution = 100%)(See Appendix 3).
-
-
-Use the highest population minor allele frequency (MAF) in any given continental population with >2,000 alleles (European non-Finnish, African, East Asian, South Asian, Latino) (PMID 30311383).",Disease-specific
-GAMT (HGNC:4136),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-GAMT (HGNC:4136),BS2,Strong,Observed in the homozygous state in a healthy adult.,None
-GAMT (HGNC:4136),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-GAMT (HGNC:4136),BS3,Supporting,"30% normal GAA activity when the variant is expressed in a heterologous cell type.
-GAMT specifications:
-In vitro assays in which a variant is expressed in GAMT-deficient cultured cells (e.g. GAMT-deficient fibroblasts) or in-fusion High-Fidelity cloning of GAMT transcript and site directed mutagenesis to generate missense variant overexpressed in HeLa cells and measurement of GAMT activity in cells for wild-type and missense variant. Any variant with enzyme activity at or above 30% of normal in the following publications meets BS3_Supporting (Mercimek-Mahmutoglu et al, 2014; PMID 24415674; Mercimek-Mahmutoglu et al, 2016, PMID 26319512; DesRoches et al, 2016, PMID 26003046).","Strength,Disease-specific"
-GAMT (HGNC:4136),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",NA
-GAMT (HGNC:4136),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-GAMT (HGNC:4136),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-GAMT (HGNC:4136),BP2,Supporting,"Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.
-GAMT specifications:
-Observed in cis with a pathogenic variant (to take AR inheritance into account).",None
-GAMT (HGNC:4136),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-GAMT (HGNC:4136),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-GAMT (HGNC:4136),BP4,Supporting,"GAMT specifications:
-
-
-
-
-For missense changes, REVEL score <0.5.
-
-
-For in frame insertions and deletions, use PROVEAN and Mutation Taster. Results must be consistent to count.
-
-
-For non-canonical splice site variants, use SpliceAI (
-https://spliceailookup.broadinstitute.org/
- ) and varSEAK (
-https://varseak.bio/
-) to assess the impact of variants that are not +/-1 or 2 canonical splice site variants. For SpliceAI, this criterion can be applied for scores <0.2, and for varSEAK class 1 and 2. If there is any evidence for possible creation of a cryptic splice site, this criterion should not be applied.",None
-GAMT (HGNC:4136),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-GAMT (HGNC:4136),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-GAMT (HGNC:4136),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-GAMT (HGNC:4136),BP7,Supporting,"A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
-GAMT specifications:
-Apply this criterion as described.",None
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGAMTVersion2.0.0_version=2.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGAMTVersion2.0.0_version=2.0.0.csv
deleted file mode 100644
index 699153a2a1d8752f7fa9a9e86a8a1b8c67005a64..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGAMTVersion2.0.0_version=2.0.0.csv
+++ /dev/null
@@ -1,406 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-GAMT (HGNC:4136),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-GAMT (HGNC:4136),PVS1,Very Strong,"Nonsense-mediated decay predicted
-
-
-Nonsense and frameshift variants
-
-
-
-
-All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 6) or the last 50 bases of the penultimate exon of the gene (exon 5, c.520). In that case, PVS1_Strong or PVS1_Moderate will be applied, depending on whether >10% or <10% of the protein is lost.
-
-
-
-
-Splice site variants (+1, +2, -1, -2)
-
-
-
-
-All canonical splice site pairs in GAMT are GT-AG.
-
-
-For any canonical splice site variant (+1, +2, -1, -2), the exon immediately adjacent to the variant is predicted to be skipped i.e. upstream exon skipped for canonical donor splice site variants and downstream exon skipped for canonical acceptor splice site variants.
-
-
-For the predicted in frame/out of frame consequences of exon skipping and assigned strength of PVS1, see Appendix 1.
-
-
-If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used.
-
-
-Use SpliceAI to look for nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing. Otherwise, the PVS1 strength should be reduced accordingly.
-
-
-Non-canonical splice variants, such as +3 or -3, will not meet PVS1, but could meet PS3 and/or PP3 criteria.
-
-
-
-
-Deletions (single or multi exon)
-
-
-
-
-If a single or multi-exon deletion results in an out of frame consequence, use PVS1 unless not predicted to undergo NMD. 
-
-
-If not predicted to undergo NMD, use PVS1_Strong if >10% of the protein is predicted to be removed, and use PVS1_Moderate if <10% of the protein is predicted to be removed.
-
-
-If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. Use PVS1_Strong if more than 10% of the protein is removed and PVS1_Moderate if <10% of the protein is removed.
-
-
-If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4.
-Appendix 1 can be used to predict the consequences of single exon deletions.
-
-
-
-
-Duplications
-
-
-
-
-Use the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042) to assess the impact of duplications.",None
-GAMT (HGNC:4136),PVS1,Strong,"Single exon or larger deletion resulting in loss of >10% of the protein.
- 
-
-
-Nonsense and frameshift variants
-
-
-
-
-All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 6) or the last 50 bases of the penultimate exon of the gene (exon 5, c.520). In that case, PVS1_Strong will be applied if >10% of the protein is lost.
-
-
-
-
-Splice site variants (+1, +2, -1, -2)
-
-
-
-
-All canonical splice site pairs in GAMT are GT-AG.
-
-
-For any canonical splice site variant (+1, +2, -1, -2), the exon immediately adjacent to the variant is predicted to be skipped i.e. upstream exon skipped for canonical donor splice site variants and downstream exon skipped for canonical acceptor splice site variants.
-
-
-Use SpliceAI to look for nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing. 
-
-
-For considerations for strength at which PVS1 may be applied see Appendix 1.
-
-
-If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used.
-
-
-Non-canonical splice variants, such as +3 or -3, will not meet PVS1, but could meet PS3 and/or PP3 criteria.
-
-
-
-
-Deletions (single or multi exon)
-
-
-
-
-If a single or multi-exon deletion results in an out of frame consequence, use PVS1 unless not predicted to undergo NMD.
-
-
- If not predicted to undergo NMD, use PVS1_Strong if >10% of the protein is predicted to be removed, and use PVS1_Moderate if <10% of the protein is predicted to be removed.
-
-
-If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. Use PVS1_Strong if more than 10% of the protein is removed and PVS1_Moderate if <10% of the protein is removed.
-
-
-If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4.
-Appendix 1 can be used to predict the consequences of single exon deletions.
-
-
-
-
-Duplications
-
-
-
-
-Use the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042) to assess the impact of duplications.",Strength
-GAMT (HGNC:4136),PVS1,Moderate,"Single exon or larger deletion resulting in loss of <10% of the protein.
-   
-
-
-Nonsense and frameshift variants
-
-
-
-
-All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 6) or the last 50 bases of the penultimate exon of the gene (exon 5, c.520). In that case, PVS1_Moderate will be applied if <10% of the protein is lost.
-
-
-
-
-Splice site variants (+1, +2, -1, -2)
-
-
-
-
-All canonical splice site pairs in GAMT are GT-AG.
-
-
-Use SpliceAI to look for nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing. 
-
-
-For any canonical splice site variant (+1, +2, -1, -2), if RT-PCR data predicts in-frame loss of <10% of the protein, apply PVS1_Moderate.
-
-
-If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used.
-
-
-Non-canonical splice variants, such as +3 or -3, will not meet PVS1, but could meet PS3 and/or PP3 criteria.
-
-
-
-
-Initiator codon variants
-
-
-
-
-All initiator codon variants will meet PVS1_Moderate. The next in-frame methionine is at amino acid position 42 (based on NP_000147.1).
-
-
-
-
-Deletions (single or multi exon)
-
-
-
-
-If a single or multi-exon deletion results in an out of frame consequence, use PVS1 unless not predicted to undergo NMD. 
-
-
-If not predicted to undergo NMD, use PVS1_Strong if >10% of the protein is predicted to be removed, and use PVS1_Moderate if <10% of the protein is predicted to be removed.
-
-
-If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. Use PVS1_Strong if more than 10% of the protein is removed and PVS1_Moderate if <10% of the protein is removed.
-
-
-If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4.
-Appendix 1 can be used to predict the consequences of single exon deletions.
-
-
-
-
-Duplications
-
-
-
-
-Use the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042) to assess the impact of duplications.",Strength
-GAMT (HGNC:4136),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-GAMT (HGNC:4136),PS1,Strong,"This criterion is applicable for any variant resulting in the same amino acid change as a variant that has been previously established as pathogenic by the CCDS VCEP, by assessment using these criteria, regardless of nucleotide change.
-
-
-If the variant is in the last 3 nucleotides of an exon, further analysis using splicing site prediction algorithms (see PP3) and data from the literature (if available) is required to investigate the impact on splicing.
-
-
-PS1 may also be applied for splicing variants under specific circumstances (see Table 3 in PMID: 37352859).",General recommendation
-GAMT (HGNC:4136),PS1,Moderate,"This criterion is applicable for any variant resulting in the same amino acid change as a variant that has been previously established as likely pathogenic by the CCDS VCEP, by assessment using these criteria, regardless of nucleotide change.
-
-
-If the variant is in the last 3 nucleotides of an exon, further analysis using splicing site prediction algorithms (see PP3) and data from the literature (if available) is required to investigate the impact on splicing.
-
-
-PS1_Moderate may also be applied for splicing variants under specific circumstances (see Table 3 in PMID: 37352859).","General recommendation,Strength"
-GAMT (HGNC:4136),PS1,Supporting,PS1_Supporting may be applied for splicing variants under specific circumstances (see Table 3 in PMID: 37352859).,"General recommendation,Strength"
-GAMT (HGNC:4136),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",NA
-GAMT (HGNC:4136),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-GAMT (HGNC:4136),PS3,Supporting,"PS3_Supporting can be assigned if a variant is expressed in GAMT-deficient fibroblasts, HeLa cells and has <15% of the control value, for values published in Mercimek-Mahmutoglu et al, 2014, PMID 24415674; Mercimek-Mahmutoglu et al, 2016, PMID 26319512; or DesRoches et al, 2016, PMID 26003046.","Disease-specific,Strength"
-GAMT (HGNC:4136),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",NA
-GAMT (HGNC:4136),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-GAMT (HGNC:4136),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-GAMT (HGNC:4136),PM2,Supporting,"Allele frequency <0.0004 (<0.04%) in all populations in gnomAD.
-
-
-It is acceptable for a GAMT variant to be present in controls, if heterozygous, because GAMT-D is a recessive disorder. Homozygotes should not be seen in a population database, such as gnomAD, because the penetrance of this condition in individuals with biallelic pathogenic variants is expected to be 100% and the condition is expected to present with severe symptoms early in life.
-
-
-GAMT specifications:
-
-
-
-
-All subpopulations in gnomAD v4.0 must have a maximum allele frequency less than 0.0004 (the highest population minor allele frequency of the most common pathogenic GAMT variant, c.327G>A, in gnomAD). Any variant with a frequency below this cutoff will meet PM2_Supporting.
-
-
-If homozygotes are observed, or variant is confirmed in trans with a known pathogenic variant, the variant will meet BS2 (assuming 100% penetrance for an individual with 2 pathogenic variants in trans).","Disease-specific,Strength"
-GAMT (HGNC:4136),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-GAMT (HGNC:4136),PM3,Very Strong,"Follow SVI guidance for PM3 (
-https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf
-).
-
-
-Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",Strength
-GAMT (HGNC:4136),PM3,Strong,"Follow SVI guidance for PM3 (
-https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf
-).
-
-
-Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",Strength
-GAMT (HGNC:4136),PM3,Moderate,"Follow SVI guidance for PM3 (
-https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf
-).
-
-
-Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",None
-GAMT (HGNC:4136),PM3,Supporting,"Follow SVI guidance for PM3 (
-https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf
-).
-
-
-Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",Strength
-GAMT (HGNC:4136),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-GAMT (HGNC:4136),PM4,Moderate,"GAMT specifications: Use this rule “as is” for stop loss variant, and in frame deletions and insertions of 2 or more amino acids, but downgrade to PM4_Supporting for single amino acid deletions and insertions.",None
-GAMT (HGNC:4136),PM4,Supporting,Downgrade to PM4_Supporting for single amino acid deletions and insertions.,Strength
-GAMT (HGNC:4136),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-GAMT (HGNC:4136),PM5,Moderate,"This criterion is applicable for any variant resulting in a different amino acid change, at the same amino acid position, as a variant that has been previously established as pathogenic by the CCDS VCEP, by assessment using these criteria, regardless of nucleotide change.
-
-
-If the variant is in the last 3 nucleotides of an exon, further analysis using splicing site prediction algorithms (see PP3) and data from the literature (if available) is required to investigate the impact on splicing. 
-
-
-If the variant is likely pathogenic, use PM5_Supporting.",None
-GAMT (HGNC:4136),PM5,Supporting,"This criterion is applicable for any variant resulting in a different amino acid change, at the same amino acid position, as a variant that has been previously established as likely pathogenic by the CCDS VCEP, by assessment using these criteria, regardless of nucleotide change.
-
-
-If the variant is in the last 3 nucleotides of an exon, further analysis using splicing site prediction algorithms (see PP3) and data from the literature (if available) is required to investigate the impact on splicing.  
-
-
-If the variant is likely pathogenic, use PM5.",Strength
-GAMT (HGNC:4136),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-GAMT (HGNC:4136),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",NA
-GAMT (HGNC:4136),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-GAMT (HGNC:4136),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-GAMT (HGNC:4136),PP3,Strong,"Missense variant with a REVEL score equal to or >0.932 (based on guidance from Pejaver et al, 2022, PMID: 36413997).","General recommendation,Strength"
-GAMT (HGNC:4136),PP3,Moderate,"Missense variant with a REVEL score 0.773-0.932 (based on guidance from Pejaver et al, 2022, PMID: 36413997).","General recommendation,Strength"
-GAMT (HGNC:4136),PP3,Supporting,"Missense variant with a REVEL score 0.644-0.773 (based on guidance from Pejaver et al, 2022, PMID: 36413997).
-
-
-In frame deletion or insertion predicted deleterious by PROVEAN and MutationTaster. Results must be consistent to count.
-
-
-For non-canonical splice site variants (e.g., +3, -3), predict the impact on splicing by using SpliceAI, 
-https://spliceailookup.broadinstitute.org/
- , and apply PP3 for a score equal to or >0.2 (as indicated in PMID: 37352859, Table 1 and Figure 4). Assess the possibility of activation of cryptic splice sites.","General recommendation,None"
-GAMT (HGNC:4136),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-GAMT (HGNC:4136),PP4,Strong,"4 points based on any combination of the following. Two or more data types are required to apply PP4_Strong:
-
-
-
-
-Elevated urine guanidinoacetate with or without low or low normal creatine (1 point).
-
-
-Elevated plasma guanidinoacetate with or without low or low normal creatine (2 points).
-
-
-Significantly decreased creatine peak in brain magnetic resonance spectroscopy with or without visible guanidinoacetate peak (3 points).
-
-
-GAMT enzyme activity <5% of normal (3 points).
-
-
-Variant must meet PM2_Supporting for PP4 to apply at any strength.
-
-
-For PP4 to be applied at strong, full GAMT gene sequencing, including all coding exons and intron/exon boundaries, must have been carried out. If not, consider downgrading.",Disease-specific
-GAMT (HGNC:4136),PP4,Moderate,"3 points based on any combination of the following. Two or more data types are recommended to apply PP4_Moderate:
-
-
-
-
-Elevated urine guanidinoacetate with or without low or low normal creatine (1 point).
-
-
-Elevated plasma guanidinoacetate with or without low or low normal creatine (2 points).
-
-
-Significantly decreased creatine peak in brain magnetic resonance spectroscopy with or without visible guanidinoacetate peak (3 points).
-
-
-GAMT enzyme activity <5% of normal (3 points).
-
-
-Variant must meet PM2_Supporting for PP4 to apply at any strength.",Strength
-GAMT (HGNC:4136),PP4,Supporting,"1-2 points based on: 
-
-
-
-
-Elevated urine guanidinoacetate with or without low or low normal creatine (1 point).
-
-
-Elevated plasma guanidinoacetate with or without low or low normal creatine (2 points).
-
-
-Variant must meet PM2_Supporting for PP4 to apply at any strength.",Disease-specific
-GAMT (HGNC:4136),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-GAMT (HGNC:4136),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-GAMT (HGNC:4136),BA1,Stand Alone,"Allele frequency >0.003 (0.3%) in gnomAD v4.0 in any continental population with >2000 alleles (based on the estimated prevalence 1 in 114,000, PMID 24071436) in gnomAD v4.0 (max allelic contribution = 100%; max genetic contribution = 100%).
-
-
-Use the highest population minor allele frequency (MAF) in any given continental population with >2,000 alleles (European non-Finnish, African, East Asian, South Asian, Latino) (PMID 30311383).",Disease-specific
-GAMT (HGNC:4136),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-GAMT (HGNC:4136),BS1,Strong,"Allele frequency >0.001 (0.1%) in gnomAD v4.0 in any continental population with >2000 alleles (based on the estimated prevalence 1 in 114,000 (PMID: 24071436) in gnomAD v4.0 (max allelic contribution = 40%; max genetic contribution = 100%).
-
-
-Use the highest population minor allele frequency (MAF) in any given continental population with >2,000 alleles (European non-Finnish, African, East Asian, South Asian, Latino) (PMID 30311383).",Disease-specific
-GAMT (HGNC:4136),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-GAMT (HGNC:4136),BS2,Strong,"Observed in the homozygous state in a healthy adult, or confirmed in trans with a variant that has been classified as pathogenic by the CCDS VCEP using these criteria.",None
-GAMT (HGNC:4136),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-GAMT (HGNC:4136),BS3,Supporting,"In vitro assays in which a variant is expressed in GAMT-deficient cultured cells (e.g. GAMT-deficient fibroblasts) or in-fusion High-Fidelity cloning of GAMT transcript and site directed mutagenesis to generate missense variant overexpressed in HeLa cells and measurement of GAMT activity in cells for wild-type and missense variant. Any variant with enzyme activity at or above 30% of normal in the following publications meets BS3_Supporting (Mercimek-Mahmutoglu et al, 2014; PMID 24415674; Mercimek-Mahmutoglu et al, 2016, PMID 26319512; DesRoches et al, 2016, PMID 26003046).","Disease-specific,Strength"
-GAMT (HGNC:4136),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",NA
-GAMT (HGNC:4136),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-GAMT (HGNC:4136),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-GAMT (HGNC:4136),BP2,Supporting,Observed in cis with a pathogenic variant (to take AR inheritance into account).,None
-GAMT (HGNC:4136),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-GAMT (HGNC:4136),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-GAMT (HGNC:4136),BP4,Supporting,"REVEL score <0.29 for missense variants (based on guidance from Pejaver et al, 2022, PMID: 36413997).
-
-
-In frame deletion or insertion predicted benign by PROVEAN and MutationTaster.
-
-
-No predicted impact on splicing by SpliceAI, 
-https://spliceailookup.broadinstitute.org/
- , based on a score <0.1 (as indicated in PMID: 37352859, Table 1 and Figure 4).","General recommendation,None"
-GAMT (HGNC:4136),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-GAMT (HGNC:4136),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-GAMT (HGNC:4136),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-GAMT (HGNC:4136),BP7,Strong,"Experimental evidence, such as RT-PCR, shows no impact on splicing. Follow the decision tree outlined in Figure 5, Walker et al, 2023, PMID: 37352859. Note that splicing may appear normal in compound heterozygous patients if the splicing defect generates a transcript that is degraded by nonsense-mediated decay. Therefore, caution must be used when assessing the data prior to applying this code.","General recommendation,Strength"
-GAMT (HGNC:4136),BP7,Supporting,"A synonymous (silent) variant OR an intronic variant at or beyond positions +7 and -21, for which SpliceAI, 
-https://spliceailookup.broadinstitute.org/
-, predicts no impact on splicing (score <0.1).",None
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGATMVersion1.1.0_version=1.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGATMVersion1.1.0_version=1.1.0.csv
deleted file mode 100644
index 0cb5f600430481d99439e32feb64322a688f0c8f..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGATMVersion1.1.0_version=1.1.0.csv
+++ /dev/null
@@ -1,337 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-GATM (HGNC:4175),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-GATM (HGNC:4175),PVS1,Very Strong,"Nonsense-mediated decay predicted.
-
-
-CCDS VCEP notes:
-Loss of function (LOF) of GATM is a known mechanism of disease for arginine:glycine amidinotransferase deficiency (AGAT-D). There are examples of various LOF variants, including nonsense and frameshift, in GATM in individuals with AGAT-D (
-https://databases.lovd.nl/shared/variants/GATM/unique
-). The specifications below are based on the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042).
-
-
-GATM specifications:
-Nonsense and frameshift variants
-* All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 9) or the last 50 bases of the penultimate exon (exon 8, 3’ of c.1109). In that case, PVS1_Strong or PVS1_Moderate will be applied depending on whether >10% or <10% of the protein is lost.
-
-
-Splice site variants (+1, +2, -1, -2)
-* All canonical splice site pairs in GATM are GT-AG.
-* For any canonical splice site variant (+1, +2, -1, -2), the exon immediately adjacent to the variant is predicted to be skipped i.e. upstream exon skipped for canonical donor splice site variants and downstream exon skipped for canonical acceptor splice site variants.
-* For the predicted in frame/out of frame consequences of exon skipping and considerations for strength of PVS1, see 
-Appendix 1
-.
-* If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used.
-* To apply PVS1, splice site variants must have no detectable nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing. Otherwise, the PVS1 strength should be reduced accordingly.
-* Non-canonical splice variants, such as +3 or -3, will not meet PVS1, but could meet PS3 and/or PP3 criteria.
-
-
-Deletions (single or multi exon)
-* If a single or multi-exon deletion results in an out of frame consequence, use PVS1 unless not predicted to undergo NMD. If not predicted to undergo NMD, use PVS1_Strong if >10% of the protein is predicted to be removed, and use PVS1_Moderate if <10% of the protein is predicted to be removed.
-* If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. Use PVS1_Strong if more than 10% of the protein is removed and PVS1_Moderate if <10% of the protein is removed.
-* If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4.
-* 
-Appendix 1
- can be used to predict the consequences of single exon deletions.
-
-
-Duplications
-* Use the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042) to assess the impact of duplications.",None
-GATM (HGNC:4175),PVS1,Strong,"In frame loss of >10% of the protein.
-CCDS VCEP notes:
-Loss of function (LOF) of GATM is a known mechanism of disease for arginine:glycine amidinotransferase deficiency (AGAT-D). There are examples of various LOF variants, including nonsense and frameshift, in GATM in individuals with AGAT-D (
-https://databases.lovd.nl/shared/variants/GATM/unique
-). The specifications below are based on the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042).
-
-
-GATM specifications:
-Nonsense and frameshift variants
-* All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 9) or the last 50 bases of the penultimate exon (exon 8, 3’ of c.1109). In that case, PVS1_Strong or PVS1_Moderate will be applied depending on whether >10% or <10% of the protein is lost.
-
-
-Splice site variants (+1, +2, -1, -2)
-* All canonical splice site pairs in GATM are GT-AG.
-* For any canonical splice site variant (+1, +2, -1, -2), the exon immediately adjacent to the variant is predicted to be skipped i.e. upstream exon skipped for canonical donor splice site variants and downstream exon skipped for canonical acceptor splice site variants.
-*Use SpliceAI and varSEAK to look for nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing. 
-* For considerations for strength at which PVS1 may be applied see 
-Appendix 1
-.
-* If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used.
-* Non-canonical splice variants, such as +3 or -3, will not meet PVS1, but could meet PS3 and/or PP3 criteria.
-
-
-Deletions (single or multi exon)
-* If a single or multi-exon deletion results in an out of frame consequence, use PVS1 unless not predicted to undergo NMD. If not predicted to undergo NMD, use PVS1_Strong if >10% of the protein is predicted to be removed, and use PVS1_Moderate if <10% of the protein is predicted to be removed.
-* If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. Use PVS1_Strong if more than 10% of the protein is removed and PVS1_Moderate if <10% of the protein is removed.
-* If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4.
-* 
-Appendix 1
- can be used to predict the consequences of single exon deletions.
-
-
-Duplications
-* Use the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042) to assess the impact of duplications.",Strength
-GATM (HGNC:4175),PVS1,Moderate,"Single exon or larger deletion resulting in loss of <10% of the protein, and initiator codon variants.
-
-
-CCDS VCEP notes:
-Loss of function (LOF) of GATM is a known mechanism of disease for arginine:glycine amidinotransferase deficiency (AGAT-D). There are examples of various LOF variants, including nonsense and frameshift, in GATM in individuals with AGAT-D (
-https://databases.lovd.nl/shared/variants/GATM/unique
-). The specifications below are based on the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042).  
-
-
-GATM specifications:
-
-
-Nonsense and frameshift variants
-* All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 9) or the last 50 bases of the penultimate exon (exon 8, 3’ of c.1109). In that case, PVS1_Moderate will be applied.
-
-
-Splice site variants (+1, +2, -1, -2)
-* All canonical splice site pairs in GATM are GT-AG.
-* For any canonical splice site variant (+1, +2, -1, -2), the exon immediately adjacent to the variant is predicted to be skipped i.e. upstream exon skipped for canonical donor splice site variants and downstream exon skipped for canonical acceptor splice site variants.
-*Use SpliceAI and varSEAK to look for nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing. 
-* For considerations for strength at which PVS1 may be applied see 
-Appendix 1
-.
-* If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used.
-* Non-canonical splice variants, such as +3 or -3, will not meet PVS1, but could meet PS3 and/or PP3 criteria.
-
-
-Initiator codon variants
-* To our knowledge, initiator codon variants have not been reported in GATM (01/2019) but may occur.
-* All initiator codon variants will meet PVS1_Moderate. The next in-frame methionine is at amino acid position 130 (based on NP_001473).
-
-
-Deletions (single or multi exon)
-* If a single or multi-exon deletion results in an out of frame consequence, use PVS1 unless not predicted to undergo NMD. If not predicted to undergo NMD, use PVS1_Strong if >10% of the protein is predicted to be removed, and use PVS1_Moderate if <10% of the protein is predicted to be removed.
-* If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. Use PVS1_Strong if more than 10% of the protein is removed and PVS1_Moderate if <10% of the protein is removed.
-* If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4.
-* 
-Appendix 1
- can be used to predict the consequences of single exon deletions.
-
-
-Duplications
-* Use the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042) to assess the impact of duplications.",Strength
-GATM (HGNC:4175),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-GATM (HGNC:4175),PS1,Strong,"This criterion is applicable as described.
-
-
-If the variant is in the last 3 nucleotides of an exon, further analysis using splicing site prediction algorithms (see PP3) and data from the literature (if available) is required to investigate the impact on splicing.",None
-GATM (HGNC:4175),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",NA
-GATM (HGNC:4175),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-GATM (HGNC:4175),PS3,Strong,"RT-PCR evidence of mis-splicing for non-canonical intronic variants with no evidence of normal splice products.
-
-
-GATM specifications:
-Any variant meeting the description for either in vitro expression or splicing assays can meet PS3 at the strengths given. If a variant meets the description for both e.g., a splice site variant with no evidence of abnormal splicing and deficient AGAT activity in vitro, PS3 must only be applied once.
-
-
-Splicing assays
-For non-canonical splicing variants, use PS3 if there is RT-PCR and/or RNA sequencing evidence demonstrating only abnormal splice products, with no evidence of normal splicing.
-* Evidence of abnormal splicing includes transcripts of alternative length or with specific intron or exon inclusion/exclusion. These studies can be performed on mRNA extracted from patient-derived cells, or by inserting the mutant genomic DNA into plasmid vectors and introducing these into human or other mammalian host cells.
-* Note that in patients who are compound heterozygotes for a splicing variant and another variants type that does not disrupt splicing, such as a missense variant, evidence of normal splicing is expected. However, the presence of normal splice products could complicate the assessment of the impact of the splice variant. Therefore, if there is any evidence of normal splice products, either when using RNA from patient cells or in an in vitro expression system, use PS3_Supporting.
-* PP3 may also be used for non-canonical splice variants meeting PS3 or PS3_Supporting.",Disease-specific
-GATM (HGNC:4175),PS3,Supporting,"<15% control activity when variant is expressed in HeLa cells, as reported in PMID 27233232.
-RT-PCR evidence of mis-splicing for non-canonical intronic variants with evidence of normal splice products.
-
-
-GATM specifications:
-Any variant meeting the description for either in vitro expression or splicing assays can meet PS3 at the strengths given. If a variant meets the description for both e.g., a splice site variant with no evidence of abnormal splicing and deficient AGAT activity in vitro, PS3 must only be applied once.  
-
-
-In vitro expression
-AGAT activity data from an in vitro assay in which GATM variants were overexpressed in HeLa cells has been published (DesRoches et al, 2016; PMID 27233232). Any variant with AGAT activity at or below 15% of normal in this paper meets PS3_Supporting (see 
-Appendix 2
- for further details on AGAT functional assays).  
-
-
-Splicing assays
-For non-canonical splicing variants, use PS3 if there is RT-PCR and/or RNA sequencing evidence demonstrating only abnormal splice products, with no evidence of normal splicing.
-* Evidence of abnormal splicing includes transcripts of alternative length or with specific intron or exon inclusion/exclusion. These studies can be performed on mRNA extracted from patient-derived cells, or by inserting the mutant genomic DNA into plasmid vectors and introducing these into human or other mammalian host cells.
-* Note that in patients who are compound heterozygotes for a splicing variant and another variants type that does not disrupt splicing, such as a missense variant, evidence of normal splicing is expected. However, the presence of normal splice products could complicate the assessment of the impact of the splice variant. Therefore, if there is any evidence of normal splice products, either when using RNA from patient cells or in an in vitro expression system, use PS3_Supporting.
-* PP3 may also be used for non-canonical splice variants meeting PS3 or PS3_Supporting.",Disease-specific
-GATM (HGNC:4175),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",NA
-GATM (HGNC:4175),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-GATM (HGNC:4175),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-GATM (HGNC:4175),PM2,Supporting,"Allele frequency <0.000055 (<0.0055%) in all populations in gnomAD.
-
-
-CCDS VCEP notes: It is acceptable for a GATM variant to be present in controls, if heterozygous, because AGAT-D is a recessive disorder. Homozygotes should not be seen in a population database, such as gnomAD, because the penetrance of this condition in individuals with biallelic pathogenic variants is expected to be 100%. 
-
-
-GATM specifications:
-
-
-
-
-All subpopulations in gnomAD must have a maximum allele frequency less than 0.000055 (based on the prevalence of the most common suspected pathogenic variants, c.484+1G>T and p.Arg169Ter) (see Appendix 3). Note – PM2 will NOT be used at moderate strength; PM2 will only be applied as a Supporting criterion.
-
-
-If homozygotes are observed, the variant will meet BS2 (assuming 100% penetrance for an individual with 2 pathogenic variants in trans).","Disease-specific,Strength"
-GATM (HGNC:4175),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-GATM (HGNC:4175),PM3,Very Strong,"Follow SVI guidance for PM3 (
-https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf
-).
-
-
-Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",Strength
-GATM (HGNC:4175),PM3,Strong,"Follow SVI guidance for PM3 (
-https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf
-).
-
-
-Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",Strength
-GATM (HGNC:4175),PM3,Moderate,"Follow SVI guidance for PM3 (
-https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf
-).
-
-
-Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",None
-GATM (HGNC:4175),PM3,Supporting,"Follow SVI guidance for PM3 (
-https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf
-).
-
-
-Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",Strength
-GATM (HGNC:4175),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-GATM (HGNC:4175),PM4,Moderate,"CCDS VCEP notes: Stop loss variants in GATM have not been reported, as far as we are aware. 
-
-
-GATM specifications: Use this rule “as is” for in frame deletions and insertions of 2 or more amino acids, but downgrade to PM4_Supporting for single amino acid deletions and insertions.",None
-GATM (HGNC:4175),PM4,Supporting,Downgrade to PM4_Supporting for in frame deletion/insertion of a single amino acid.,Strength
-GATM (HGNC:4175),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-GATM (HGNC:4175),PM5,Moderate,"If the pathogenicity of another missense change at the same amino acid residue is unknown, determine its pathogenicity using these specifications in order to determine if this criterion can be used. If the variant is pathogenic, use PM5. If the variant is likely pathogenic, use PM5_Supporting.",None
-GATM (HGNC:4175),PM5,Supporting,Missense change at an amino acid residue where a different missense change determined to be likely pathogenic has been seen before.,Strength
-GATM (HGNC:4175),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-GATM (HGNC:4175),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",NA
-GATM (HGNC:4175),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-GATM (HGNC:4175),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-GATM (HGNC:4175),PP3,Moderate,"Non-canonical splice site variant predicted to be more deleterious, by SpliceAI and varSEAK, than a previously observed pathogenic variant at the same nucleotide.",None
-GATM (HGNC:4175),PP3,Supporting,"REVEL score >0.75 for missense variants.
-
-
-In frame deletion or insertion predicted deleterious by PROVEAN and MutationTaster.
-
-
-Predicted impact on splicing by SpliceAI and varSEAK. GATM specifications:
-
-
-For missense changes, those with a REVEL score more than 0.75 will meet PP3.
-
-
-For in frame insertions and deletions, use PROVEAN and Mutation Taster. Results must be consistent to count.
-
-
-For non-canonical splice site variants (e.g., +3, -3), use SpliceAI ((
-https://spliceailookup.broadinstitute.org/
- ) and varSEAK (
-https://varseak.bio/
-). Results must be consistent to apply this criterion.
-
-
-For SpliceAI, any donor loss or acceptor loss with a score >0.5. For varSEAK, any variant with splicing class 4 or 5. Evidence for creation of a cryptic splice site should also be assessed.
-
-
-Do not apply this rule for canonical splice site changes meeting PVS1.",None
-GATM (HGNC:4175),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-GATM (HGNC:4175),PP4,Strong,"4 or more points based on any combination of the following. Two or more data types are required to meet Strong:
-• Low urine guanidinoacetate with or without low or low normal creatine (1 point)
-• Low plasma guanidinoacetate with or without low or low normal creatine (2 points)
-• Significantly decreased creatine peak in brain magnetic resonance spectroscopy (3 points)
-• AGAT enzyme activity <5% of normal (3 points)
-
-
-* Variant must meet PM2_Supporting for PP4 to apply at any strength.
-* For PP4 to be applied at strong, full GATM gene sequencing, including all coding exons and intron/exon boundaries, must have been carried out. If not, consider downgrading.",Disease-specific
-GATM (HGNC:4175),PP4,Moderate,"3 points based on any combination of the following. Two or more data types are recommended to reach moderate:
-• Low urine guanidinoacetate with or without low or low normal creatine (1 point)
-• Low plasma guanidinoacetate with or without low or low normal creatine (2 points)
-• Significantly decreased creatine peak in brain magnetic resonance spectroscopy (3 points)
-• AGAT enzyme activity <5% of normal (3 points)
-
-
-Variant must meet PM2_Supporting for PP4 to apply at any strength.",Strength
-GATM (HGNC:4175),PP4,Supporting,"1-2 points based on:
-• Low urine guanidinoacetate with or without low or low normal creatine (1 point)
-• Low plasma guanidinoacetate with or without low or low normal creatine (2 points)
-Variant must meet PM2_Supporting for PP4 to apply at any strength.",Disease-specific
-GATM (HGNC:4175),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-GATM (HGNC:4175),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-GATM (HGNC:4175),BA1,Stand Alone,"Allele frequency >0.0005 (0.05%) in gnomAD in any continental population in gnomAD with >2000 alleles.
-
-
-
-
-Any variant with a frequency >0.0005 (max allelic contribution = 100% and max genetic contribution = 100% based on estimated prevalence of 1 in 3,450,000 (PMID 27233232), and penetrance of 100%) in a continental population with >2000 alleles (European non-Finnish, African, East Asian, South Asian, Latino) (PMID 30311383).
-
-
-Use the highest population minor allele frequency (MAF) in any given continental population with >2,000 alleles (European non-Finnish, African, East Asian, South Asian, Latino) (PMID 30311383).",Disease-specific
-GATM (HGNC:4175),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-GATM (HGNC:4175),BS1,Strong,"Allele frequency >0.0001 (0.01%) in gnomAD in any continental population in gnomAD with >2000 alleles.
-
-
-
-
-Any variant with a frequency >0.0001 (max allelic contribution = 25% and max genetic contribution = 100% based on estimated prevalence of 1 in 3,450,000, (PMID 27233232), and penetrance of 100%) in a continental population with >2000 (European non-Finnish, African, East Asian, South Asian, Latino) (PMID 30311383) (see Appendix 3).
-
-
-Use the highest population minor allele frequency (MAF) in any given continental population with >2,000 alleles (European non-Finnish, African, East Asian, South Asian, Latino) (PMID 30311383).",Disease-specific
-GATM (HGNC:4175),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-GATM (HGNC:4175),BS2,Strong,Observed in the homozygous state in a healthy adult.,Disease-specific
-GATM (HGNC:4175),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-GATM (HGNC:4175),BS3,Supporting,">30% normal GAA activity when the variant is expressed in a heterologous cell type.
-GATM specifications:
-In vitro assays in which a variant is expressed in AGAT-deficient cultured cells (e.g. AGAT-deficient fibroblasts) or in-fusion High-Fidelity cloning of GATM transcript and site directed mutagenesis to generate missense variant overexpressed in HeLa cells and measurement of AGAT activity in cells for wild-type and missense variant. Any variant with enzyme activity at or above 30% of normal in DesRoches et al, 2016, PMID 27233232, meets BS3_Supporting.","Disease-specific,Strength"
-GATM (HGNC:4175),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",NA
-GATM (HGNC:4175),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-GATM (HGNC:4175),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-GATM (HGNC:4175),BP2,Supporting,"Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.
-GATM specifications:
-Observed in cis with a pathogenic variant (to take AR inheritance into account).",None
-GATM (HGNC:4175),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-GATM (HGNC:4175),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-GATM (HGNC:4175),BP4,Supporting,"REVEL score <0.15 for missense variants.
-
-
-In frame deletion or insertion predicted benign by PROVEAN and MutationTaster.
-
-
-No predicted impact on splicing by SpliceAI and varSEAK.
-GATM specifications:
-
-
-For missense changes, REVEL score <0.15.
-
-
-For in frame insertions and deletions, use PROVEAN and Mutation Taster. Results must be consistent to count.
-
-
-For non-canonical splice site variants, use SpliceAI (
-https://spliceailookup.broadinstitute.org/
- ) and varSEAK (
-https://varseak.bio/
-) to assess the impact of variants that are not +/-1 or 2 canonical splice site variants. For SpliceAI, this criterion can be applied for scores <0.2, and for varSEAK class 1 and 2. If there is any evidence for possible creation of a cryptic splice site, this criterion should not be applied.",None
-GATM (HGNC:4175),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-GATM (HGNC:4175),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-GATM (HGNC:4175),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-GATM (HGNC:4175),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,None
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGATMVersion1_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGATMVersion1_version=1.0.0.csv
deleted file mode 100644
index 5b50dc6037267d5a737c620404d135459b56837d..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGATMVersion1_version=1.0.0.csv
+++ /dev/null
@@ -1,568 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-GATM (HGNC:4175),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-GATM (HGNC:4175),PVS1,Very Strong,"Nonsense-mediated decay predicted.
-
-
-
-
-CCDS VCEP notes:
-Loss of function (LOF) of GATM is a known mechanism of disease for guanidinoacetate methyltransferase deficiency (AGAT-D). There are examples of various LOF variants, including nonsense and frameshift, in GATM in individuals with AGAT-D (
-https://databases.lovd.nl/shared/variants/GATM?search_var_status=%3D%22Marked%22%7C%3D%22Public%22
- ). The specifications below are based on the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042).
-GATM specifications:
-
-
-Nonsense and frameshift variants
-
-
-
-
-All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 9) or the last 50 bases of the penultimate exon (exon 8, 3’ of c.1109). In that case, PVS1_Moderate will be applied.
-
-
-
-
-Splice site variants (+1, +2, -1, -2)
-
-
-
-
-All canonical splice site pairs in GATM are GT-AG.
-
-
-For any canonical splice site variant (+1, +2, -1, -2), the exon immediately adjacent to the variant is predicted to be skipped i.e. upstream exon skipped for canonical donor splice site variants and downstream exon skipped for canonical acceptor splice site variants.
-
-
-For the predicted in frame/out of frame consequences of exon skipping and assigned strength of PVS1, see Appendix 1.
-
-
-If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used.
-
-
-To apply PVS1, splice site variants must have no detectable nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing. Otherwise, the PVS1 strength should be reduced accordingly.
-
-
-Non-canonical splice variants, such as +3 or -3, will not meet PVS1, but could meet PS3 and/or PP3 criteria.
-
-
-
-
-Initiator codon variants
-
-
-
-
-To our knowledge, initiator codon variants have not been reported in GATM (01/2019) but may occur.
-
-
-All initiator codon variants will meet PVS1_Moderate. The next in-frame methionine is at amino acid position 130 (based on NP_001473).
-
-
-
-
-Deletions (single or multi exon)
-
-
-
-
-If a single or multi-exon deletion results in an out of frame consequence, use PVS1 unless not predicted to undergo NMD. If not predicted to undergo NMD, use PVS1_Strong if >10% of the protein is predicted to be removed, and use PVS1_Moderate if <10% of the protein is predicted to be removed.
-
-
-If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. Use PVS1_Strong if more than 10% of the protein is removed and PVS1_Moderate if <10% of the protein is removed.
-
-
-If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4.
-
-
-Appendix 1 can be used to predict the consequences of single exon deletions.
-
-
-
-
-Duplications  
-
-
-
-
-Use the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042) to assess the impact of duplications.",None
-GATM (HGNC:4175),PVS1,Strong,"In frame loss of >10% of the protein.
-CCDS VCEP notes:
-Loss of function (LOF) of GATM is a known mechanism of disease for guanidinoacetate methyltransferase deficiency (AGAT-D). There are examples of various LOF variants, including nonsense and frameshift, in GATM in individuals with AGAT-D (
-https://databases.lovd.nl/shared/variants/GATM?search_var_status=%3D%22Marked%22%7C%3D%22Public%22
- ). The specifications below are based on the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042).
-GATM specifications:
-
-
-
-
-Nonsense and frameshift variants
-
-
-
-
-All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 9) or the last 50 bases of the penultimate exon (exon 8, 3’ of c.1109). In that case, PVS1_Moderate will be applied.
-
-
-
-
-Splice site variants (+1, +2, -1, -2)
-
-
-
-
-All canonical splice site pairs in GATM are GT-AG.
-
-
-For any canonical splice site variant (+1, +2, -1, -2), the exon immediately adjacent to the variant is predicted to be skipped i.e. upstream exon skipped for canonical donor splice site variants and downstream exon skipped for canonical acceptor splice site variants.
-
-
-For the predicted in frame/out of frame consequences of exon skipping and assigned strength of PVS1, see Appendix 1.
-
-
-If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used.
-
-
-To apply PVS1, splice site variants must have no detectable nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing. Otherwise, the PVS1 strength should be reduced accordingly.
-
-
-Non-canonical splice variants, such as +3 or -3, will not meet PVS1, but could meet PS3 and/or PP3 criteria.
-
-
-
-
-Initiator codon variants
-
-
-
-
-To our knowledge, initiator codon variants have not been reported in GATM (01/2019) but may occur.
-
-
-All initiator codon variants will meet PVS1_Moderate. The next in-frame methionine is at amino acid position 130 (based on NP_001473).
-
-
-
-
-Deletions (single or multi exon)
-
-
-
-
-If a single or multi-exon deletion results in an out of frame consequence, use PVS1 unless not predicted to undergo NMD. If not predicted to undergo NMD, use PVS1_Strong if >10% of the protein is predicted to be removed, and use PVS1_Moderate if <10% of the protein is predicted to be removed.
-
-
-If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. Use PVS1_Strong if more than 10% of the protein is removed and PVS1_Moderate if <10% of the protein is removed.
-
-
-If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4.
-
-
-Appendix 1 can be used to predict the consequences of single exon deletions.
-
-
-
-
-Duplications  
-
-
-
-
-Use the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042) to assess the impact of duplications.",Strength
-GATM (HGNC:4175),PVS1,Moderate,"Initiator codon variant.
-
-
-Single exon or larger deletion resulting in loss of <10% of the protein.
-
-
-
-
-CCDS VCEP notes:
-Loss of function (LOF) of GATM is a known mechanism of disease for guanidinoacetate methyltransferase deficiency (AGAT-D). There are examples of various LOF variants, including nonsense and frameshift, in GATM in individuals with AGAT-D (
-https://databases.lovd.nl/shared/variants/GATM?search_var_status=%3D%22Marked%22%7C%3D%22Public%22
- ). The specifications below are based on the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042).
-GATM specifications:
-
-
-Nonsense and frameshift variants
-
-
-
-
-All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 9) or the last 50 bases of the penultimate exon (exon 8, 3’ of c.1109). In that case, PVS1_Moderate will be applied.
-
-
-
-
-Splice site variants (+1, +2, -1, -2)
-
-
-
-
-All canonical splice site pairs in GATM are GT-AG.
-
-
-For any canonical splice site variant (+1, +2, -1, -2), the exon immediately adjacent to the variant is predicted to be skipped i.e. upstream exon skipped for canonical donor splice site variants and downstream exon skipped for canonical acceptor splice site variants.
-
-
-For the predicted in frame/out of frame consequences of exon skipping and assigned strength of PVS1, see Appendix 1.
-
-
-If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used.
-
-
-To apply PVS1, splice site variants must have no detectable nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing. Otherwise, the PVS1 strength should be reduced accordingly.
-
-
-Non-canonical splice variants, such as +3 or -3, will not meet PVS1, but could meet PS3 and/or PP3 criteria.
-
-
-
-
-Initiator codon variants
-
-
-
-
-To our knowledge, initiator codon variants have not been reported in GATM (01/2019) but may occur.
-
-
-All initiator codon variants will meet PVS1_Moderate. The next in-frame methionine is at amino acid position 130 (based on NP_001473).
-
-
-
-
-Deletions (single or multi exon)
-
-
-
-
-If a single or multi-exon deletion results in an out of frame consequence, use PVS1 unless not predicted to undergo NMD. If not predicted to undergo NMD, use PVS1_Strong if >10% of the protein is predicted to be removed, and use PVS1_Moderate if <10% of the protein is predicted to be removed.
-
-
-If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. Use PVS1_Strong if more than 10% of the protein is removed and PVS1_Moderate if <10% of the protein is removed.
-
-
-If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4.
-
-
-Appendix 1 can be used to predict the consequences of single exon deletions.
-
-
-
-
-Duplications  
-
-
-
-
-Use the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042) to assess the impact of duplications.",Strength
-GATM (HGNC:4175),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-GATM (HGNC:4175),PS1,Strong,"CCDS VCEP notes:
-
-
-
-
-This criterion is applicable as described.
-
-
-If the variant is in the last 3 nucleotides of an exon, further analysis using splicing site prediction algorithms (see PP3) and data from the literature (if available) is required to investigate the impact on splicing.",None
-GATM (HGNC:4175),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",NA
-GATM (HGNC:4175),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-GATM (HGNC:4175),PS3,Strong,"RT-PCR evidence of mis-splicing for non-canonical intronic variants with no evidence of normal splice products.
-
-
-
-
-GATM specifications:
-Any variant meeting the description for either in vitro expression or splicing assays can meet PS3 at the strengths given below. If a variant meets the description for both e.g., a splice site variant with no evidence of abnormal splicing and deficient AGAT activity in vitro, PS3 must only be counted once.
-In vitro expression
-AGAT activity data from an in vitro assay in which GATM variants were overexpressed in HeLa cells has been published (DesRoches et al, 2016; PMID 27233232). Any variant with AGAT activity at or below 15% of normal in this paper meets PS3_Supporting (see Appendix 2 for further details on AGAT functional assays).
-Splicing assays
-For non-canonical splicing variants, use PS3 if there is RT-PCR and/or RNA sequencing evidence demonstrating only abnormal splice products, with no evidence of normal splicing.
-
-
-
-
-Evidence of abnormal splicing includes transcripts of alternative length or with specific intron or exon inclusion/exclusion. These studies can be performed on mRNA extracted from patient-derived cells, or by inserting the mutant genomic DNA into plasmid vectors and introducing these into human or other mammalian host cells.
-
-
-Note that in patients who are compound heterozygotes for a splicing variant and another variants type that does not disrupt splicing, such as a missense variant, evidence of normal splicing is expected. However, the presence of normal splice products could complicate the assessment of the impact of the splice variant. Therefore, if there is any evidence of normal splice products, either when using RNA from patient cells or in an in vitro expression system, use PS3_Supporting.
-
-
-PP3 may also be used for non-canonical splice variants meeting PS3 or PS3_Supporting.",Disease-specific
-GATM (HGNC:4175),PS3,Supporting,"<15% control activity when variant is expressed in HeLa cells, as reported in PMID 27233232.
-
-
-RT-PCR evidence of mis-splicing for non-canonical intronic variants with evidence of normal splice products.
-
-
-
-
-GATM specifications:
-Any variant meeting the description for either in vitro expression or splicing assays can meet PS3 at the strengths given below. If a variant meets the description for both e.g., a splice site variant with no evidence of abnormal splicing and deficient AGAT activity in vitro, PS3 must only be counted once.
-In vitro expression
-AGAT activity data from an in vitro assay in which GATM variants were overexpressed in HeLa cells has been published (DesRoches et al, 2016; PMID 27233232). Any variant with AGAT activity at or below 15% of normal in this paper meets PS3_Supporting (see Appendix 2 for further details on AGAT functional assays).
-Splicing assays
-For non-canonical splicing variants, use PS3 if there is RT-PCR and/or RNA sequencing evidence demonstrating only abnormal splice products, with no evidence of normal splicing.
-
-
-
-
-Evidence of abnormal splicing includes transcripts of alternative length or with specific intron or exon inclusion/exclusion. These studies can be performed on mRNA extracted from patient-derived cells, or by inserting the mutant genomic DNA into plasmid vectors and introducing these into human or other mammalian host cells.
-
-
-Note that in patients who are compound heterozygotes for a splicing variant and another variants type that does not disrupt splicing, such as a missense variant, evidence of normal splicing is expected. However, the presence of normal splice products could complicate the assessment of the impact of the splice variant. Therefore, if there is any evidence of normal splice products, either when using RNA from patient cells or in an in vitro expression system, use PS3_Supporting.
-
-
-PP3 may also be used for non-canonical splice variants meeting PS3 or PS3_Supporting.",Disease-specific
-GATM (HGNC:4175),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",NA
-GATM (HGNC:4175),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-GATM (HGNC:4175),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-GATM (HGNC:4175),PM2,Supporting,"Allele frequency <0.000055 (<0.0055%) in all populations in gnomAD.
-CCDS VCEP notes:
-It is acceptable for a GATM variant to be present in controls, if heterozygous, because AGAT-D is a recessive disorder. Homozygotes should not be seen in a population database, such as gnomAD, because the penetrance of this condition in individuals with biallelic pathogenic variants is expected to be 100%.
-GATM specifications:
-
-
-All subpopulations in gnomAD must have a maximum allele frequency less than 0.000055 (based on the prevalence of the most common suspected pathogenic variants, c.484+1G>T and p.Arg169Ter) (see Appendix 3).
-Note – PM2 will NOT be used at moderate strength; PM2 will only be applied as a Supporting criterion.
-
-
-If homozygotes are observed, the variant will meet BS2 (assuming 100% penetrance for an individual with 2 pathogenic variants in trans).","Strength,Disease-specific"
-GATM (HGNC:4175),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-GATM (HGNC:4175),PM3,Very Strong,"Consult specifications for assigning strength of evidence for PM3.
-GATM specifications:
-
-
-
-
-Following SVI guidance for PM3 (
-https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf
-), use the scoring system below.
-
-
-Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",Strength
-GATM (HGNC:4175),PM3,Strong,"Consult specifications for assigning strength of evidence for PM3.
-GATM specifications:
-
-
-
-
-Following SVI guidance for PM3 (
-https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf
-), use the scoring system below.
-
-
-Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",Strength
-GATM (HGNC:4175),PM3,Moderate,"Consult specifications for assigning strength of evidence for PM3.
-GATM specifications:
-
-
-
-
-Following SVI guidance for PM3 (
-https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf
-), use the scoring system below.
-
-
-Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",None
-GATM (HGNC:4175),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-GATM (HGNC:4175),PM4,Moderate,"In frame deletion/insertions of two or more amino acids but less than one exon
-CCDS VCEP notes:
-• Stop loss variants in GATM have not been reported, as far as we are aware.
-GATM specifications:
-Use this rule “as is” for in frame deletions and insertions of 2 or more amino acids, but downgrade to PM4_Supporting for single amino acid deletions and insertions.",None
-GATM (HGNC:4175),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-GATM (HGNC:4175),PM5,Moderate,"GATM specifications:
-
-
-
-
-If the pathogenicity of another missense change at the same amino acid residue is unknown, determine its pathogenicity using these specifications in order to determine if this criterion can be used. If the variant is pathogenic, use PM5. If the variant is likely pathogenic, use PM5_Supporting.",None
-GATM (HGNC:4175),PM5,Supporting,Missense change at an amino acid residue where a different missense change determined to be likely pathogenic has been seen before.,Strength
-GATM (HGNC:4175),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-GATM (HGNC:4175),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",NA
-GATM (HGNC:4175),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-GATM (HGNC:4175),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-GATM (HGNC:4175),PP3,Moderate,"Non-canonical splice site variant predicted to be more deleterious than a previously observed pathogenic variant at the same nucleotide.
-GATM specifications:
-
-
-For missense changes, those with a REVEL score more than 0.75 will meet PP3.
-
-
-For in frame insertions and deletions, use PROVEAN and Mutation Taster. Results must be consistent to count.
-
-
-For non-canonical splice site variants (e.g., +3, -3), use SpliceAI ((
-https://spliceailookup.broadinstitute.org/
- ) and varSEAK (
-https://varseak.bio/
-). Results must be consistent to apply this criterion.
-
-
-For SpliceAI, any donor loss or acceptor loss with a score >0.5. For varSEAK, any variant with splicing class 4 or 5. Evidence for creation of a cryptic splice site should also be assessed.
-
-
-Do not apply this rule for canonical splice site changes meeting PVS1.
-
-
-Upgrade to PP3_Moderate if a different non-canonical splice site variant at the same position is known to be pathogenic AND the newly observed variant is at least as deleterious as the previously observed variant, based on in silico prediction (Human Splicing Finder, MaxEntScan) e.g. variant being interpreted is +3C>G, previously reported variant is +3C>T and +3C>G is predicted to be more deleterious than +3C>T.",None
-GATM (HGNC:4175),PP3,Supporting,"REVEL score >0.75 for missense variants.
-
-
-In frame deletion or insertion predicted deleterious by PROVEAN and MutationTaster.
-
-
-Predicted impact on splicing by SpliceAI and varSEAK.
-GATM specifications:
-
-
-For missense changes, those with a REVEL score more than 0.75 will meet PP3.
-
-
-For in frame insertions and deletions, use PROVEAN and Mutation Taster. Results must be consistent to count.
-
-
-For non-canonical splice site variants (e.g., +3, -3), use SpliceAI ((
-https://spliceailookup.broadinstitute.org/
- ) and varSEAK (
-https://varseak.bio/
-). Results must be consistent to apply this criterion.
-
-
-For SpliceAI, any donor loss or acceptor loss with a score >0.5. For varSEAK, any variant with splicing class 4 or 5. Evidence for creation of a cryptic splice site should also be assessed.
-
-
-Do not apply this rule for canonical splice site changes meeting PVS1.
-
-
-Upgrade to PP3_Moderate if a different non-canonical splice site variant at the same position is known to be pathogenic AND the newly observed variant is at least as deleterious as the previously observed variant, based on in silico prediction (Human Splicing Finder, MaxEntScan) e.g. variant being interpreted is +3C>G, previously reported variant is +3C>T and +3C>G is predicted to be more deleterious than +3C>T.",None
-GATM (HGNC:4175),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-GATM (HGNC:4175),PP4,Strong,"Any combination of the data listed for PP4_Moderate and PP4.
-(see points scheme in main document)
-GATM specifications:
-The following table shows the weight used for PP4 depending upon the data that is available. Assign points for each type of data present, and then add up the points.
-PP4 = 1-2 points
-PP4_Moderate = 3 points
-PP4_Strong = 4 points
-Two or more data types are recommended to reach moderate and required to reach strong.
-
-
-
-
-Variant must meet PM2_Supporting for PP4 to apply at any strength.
-
-
-For PP4 to be applied at strong, full GATM gene sequencing, including all coding exons and intron/exon boundaries, must have been carried out. If not, consider downgrading.",Disease-specific
-GATM (HGNC:4175),PP4,Moderate,"Significantly decreased creatine peak on 1H-MRS.
-
-
-GATM activity <5% normal in fibroblasts.
-GATM specifications:
-The following table shows the weight used for PP4 depending upon the data that is available. Assign points for each type of data present, and then add up the points.
-PP4 = 1-2 points
-PP4_Moderate = 3 points
-PP4_Strong = 4 points
-Two or more data types are recommended to reach moderate and required to reach strong.
-
-
-Variant must meet PM2_Supporting for PP4 to apply at any strength.
-
-
-For PP4 to be applied at strong, full GATM gene sequencing, including all coding exons and intron/exon boundaries, must have been carried out. If not, consider downgrading.",Strength
-GATM (HGNC:4175),PP4,Supporting,"Low GAA in plasma and low to low-normal creatine in plasma.
-GATM specifications:
-The following table shows the weight used for PP4 depending upon the data that is available. Assign points for each type of data present, and then add up the points.
-PP4 = 1-2 points
-PP4_Moderate = 3 points
-PP4_Strong = 4 points
-Two or more data types are recommended to reach moderate and required to reach strong.
-
-
-Variant must meet PM2_Supporting for PP4 to apply at any strength.
-
-
-For PP4 to be applied at strong, full GATM gene sequencing, including all coding exons and intron/exon boundaries, must have been carried out. If not, consider downgrading.",Disease-specific
-GATM (HGNC:4175),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-GATM (HGNC:4175),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-GATM (HGNC:4175),BA1,Stand Alone,"Allele frequency >0.0005 (0.05%) in gnomAD in any continental population in gnomAD with >2000 alleles.
-GATM specifications:
-
-
-
-
-Any variant with a frequency >0.0005 (max allelic contribution = 100% and max genetic contribution = 100% based on estimated prevalence of 1 in 3,450,000 (PMID 27233232), and penetrance of 100%) in a continental population with >2000 alleles (European non-Finnish, African, East Asian, South Asian, Latino) (PMID 30311383)(See Appendix 3).
-
-
-Use the highest population minor allele frequency (MAF) in any given continental population with >2,000 alleles (European non-Finnish, African, East Asian, South Asian, Latino) (PMID 30311383).",Disease-specific
-GATM (HGNC:4175),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-GATM (HGNC:4175),BS1,Strong,"Allele frequency >0.0001 (0.01%) in gnomAD in any continental population in gnomAD with >2000 alleles.
-GATM specifications:
-
-
-
-
-Any variant with a frequency >0.0001 (max allelic contribution = 25% and max genetic contribution = 100% based on estimated prevalence of 1 in 3,450,000, (PMID 27233232), and penetrance of 100%) in a continental population with >2000 (European non-Finnish, African, East Asian, South Asian, Latino) (PMID 30311383) (see Appendix 3).
-
-
-Use the highest population minor allele frequency (MAF) in any given continental population with >2,000 alleles (European non-Finnish, African, East Asian, South Asian, Latino) (PMID 30311383).",Disease-specific
-GATM (HGNC:4175),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-GATM (HGNC:4175),BS2,Strong,Observed in the homozygous state in a healthy adult.,Disease-specific
-GATM (HGNC:4175),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-GATM (HGNC:4175),BS3,Supporting,"30% normal GAA activity when the variant is expressed in a heterologous cell type.
-GATM specifications:
-In vitro assays
-In vitro assays in which a variant is expressed in AGAT-deficient cultured cells (e.g. AGAT-deficient fibroblasts) or in-fusion High-Fidelity cloning of GATM transcript and site directed mutagenesis to generate missense variant overexpressed in HeLa cells and measurement of AGAT activity in cells for wild-type and missense variant. Any variant with enzyme activity at or above 30% of normal in DesRoches et al, 2016, PMID 27233232, meets BS3_Supporting.","Strength,Disease-specific"
-GATM (HGNC:4175),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",NA
-GATM (HGNC:4175),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-GATM (HGNC:4175),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-GATM (HGNC:4175),BP2,Supporting,"Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.
-GATM specifications:
-Observed in cis with a pathogenic variant (to take AR inheritance into account).",None
-GATM (HGNC:4175),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-GATM (HGNC:4175),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-GATM (HGNC:4175),BP4,Supporting,"REVEL score <0.15 for missense variants.
-
-
-In frame deletion or insertion predicted benign by PROVEAN and MutationTaster.
-
-
-No predicted impact on splicing by SpliceAI and varSEAK.
-GATM specifications:
-
-
-For missense changes, REVEL score <0.15.
-
-
-For in frame insertions and deletions, use PROVEAN and Mutation Taster. Results must be consistent to count.
-
-
-For non-canonical splice site variants, use SpliceAI (
-https://spliceailookup.broadinstitute.org/
- ) and varSEAK (
-https://varseak.bio/
-) to assess the impact of variants that are not +/-1 or 2 canonical splice site variants. For SpliceAI, this criterion can be applied for scores <0.2, and for varSEAK class 1 and 2. If there is any evidence for possible creation of a cryptic splice site, this criterion should not be applied.",None
-GATM (HGNC:4175),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-GATM (HGNC:4175),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-GATM (HGNC:4175),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-GATM (HGNC:4175),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,None
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGATMVersion2.0.0_version=2.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGATMVersion2.0.0_version=2.0.0.csv
deleted file mode 100644
index ce6af02e18e217cfc353b41356c76304abb15e12..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGATMVersion2.0.0_version=2.0.0.csv
+++ /dev/null
@@ -1,272 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-GATM (HGNC:4175),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-GATM (HGNC:4175),PVS1,Very Strong,"Nonsense-mediated decay predicted.
-
-
-CCDS VCEP notes:
-Loss of function (LOF) of GATM is a known mechanism of disease for arginine:glycine amidinotransferase deficiency (AGAT-D). There are examples of various LOF variants, including nonsense and frameshift, in GATM in individuals with AGAT-D (
-https://databases.lovd.nl/shared/variants/GATM/unique
-). The specifications below are based on the PVS1 decision tree (see Appendix 1) (based on Figure 1, Abou Tayoun et al, 2018, PMID 30192042).
-
-
-GATM specifications:
-Nonsense and frameshift variants
-* All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 9) or the last 50 bases of the penultimate exon (exon 8, 3’ of c.1109). In that case, please refer to the PVS1 flowchart for guidance on PVS1 weight (Appendix 1).
-
-
-Splice site variants (+1, +2, -1, -2)
-* All canonical splice site pairs in GATM are GT-AG.
-* For any canonical splice site variant (+1, +2, -1, -2), the exon immediately adjacent to the variant is predicted to be skipped i.e. upstream exon skipped for canonical donor splice site variants and downstream exon skipped for canonical acceptor splice site variants. However, to apply PVS1 at the very strong level, splice site variants must have no detectable nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing, as predicted by SpliceAI. Otherwise, the PVS1 strength should be reduced accordingly.
-* For the predicted in frame/out of frame consequences of exon skipping and considerations for strength of PVS1, see Appendix 1 (PVS1 flowchart) and Appendix 2 (predicted impact of exon loss).
-* If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used.
-* Non-canonical splice variants, such as +3 or -3, may also meet PVS1 - refer to Walker et al, PMID: 37352859.
-
-
-Deletions (single or multi exon)
-* If a single or multi-exon deletion results in an out of frame consequence, use PVS1 at the very strong level unless not predicted to undergo NMD. If not predicted to undergo NMD, please refer to Appendix 1 (PVS1 flowchart) and Appendix 2 (predicted impact of exon loss).
-* If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. For weight of PVS1, see Appendix 1 (PVS1 flowchart) and Appendix 2 (predicted impact of exon loss) .
-* If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4.
-
-
-Duplications
-* To assess the impact of duplications, see Appendix 1 (PVS1 flowchart) and Appendix 2 (predicted impact of exon loss).",None
-GATM (HGNC:4175),PVS1,Strong,"In frame loss of >10% of the protein.
-CCDS VCEP notes:
-Loss of function (LOF) of GATM is a known mechanism of disease for arginine:glycine amidinotransferase deficiency (AGAT-D). There are examples of various LOF variants, including nonsense and frameshift, in GATM in individuals with AGAT-D (
-https://databases.lovd.nl/shared/variants/GATM/unique
-). The specifications below are based on the PVS1 decision tree (see Appendix 1) (Figure 1, Abou Tayoun et al, 2018, PMID 30192042).
-
-
-GATM specifications:
-Nonsense and frameshift variants
-* All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 9) or the last 50 bases of the penultimate exon (exon 8, 3’ of c.1109). In that case, please refer to the PVS1 flowchart for guidance on PVS1 weight (Appendix 1).
-
-
-Splice site variants (+1, +2, -1, -2)
-* All canonical splice site pairs in GATM are GT-AG.
-* For any canonical splice site variant (+1, +2, -1, -2), the exon immediately adjacent to the variant is predicted to be skipped i.e. upstream exon skipped for canonical donor splice site variants and downstream exon skipped for canonical acceptor splice site variants. However, it is recommended to use SpliceAI to look for nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing. 
-* For considerations for strength at which PVS1 may be applied see Appendix 1 (PVS1 flowchart) and Appendix 2 (predicted impact of exon loss) .
-* If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used.
-* Non-canonical splice variants, such as +3 or -3, may also meet PVS1 - refer to Walker et al, PMID: 37352859.
-
-
-Deletions (single or multi exon)
-* If a single or multi-exon deletion results in an out of frame consequence, use PVS1 at the very strong level unless not predicted to undergo NMD. If not predicted to undergo NMD, please refer to Appendix 1 (PVS1 flowchart) and Appendix 2 (predicted impact of exon loss).
-* If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. For weight of PVS1, see Appendix 1 (PVS1 flowchart) and Appendix 2 (predicted impact of exon loss) .
-* If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4.
-
-
-Duplications
-* To assess the impact of duplications, see Appendix 1 (PVS1 flowchart) and Appendix 2 (predicted impact of exon loss).",Strength
-GATM (HGNC:4175),PVS1,Moderate,"Single exon or larger deletion resulting in loss of <10% of the protein, and initiator codon variants.
-
-
-CCDS VCEP notes:
-Loss of function (LOF) of GATM is a known mechanism of disease for arginine:glycine amidinotransferase deficiency (AGAT-D). There are examples of various LOF variants, including nonsense and frameshift, in GATM in individuals with AGAT-D (
-https://databases.lovd.nl/shared/variants/GATM/unique
-). The specifications below are based on the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042).  
-
-
-GATM specifications:
-
-
-Nonsense and frameshift variants
-* All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 9) or the last 50 bases of the penultimate exon (exon 8, 3’ of c.1109). In that case, please refer to the PVS1 flowchart for guidance on PVS1 weight (Appendix 1).
-
-
-Splice site variants (+1, +2, -1, -2)
-* All canonical splice site pairs in GATM are GT-AG.
-* For any canonical splice site variant (+1, +2, -1, -2), the exon immediately adjacent to the variant is predicted to be skipped i.e. upstream exon skipped for canonical donor splice site variants and downstream exon skipped for canonical acceptor splice site variants. However, it is recommended to look for nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing. 
-* For considerations for strength at which PVS1 may be applied see Appendix 1 (PVS1 flowchart) and Appendix 2 (predicted impact of exon loss).
-* If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used.
-* Non-canonical splice variants, such as +3 or -3, may also meet PVS1 (refer to Walker et al, PMID: 37352859).
-
-
-Initiator codon variants
-* All initiator codon variants will meet PVS1_Moderate. The next in-frame methionine is at amino acid position 130 (based on NP_001473). 
-
-
-Deletions (single or multi exon)
-* If a single or multi-exon deletion results in an out of frame consequence, use PVS1 at the very strong level unless not predicted to undergo NMD. If not predicted to undergo NMD, please refer to Appendix 1 (PVS1 flowchart) and Appendix 2 (predicted impact of exon loss).
-* If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. For weight of PVS1, see Appendix 1 (PVS1 flowchart) and Appendix 2 (predicted impact of exon loss) .
-* If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4.
-
-
-Duplications
-* To assess the impact of duplications, see Appendix 1 (PVS1 flowchart) and Appendix 2 (predicted impact of exon loss).",Strength
-GATM (HGNC:4175),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-GATM (HGNC:4175),PS1,Strong,"This criterion is applicable as is for any variant resulting in the same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-
-
-If the variant is in the last 3 nucleotides of an exon, further analysis using splicing site prediction algorithms (see PP3) and data from the literature (if available) is required to investigate the impact on splicing.
-
-
-PS1 may also be applied for splicing variants under specific circumstances (see Table 3 in PMID: 37352859).",General recommendation
-GATM (HGNC:4175),PS1,Moderate,"This criterion is applicable as for any variant resulting in the same amino acid change as a previously established likely pathogenic variant regardless of nucleotide change.
-
-
-If the variant is in the last 3 nucleotides of an exon, further analysis using splicing site prediction algorithms (see PP3) and data from the literature (if available) is required to investigate the impact on splicing.
-
-
-PS1_Moderate may also be applied for splicing variants under specific circumstances (see Table 3 in PMID: 37352859).","General recommendation,Strength"
-GATM (HGNC:4175),PS1,Supporting,PS1_Supporting may be applied for splicing variants under specific circumstances (see Table 3 in PMID: 37352859).,"General recommendation,Strength"
-GATM (HGNC:4175),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",NA
-GATM (HGNC:4175),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-GATM (HGNC:4175),PS3,Supporting,"AGAT activity data from an in vitro assay in which GATM variants were overexpressed in HeLa cells has been published (DesRoches et al, 2016; PMID 27233232). Any variant with AGAT activity at or below 15% of normal in this paper meets PS3_Supporting (see Appendix 3 for further details on AGAT functional assays).","Disease-specific,Strength"
-GATM (HGNC:4175),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",NA
-GATM (HGNC:4175),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-GATM (HGNC:4175),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-GATM (HGNC:4175),PM2,Supporting,"Allele frequency <0.000055 (<0.0055%) in all populations in gnomAD.
-
-
-CCDS VCEP notes: It is acceptable for a GATM variant to be present in controls, if heterozygous, because AGAT-D is a recessive disorder. Homozygotes should not be seen in a population database, such as gnomAD, because the penetrance of this condition in individuals with biallelic pathogenic variants is expected to be 100%. 
-
-
-GATM specifications:
-
-
-
-
-All subpopulations in gnomAD must have a maximum allele frequency less than 0.000055 (based on the prevalence of the most common suspected pathogenic variants, c.484+1G>T and p.Arg169Ter) (see Appendix 4). Use the current version recommended by SVI; version number will be stated in classification summary.
-
-
-Note – PM2 will NOT be used at moderate strength; PM2 will only be applied as a Supporting criterion.
-
-
-If homozygotes are observed, the variant will meet BS2 (assuming 100% penetrance for an individual with 2 pathogenic variants in trans).","Disease-specific,Strength"
-GATM (HGNC:4175),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-GATM (HGNC:4175),PM3,Very Strong,"Follow SVI guidance for PM3 (
-https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf
-).
-
-
-Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",Strength
-GATM (HGNC:4175),PM3,Strong,"Follow SVI guidance for PM3 (
-https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf
-).
-
-
-Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",Strength
-GATM (HGNC:4175),PM3,Moderate,"Follow SVI guidance for PM3 (
-https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf
-).
-
-
-Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",None
-GATM (HGNC:4175),PM3,Supporting,"Follow SVI guidance for PM3 (
-https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf
-).
-
-
-Parental testing, or another appropriate molecular method (such as cloning each allele separately followed by sequencing), must have been performed in order to confirm that the variants are in trans if the patient is compound heterozygous.",Strength
-GATM (HGNC:4175),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-GATM (HGNC:4175),PM4,Moderate,"CCDS VCEP notes: Stop loss variants in GATM have not been reported, as far as we are aware. 
-
-
-GATM specifications: Use this rule “as is” for in frame deletions and insertions of 2 or more amino acids, but downgrade to PM4_Supporting for single amino acid deletions and insertions.",None
-GATM (HGNC:4175),PM4,Supporting,Downgrade to PM4_Supporting for in frame deletion/insertion of a single amino acid.,Strength
-GATM (HGNC:4175),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-GATM (HGNC:4175),PM5,Moderate,"If the pathogenicity of another missense change at the same amino acid residue is unknown, determine its pathogenicity using these specifications in order to determine if this criterion can be used. If the variant is pathogenic, use PM5. If the variant is likely pathogenic, use PM5_Supporting.",None
-GATM (HGNC:4175),PM5,Supporting,Missense change at an amino acid residue where a different missense change determined to be likely pathogenic has been seen before.,Strength
-GATM (HGNC:4175),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-GATM (HGNC:4175),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",NA
-GATM (HGNC:4175),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-GATM (HGNC:4175),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-GATM (HGNC:4175),PP3,Moderate,"Missense variant with a REVEL score >0.773 (based on guidance from Pejaver et al, 2022, PMID: 36413997).","General recommendation,Strength"
-GATM (HGNC:4175),PP3,Supporting,"Missense variant with a REVEL score 0.644-0.773 (based on guidance from Pejaver et al, 2022, PMID: 36413997).
-
-
-In frame deletion or insertion predicted deleterious by PROVEAN and MutationTaster. Results must be consistent to count.
-
-
-For non-canonical splice site variants (e.g., +3, -3), predict the impact on splicing by using SpliceAI, 
-https://spliceailookup.broadinstitute.org/
- , and apply PP3 for a score equal to or >0.2 (as indicated in PMID: 37352859, Table 1 and Figure 4). Assess the possibility of activation of cryptic splice sites.",General recommendation
-GATM (HGNC:4175),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-GATM (HGNC:4175),PP4,Strong,"4 or more points based on any combination of the following. Two or more data types are required to meet Strong:
-• Low urine guanidinoacetate with or without low or low normal creatine (1 point)
-• Low plasma guanidinoacetate with or without low or low normal creatine (2 points)
-• Significantly decreased creatine peak in brain magnetic resonance spectroscopy (3 points)
-• AGAT enzyme activity <5% of normal (3 points)
-
-
-* Variant must meet PM2_Supporting for PP4 to apply at any strength.
-* For PP4 to be applied at strong, full GATM gene sequencing, including all coding exons and intron/exon boundaries, must have been carried out. If not, consider downgrading.",Disease-specific
-GATM (HGNC:4175),PP4,Moderate,"3 points based on any combination of the following. Two or more data types are recommended to reach moderate:
-• Low urine guanidinoacetate with or without low or low normal creatine (1 point)
-• Low plasma guanidinoacetate with or without low or low normal creatine (2 points)
-• Significantly decreased creatine peak in brain magnetic resonance spectroscopy (3 points)
-• AGAT enzyme activity <5% of normal (3 points)
-
-
-Variant must meet PM2_Supporting for PP4 to apply at any strength.",Strength
-GATM (HGNC:4175),PP4,Supporting,"1-2 points based on:
-• Low urine guanidinoacetate with or without low or low normal creatine (1 point)
-• Low plasma guanidinoacetate with or without low or low normal creatine (2 points)
-Variant must meet PM2_Supporting for PP4 to apply at any strength.",Disease-specific
-GATM (HGNC:4175),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-GATM (HGNC:4175),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-GATM (HGNC:4175),BA1,Stand Alone,"GrpMax >0.0005 (0.05%) in gnomAD
-
-
-
-
-Any variant with a GrpMax (lower bound 95%ile) >0.0005 in gnomAD. Use the current version recommended by SVI; version number will be stated in classification summary. 
-
-
-Threshold based on (max allelic contribution = 100% and max genetic contribution = 100% based on estimated prevalence of 1 in 3,450,000 (PMID 27233232), and penetrance of 100%) (PMID 30311383) (see Appendix 3)",Disease-specific
-GATM (HGNC:4175),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-GATM (HGNC:4175),BS1,Strong,"GrpMax >0.0001 (0.01%) in gnomAD
-
-
-
-
-Any variant with a GrpMax (lower bound 95%ile) >0.0001 in gnomAD. Use the current version recommended by SVI; version number will be stated in classification summary.
-
-
- Threshold based on max allelic contribution = 25% and max genetic contribution = 100% based on estimated prevalence of 1 in 3,450,000, (PMID 27233232), and penetrance of 100%) (PMID 30311383) (see Appendix 3).",Disease-specific
-GATM (HGNC:4175),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-GATM (HGNC:4175),BS2,Strong,Observed in the homozygous state in a healthy adult.,Disease-specific
-GATM (HGNC:4175),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-GATM (HGNC:4175),BS3,Supporting,"In vitro assays in which a variant is expressed in AGAT-deficient cultured cells (e.g. AGAT-deficient fibroblasts) or in-fusion High-Fidelity cloning of GATM transcript and site directed mutagenesis to generate missense variant overexpressed in HeLa cells and measurement of AGAT activity in cells for wild-type and missense variant. Any variant with enzyme activity at or above 30% of normal in DesRoches et al, 2016, PMID 27233232, meets BS3_Supporting.","Disease-specific,Strength"
-GATM (HGNC:4175),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",NA
-GATM (HGNC:4175),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-GATM (HGNC:4175),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-GATM (HGNC:4175),BP2,Supporting,Observed in cis with a pathogenic variant (to take AR inheritance for AGAT deficiency into account).,None
-GATM (HGNC:4175),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-GATM (HGNC:4175),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-GATM (HGNC:4175),BP4,Supporting,"REVEL score <0.29 for missense variants (based on guidance from Pejaver et al, 2022, PMID: 36413997).
-
-
-In frame deletion or insertion predicted benign by MutPredIndel and MutationTaster.
-
-
-No predicted impact on splicing by SpliceAI, 
-https://spliceailookup.broadinstitute.org/
- , based on a score <0.1 (as indicated in PMID: 37352859, Table 1 and Figure 4).","General recommendation,None"
-GATM (HGNC:4175),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-GATM (HGNC:4175),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-GATM (HGNC:4175),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-GATM (HGNC:4175),BP7,Strong,"Experimental evidence, such as RT-PCR, shows no impact on splicing. Follow the decision tree outlined in Figure 5, Walker et al, 2023, PMID: 37352859. Note that splicing may appear normal in compound heterozygous patients with one allele that is degraded by nonsense-mediated decay as the results of a frameshift and premature termination codon due to splicing defect. Therefore. caution must be used in asessing the data prior to applying this code.","General recommendation,Strength"
-GATM (HGNC:4175),BP7,Supporting,"A synonymous (silent) variant OR an intronic variant at or beyond positions +7 and -21, for which SpliceAI, 
-https://spliceailookup.broadinstitute.org/
-, predicts no impact on splicing (score <0.1) (see Walker et al, 2023, PMID: 37352859).",None
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSLC6A8Version1.1.0_version=1.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSLC6A8Version1.1.0_version=1.1.0.csv
deleted file mode 100644
index 0f8d3dfece84434f8dd26a36e7344c00f333a4d2..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSLC6A8Version1.1.0_version=1.1.0.csv
+++ /dev/null
@@ -1,209 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-SLC6A8 (HGNC:11055),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-SLC6A8 (HGNC:11055),PVS1,Very Strong,"Loss of function is a known mechanism of disease for Creatine Transporter Deficiency.
-
-
-Specifications are based on the decision tree as outlined in Tayoun etal, 2018 (Hum Mutat. 2018 Nov;39(11):1517-1524; PMID: 30192042) SLC6A8: PVS1, at appropriate strength, is applicable as described in Abou Tayoun et al, 2018 (PMID: 30192042)",None
-SLC6A8 (HGNC:11055),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SLC6A8 (HGNC:11055),PS1,Strong,PS1 is applicable as described.,None
-SLC6A8 (HGNC:11055),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-SLC6A8 (HGNC:11055),PS2,Strong,"Note: Confirmation of paternity in females only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.
-
-
-X-linked disorder. Only maternity needs to be confirmed.","Disease-specific,None"
-SLC6A8 (HGNC:11055),PS2,Moderate,Newly hemizygous male with the variant identified de novo in the mother with no family history of other affected males.,"Disease-specific,Strength"
-SLC6A8 (HGNC:11055),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-SLC6A8 (HGNC:11055),PS3,Strong,"RT-PCR evidence of mis-splicing for non-canonical intronic variants.
-
-
-For non-canonical splicing variants, RT-PCR evidence demonstrating transcripts of alternative length or specific intron or exon inclusion/exclusion. These studies can be performed in patient derived cells, by placing the mutant genomic DNA into plasmid vectors, or by over-expressing mutant transcript. Assays should demonstrate defective splicing with RT-PCR analysis or RNA sequencing to confirm alternative transcripts.",Disease-specific
-SLC6A8 (HGNC:11055),PS3,Supporting,"Creatine transport activity <10% wild type with less than or equal to 125uM creatine used in SLC6A8 deficient fibroblasts
-
-
-RT-PCR evidence of mis-splicing for non-canonical intronic variants with evidence of normal splice products.
-For non-canonical splicing variants, RT-PCR evidence demonstrating transcripts of alternative length or specific intron or exon inclusion/exclusion. These studies can be performed in patient derived cells, by placing the mutant genomic DNA into plasmid vectors, or by over-expressing mutant transcript. Assays should demonstrate defective splicing with RT-PCR analysis or RNA sequencing to confirm alternative transcripts.",Disease-specific
-SLC6A8 (HGNC:11055),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-SLC6A8 (HGNC:11055),PS4,Very Strong,"4 independent male probands with elevated urine creatine/creatinine ratio on one occasion at minimum, in addition to any proband used for PP4.
-
-
-Variant must meet PM2_Supporting criterion for PS4 to apply.",Strength
-SLC6A8 (HGNC:11055),PS4,Strong,"3 independent male probands with elevated urine creatine/creatinine ratio on one occasion at minimum, in addition to any proband used for PP4.
-
-
-Variant must meet PM2_Supporting criterion for PS4 to apply.",Disease-specific
-SLC6A8 (HGNC:11055),PS4,Moderate,"2 independent male probands with elevated urine creatine/creatinine ratio on one occasion at minimum, in addition to any proband used for PP4.
-
-
-Variant must meet PM2_Supporting criterion for PS4 to apply.",Strength
-SLC6A8 (HGNC:11055),PS4,Supporting,"One independent male proband in addition to any proband used for PP4.
-
-
-Variant must meet PM2_Supporting criterion for PS4 to apply.",Strength
-SLC6A8 (HGNC:11055),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-SLC6A8 (HGNC:11055),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-SLC6A8 (HGNC:11055),PM2,Supporting,Absent/rare from controls in an ethnically-matched cohort population sample. Threshold: <0.00002 (0.002%) AND 0 hemizygotes in gnomAD.,Disease-specific
-SLC6A8 (HGNC:11055),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-SLC6A8 (HGNC:11055),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-SLC6A8 (HGNC:11055),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,None
-SLC6A8 (HGNC:11055),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SLC6A8 (HGNC:11055),PM5,Moderate,Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.,None
-SLC6A8 (HGNC:11055),PM5,Supporting,Missense change at an amino acid residue where a different missense change determined to be likely pathogenic has been seen before.,Strength
-SLC6A8 (HGNC:11055),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-SLC6A8 (HGNC:11055),PM6,Moderate,Variant identified as de novo in an affected male with the mother negative for the variant but maternity not confirmed.,No change
-SLC6A8 (HGNC:11055),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-SLC6A8 (HGNC:11055),PP1,Strong,"3 affected segregations + 0 unaffected segregations OR
-
-
-2 affected segregations + 3 unaffected segregations",Strength
-SLC6A8 (HGNC:11055),PP1,Moderate,2 affected segregations + 0 unaffected segregations.,Strength
-SLC6A8 (HGNC:11055),PP1,Supporting,1 affected family member + 3 unaffected segregations.,Disease-specific
-SLC6A8 (HGNC:11055),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-SLC6A8 (HGNC:11055),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-SLC6A8 (HGNC:11055),PP3,Supporting,"REVEL score >0.75 for missense variants
-
-
-In frame deletion or insertion predicted deleterious by PROVEAN, MutPred indel, and MutationTaster.
-
-
-Predicted impact on splicing by SpliceAI and varSEAK.",None
-SLC6A8 (HGNC:11055),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-SLC6A8 (HGNC:11055),PP4,Strong,"4 or more points based on combinations of the following. 
-
-
-
-
-Elevated urine creatine/creatinine ratio on one occasion (1 point)
-
-
-Elevated urine creatine/creatinine ratio on more than one occasion (2 points)
-
-
-Significantly decreased creatine peak, with absent guanidinoacetate peak, if reported (3 points)
-
-
-Deficient creatine uptake in cultured fibroblasts (<10% of normal with <125uM creatine) (3 points)
-
-
-
-
-Additional specifications:
-
-
-
-
-Two or more data types are required for PP4_Strong.
-
-
-An individual used to assign PP4, at any weight, cannot be also included for PS4 count. If multiple unrelated probands with the variant have been identified, it is recommended that the case with the highest PP4 points is assigned the appropriate weight for PP4, and the other cases are used for PS4.
-
-
-Variant must meet PM2_Supporting for PP4 to apply at any strength.
-
-
-For PP4 to be applied at strong, full SLC6A8 gene sequencing, including all coding exons and intron/exon boundaries, must have been carried out. If not, consider downgrading.",Disease-specific
-SLC6A8 (HGNC:11055),PP4,Moderate,"3 or more points based on: 
-
-
-
-
-Elevated urine creatine/creatinine ratio on one occasion (1 point)
-
-
-Elevated urine creatine/creatinine ratio on more than one occasion (2 points)
-
-
-Significantly decreased creatine peak, with absent guanidinoacetate peak, if reported (3 points)
-
-
-Deficient creatine uptake in cultured fibroblasts (<10% of normal with <125uM creatine) (3 points)
-
-
-
-
-Additional specifications:
-
-
-
-
-Two or more data types are recommended for PP4_Moderate.
-
-
-An individual used to assign PP4, at any weight, cannot be also included for PS4 count. If multiple unrelated probands with the variant have been identified, it is recommended that the case with the highest PP4 points is assigned the appropriate weight for PP4, and the other cases are used for PS4.
-
-
-Variant must meet PM2_Supporting for PP4 to apply at any strength.",Strength
-SLC6A8 (HGNC:11055),PP4,Supporting,"1-2 or more points based on: 
-
-
-
-
-Elevated urine creatine/creatinine ratio on one occasion (1 point)
-
-
-Elevated urine creatine/creatinine ratio on more than one occasion (2 points)
-
-
-
-
-Additional specifications:
-
-
-
-
-An individual used to assign PP4, at any weight, cannot be also included for PS4 count. If multiple unrelated probands with the variant have been identified, it is recommended that the case with the highest PP4 points is assigned the appropriate weight for PP4, and the other cases are used for PS4.
-
-
-Variant must meet PM2_Supporting for PP4 to apply at any strength.",Disease-specific
-SLC6A8 (HGNC:11055),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SLC6A8 (HGNC:11055),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-SLC6A8 (HGNC:11055),BA1,Stand Alone,Allele frequency >0.0020 (0.2%) OR ≥10 hemizygotes in gnomAD,Disease-specific
-SLC6A8 (HGNC:11055),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-SLC6A8 (HGNC:11055),BS1,Strong,Allele frequency > 0.0002 (0.02%) OR ≥ 5 hemizygotes in gnomAD,Disease-specific
-SLC6A8 (HGNC:11055),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-SLC6A8 (HGNC:11055),BS2,Strong,Observed in the homozygous state in a healthy adult,None
-SLC6A8 (HGNC:11055),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-SLC6A8 (HGNC:11055),BS3,Supporting,"Creatine transport assay demonstrating ≥50% normal transport activity using physiological creatine concentrations (≤125μM creatine).
-
-
-RT-PCR evidence demonstrating no observable effect of splicing.
-
-
-Expression assay demonstrating wild type transcript levels","Disease-specific,Strength"
-SLC6A8 (HGNC:11055),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-SLC6A8 (HGNC:11055),BS4,Strong,Lack of segregation in affected members of a family.,None
-SLC6A8 (HGNC:11055),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-SLC6A8 (HGNC:11055),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-SLC6A8 (HGNC:11055),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-SLC6A8 (HGNC:11055),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SLC6A8 (HGNC:11055),BP4,Supporting,"REVEL score <0.2 for missense variants
-
-
-In frame deletion or insertion predicted benign by PROVEAN, MutPred indel, and MutationTaster.
-
-
-No predicted impact on splicing by SpliceAI and varSEAK.",None
-SLC6A8 (HGNC:11055),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-SLC6A8 (HGNC:11055),BP5,Supporting,"Variant found in a case with an alternate molecular basis for disease.
-BP5 applicable as described; the case must have specific features of creatine transporter deficiency, such as low creatine on brain magnetic resonance spectroscopy, or elevated urine creatine in order to apply this criterion. Presence of developmental delay and seizures is not sufficient.",None
-SLC6A8 (HGNC:11055),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SLC6A8 (HGNC:11055),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-SLC6A8 (HGNC:11055),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,None
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSLC6A8Version1.2.0_version=1.2.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSLC6A8Version1.2.0_version=1.2.0.csv
deleted file mode 100644
index 7ef54b654566f05f767860eae49835af76d34a84..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSLC6A8Version1.2.0_version=1.2.0.csv
+++ /dev/null
@@ -1,208 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-SLC6A8 (HGNC:11055),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-SLC6A8 (HGNC:11055),PVS1,Very Strong,"Loss of function is a known mechanism of disease for Creatine Transporter Deficiency.
-
-
-Specifications are based on the decision tree as outlined in Tayoun etal, 2018 (Hum Mutat. 2018 Nov;39(11):1517-1524; PMID: 30192042) SLC6A8: PVS1, at appropriate strength, is applicable as described in Abou Tayoun et al, 2018 (PMID: 30192042)",None
-SLC6A8 (HGNC:11055),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SLC6A8 (HGNC:11055),PS1,Strong,PS1 is applicable as described.,"General recommendation,None"
-SLC6A8 (HGNC:11055),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-SLC6A8 (HGNC:11055),PS2,Strong,"Note: Confirmation of paternity in females only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.
-
-
-X-linked disorder. Only maternity needs to be confirmed.","Disease-specific,None"
-SLC6A8 (HGNC:11055),PS2,Moderate,Newly hemizygous male with the variant identified de novo in the mother with no family history of other affected males.,"Disease-specific,Strength"
-SLC6A8 (HGNC:11055),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-SLC6A8 (HGNC:11055),PS3,Strong,"RT-PCR evidence of mis-splicing for non-canonical intronic variants.
-
-
-For non-canonical splicing variants, RT-PCR evidence demonstrating transcripts of alternative length or specific intron or exon inclusion/exclusion. These studies can be performed in patient derived cells, by placing the mutant genomic DNA into plasmid vectors, or by over-expressing mutant transcript. Assays should demonstrate defective splicing with RT-PCR analysis or RNA sequencing to confirm alternative transcripts.",Disease-specific
-SLC6A8 (HGNC:11055),PS3,Supporting,"Creatine transport activity <10% wild type with less than or equal to 125uM creatine used in SLC6A8 deficient fibroblasts
-
-
-RT-PCR evidence of mis-splicing for non-canonical intronic variants with evidence of normal splice products. For non-canonical splicing variants, RT-PCR evidence demonstrating transcripts of alternative length or specific intron or exon inclusion/exclusion. These studies can be performed in patient derived cells, by placing the mutant genomic DNA into plasmid vectors, or by over-expressing mutant transcript. Assays should demonstrate defective splicing with RT-PCR analysis or RNA sequencing to confirm alternative transcripts.","Disease-specific,Strength"
-SLC6A8 (HGNC:11055),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-SLC6A8 (HGNC:11055),PS4,Very Strong,"4 independent male probands with elevated urine creatine/creatinine ratio on one occasion at minimum, in addition to any proband used for PP4.
-
-
-Variant must meet PM2_Supporting criterion for PS4 to apply.",Strength
-SLC6A8 (HGNC:11055),PS4,Strong,"3 independent male probands with elevated urine creatine/creatinine ratio on one occasion at minimum, in addition to any proband used for PP4.
-
-
-Variant must meet PM2_Supporting criterion for PS4 to apply.",Disease-specific
-SLC6A8 (HGNC:11055),PS4,Moderate,"2 independent male probands with elevated urine creatine/creatinine ratio on one occasion at minimum, in addition to any proband used for PP4.
-
-
-Variant must meet PM2_Supporting criterion for PS4 to apply.",Strength
-SLC6A8 (HGNC:11055),PS4,Supporting,"One independent male proband in addition to any proband used for PP4.
-
-
-Variant must meet PM2_Supporting criterion for PS4 to apply.",Strength
-SLC6A8 (HGNC:11055),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-SLC6A8 (HGNC:11055),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-SLC6A8 (HGNC:11055),PM2,Supporting,Absent/rare from controls in an ethnically-matched cohort population sample. Threshold: <0.00002 (0.002%) AND 0 hemizygotes in gnomAD.,Disease-specific
-SLC6A8 (HGNC:11055),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-SLC6A8 (HGNC:11055),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-SLC6A8 (HGNC:11055),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,None
-SLC6A8 (HGNC:11055),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SLC6A8 (HGNC:11055),PM5,Moderate,Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.,None
-SLC6A8 (HGNC:11055),PM5,Supporting,Missense change at an amino acid residue where a different missense change determined to be likely pathogenic has been seen before.,Strength
-SLC6A8 (HGNC:11055),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-SLC6A8 (HGNC:11055),PM6,Moderate,Variant identified as de novo in an affected male with the mother negative for the variant but maternity not confirmed.,No change
-SLC6A8 (HGNC:11055),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-SLC6A8 (HGNC:11055),PP1,Strong,"3 affected segregations + 0 unaffected segregations OR
-
-
-2 affected segregations + 3 unaffected segregations",Strength
-SLC6A8 (HGNC:11055),PP1,Moderate,2 affected segregations + 0 unaffected segregations.,Strength
-SLC6A8 (HGNC:11055),PP1,Supporting,1 affected family member + 3 unaffected segregations.,Disease-specific
-SLC6A8 (HGNC:11055),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-SLC6A8 (HGNC:11055),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-SLC6A8 (HGNC:11055),PP3,Supporting,"REVEL score >0.75 for missense variants
-
-
-In frame deletion or insertion predicted deleterious by PROVEAN, MutPred indel, and MutationTaster.
-
-
-Predicted impact on splicing by SpliceAI and varSEAK.",General recommendation
-SLC6A8 (HGNC:11055),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-SLC6A8 (HGNC:11055),PP4,Strong,"4 or more points based on combinations of the following. 
-
-
-
-
-Elevated urine creatine/creatinine ratio on one occasion (1 point)
-
-
-Elevated urine creatine/creatinine ratio on more than one occasion (2 points)
-
-
-Significantly decreased creatine peak, with absent guanidinoacetate peak, if reported (3 points)
-
-
-Deficient creatine uptake in cultured fibroblasts (<10% of normal with <125uM creatine) (3 points)
-
-
-
-
-Additional specifications:
-
-
-
-
-Two or more data types are required for PP4_Strong.
-
-
-An individual used to assign PP4, at any weight, cannot be also included for PS4 count. If multiple unrelated probands with the variant have been identified, it is recommended that the case with the highest PP4 points is assigned the appropriate weight for PP4, and the other cases are used for PS4.
-
-
-Variant must meet PM2_Supporting for PP4 to apply at any strength.
-
-
-For PP4 to be applied at strong, full SLC6A8 gene sequencing, including all coding exons and intron/exon boundaries, must have been carried out. If not, consider downgrading.",Disease-specific
-SLC6A8 (HGNC:11055),PP4,Moderate,"3 or more points based on: 
-
-
-
-
-Elevated urine creatine/creatinine ratio on one occasion (1 point)
-
-
-Elevated urine creatine/creatinine ratio on more than one occasion (2 points)
-
-
-Significantly decreased creatine peak, with absent guanidinoacetate peak, if reported (3 points)
-
-
-Deficient creatine uptake in cultured fibroblasts (<10% of normal with <125uM creatine) (3 points)
-
-
-
-
-Additional specifications:
-
-
-
-
-Two or more data types are recommended for PP4_Moderate.
-
-
-An individual used to assign PP4, at any weight, cannot be also included for PS4 count. If multiple unrelated probands with the variant have been identified, it is recommended that the case with the highest PP4 points is assigned the appropriate weight for PP4, and the other cases are used for PS4.
-
-
-Variant must meet PM2_Supporting for PP4 to apply at any strength.",Strength
-SLC6A8 (HGNC:11055),PP4,Supporting,"1-2 or more points based on: 
-
-
-
-
-Elevated urine creatine/creatinine ratio on one occasion (1 point)
-
-
-Elevated urine creatine/creatinine ratio on more than one occasion (2 points)
-
-
-
-
-Additional specifications:
-
-
-
-
-An individual used to assign PP4, at any weight, cannot be also included for PS4 count. If multiple unrelated probands with the variant have been identified, it is recommended that the case with the highest PP4 points is assigned the appropriate weight for PP4, and the other cases are used for PS4.
-
-
-Variant must meet PM2_Supporting for PP4 to apply at any strength.",Disease-specific
-SLC6A8 (HGNC:11055),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SLC6A8 (HGNC:11055),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-SLC6A8 (HGNC:11055),BA1,Stand Alone,Allele frequency >0.0020 (0.2%) OR ≥10 hemizygotes in gnomAD,Disease-specific
-SLC6A8 (HGNC:11055),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-SLC6A8 (HGNC:11055),BS1,Strong,Allele frequency > 0.0002 (0.02%) OR ≥ 5 hemizygotes in gnomAD,Disease-specific
-SLC6A8 (HGNC:11055),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-SLC6A8 (HGNC:11055),BS2,Strong,"The variant is observed in ≥2 hemizygotes in gnomAD, or one or more hemizygous male(s) or homozygous female(s) who have documented normal urine creatine/creatine ratio.",None
-SLC6A8 (HGNC:11055),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-SLC6A8 (HGNC:11055),BS3,Supporting,"Creatine transport assay demonstrating ≥50% normal transport activity using physiological creatine concentrations (≤125μM creatine).
-
-
-RT-PCR evidence demonstrating no observable effect of splicing.
-
-
-Expression assay demonstrating wild type transcript levels","Disease-specific,Strength"
-SLC6A8 (HGNC:11055),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-SLC6A8 (HGNC:11055),BS4,Strong,Lack of segregation in affected members of a family.,None
-SLC6A8 (HGNC:11055),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-SLC6A8 (HGNC:11055),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-SLC6A8 (HGNC:11055),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-SLC6A8 (HGNC:11055),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SLC6A8 (HGNC:11055),BP4,Supporting,"REVEL score <0.2 for missense variants
-
-
-In frame deletion or insertion predicted benign by PROVEAN, MutPred indel, and MutationTaster.
-
-
-No predicted impact on splicing by SpliceAI and varSEAK.",General recommendation
-SLC6A8 (HGNC:11055),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-SLC6A8 (HGNC:11055),BP5,Supporting,"Variant found in a case with an alternate molecular basis for disease.
-BP5 applicable as described; the case must have specific features of creatine transporter deficiency, such as low creatine on brain magnetic resonance spectroscopy, or elevated urine creatine in order to apply this criterion. Presence of developmental delay and seizures is not sufficient.",None
-SLC6A8 (HGNC:11055),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SLC6A8 (HGNC:11055),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-SLC6A8 (HGNC:11055),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,"General recommendation,None"
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSLC6A8Version1_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSLC6A8Version1_version=1.0.0.csv
deleted file mode 100644
index cf056a7007dd0352050176cad161a1910d34a2d7..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCerebralCreatineDeficiencySyndromesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSLC6A8Version1_version=1.0.0.csv
+++ /dev/null
@@ -1,190 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-SLC6A8 (HGNC:11055),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-SLC6A8 (HGNC:11055),PVS1,Very Strong,"Loss of function is a known mechanism of disease for Creatine Transporter Deficiency.
-
-
-Specifications are based on the decision tree as outlined in Tayoun etal, 2018 (Hum Mutat. 2018 Nov;39(11):1517-1524; PMID: 30192042) SLC6A8: PVS1 is applicable as described in Abou Tayoun et al, 2018 (PMID: 30192042)",None
-SLC6A8 (HGNC:11055),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SLC6A8 (HGNC:11055),PS1,Strong,PS1 is applicable as described.,None
-SLC6A8 (HGNC:11055),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-SLC6A8 (HGNC:11055),PS2,Strong,"Note: Confirmation of paternity in females only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity",None
-SLC6A8 (HGNC:11055),PS2,Moderate,Newly hemizygous male with variant identified in mother.,"Strength,Disease-specific"
-SLC6A8 (HGNC:11055),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-SLC6A8 (HGNC:11055),PS3,Strong,"RT-PCR evidence of mis-splicing for non-canonical intronic variants
-For non-canonical splicing variants, RT-PCR evidence demonstrating transcripts of alternative length or specific intron or exon inclusion/exclusion. These studies can be performed in patient derived cells, by placing the mutant genomic DNA into plasmid vectors, or by over-expressing mutant transcript. Assays should demonstrate defective splicing with RT-PCR analysis or RNA sequencing to confirm alternative transcripts.",Disease-specific
-SLC6A8 (HGNC:11055),PS3,Supporting,"Creatine transport activity <10% wild type with less than or equal to 125uM creatine used in SLC6A8 deficient fibroblasts
-
-
-RT-PCR evidence of mis-splicing for non-canonical intronic variants with evidence of normal splice products.
-For non-canonical splicing variants, RT-PCR evidence demonstrating transcripts of alternative length or specific intron or exon inclusion/exclusion. These studies can be performed in patient derived cells, by placing the mutant genomic DNA into plasmid vectors, or by over-expressing mutant transcript. Assays should demonstrate defective splicing with RT-PCR analysis or RNA sequencing to confirm alternative transcripts.",Disease-specific
-SLC6A8 (HGNC:11055),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-SLC6A8 (HGNC:11055),PS4,Very Strong,"4 independent male probands with elevated urine creatine/creatinine ratio on one occasion at minimum, in addition to any proband used for PP4.
-
-
-Variant must meet PM2_Supporting criterion for PS4 to apply.",Strength
-SLC6A8 (HGNC:11055),PS4,Strong,"3 independent male probands with elevated urine creatine/creatinine ratio on one occasion at minimum, in addition to any proband used for PP4.
-
-
-Variant must meet PM2_Supporting criterion for PS4 to apply.",Disease-specific
-SLC6A8 (HGNC:11055),PS4,Moderate,"2 independent male probands with elevated urine creatine/creatinine ratio on one occasion at minimum, in addition to any proband used for PP4.
-
-
-Variant must meet PM2_Supporting criterion for PS4 to apply.",Strength
-SLC6A8 (HGNC:11055),PS4,Supporting,One independent male proband in addition to any proband used for PP4.,Strength
-SLC6A8 (HGNC:11055),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-SLC6A8 (HGNC:11055),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-SLC6A8 (HGNC:11055),PM2,Supporting,"Absent/rare from controls in an ethnically-matched cohort population sample.
-Threshold: <0.00002 (0.002%) AND 0 hemizygotes in gnomAD.",Disease-specific
-SLC6A8 (HGNC:11055),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-SLC6A8 (HGNC:11055),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-SLC6A8 (HGNC:11055),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,None
-SLC6A8 (HGNC:11055),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SLC6A8 (HGNC:11055),PM5,Moderate,Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.,None
-SLC6A8 (HGNC:11055),PM5,Supporting,Missense change at an amino acid residue where a different missense change determined to be likely pathogenic has been seen before.,Strength
-SLC6A8 (HGNC:11055),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-SLC6A8 (HGNC:11055),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-SLC6A8 (HGNC:11055),PP1,Strong,"3 affected segregations + 0 unaffected segregations OR
-
-
-2 affected segregations + 3 unaffected segregations",Strength
-SLC6A8 (HGNC:11055),PP1,Moderate,2 affected segregations + 0 unaffected segregations.,Strength
-SLC6A8 (HGNC:11055),PP1,Supporting,1 affected family member + 3 unaffected segregations.,Disease-specific
-SLC6A8 (HGNC:11055),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-SLC6A8 (HGNC:11055),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-SLC6A8 (HGNC:11055),PP3,Supporting,"REVEL score >0.75 for missense variants
-
-
-In frame deletion or insertion predicted deleterious by PROVEAN, MutPred indel, and MutationTaster.
-
-
-Predicted impact on splicing by SpliceAI and varSEAK.",None
-SLC6A8 (HGNC:11055),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-SLC6A8 (HGNC:11055),PP4,Strong,"See points scheme in main document
-
-
-4 or more points are required for PP4_Strong; two or more data types must be available to apply PP4_Strong, full sequencing of SLC6A8, including all coding exons and intron/exon boundaries, must have been carried out. If not, consider downgrading.
-
-
-
-
-For PP4, assign points for each type of data present, and then add up the points.
-
-
-
-
-PP4 = 1-2 points, PP4_Moderate = 3 points, PP4_Strong = 4 points
-
-
-Two or more data types are recommended to reach moderate and required to reach strong.
-
-
-An individual used to assign PP4, at any weight, cannot be also included for PS4 count. If multiple unrelated probands with the variant have been identified, it is recommended that the case with the highest PP4 points is assigned the appropriate weight for PP4, and the other cases are used for PS4.
-
-
-Variant must meet PM2_Supporting for PP4 to apply at any strength.
-
-
-For PP4 to be applied at strong, full SLC6A8 gene sequencing, including all coding exons and intron/exon boundaries, must have been carried out. If not, consider downgrading.",Disease-specific
-SLC6A8 (HGNC:11055),PP4,Moderate,"See points scheme in main document.
-
-
-3 points required for PP4_Moderate.
-
-
-
-
-For PP4, assign points for each type of data present, and then add up the points.
-
-
-
-
-PP4 = 1-2 points, PP4_Moderate = 3 points, PP4_Strong = 4 points
-
-
-Two or more data types are recommended to reach moderate and required to reach strong.
-
-
-An individual used to assign PP4, at any weight, cannot be also included for PS4 count. If multiple unrelated probands with the variant have been identified, it is recommended that the case with the highest PP4 points is assigned the appropriate weight for PP4, and the other cases are used for PS4.
-
-
-Variant must meet PM2_Supporting for PP4 to apply at any strength.
-
-
-For PP4 to be applied at strong, full SLC6A8 gene sequencing, including all coding exons and intron/exon boundaries, must have been carried out. If not, consider downgrading.",Strength
-SLC6A8 (HGNC:11055),PP4,Supporting,"Elevated urine creatine/creatinine ratio.
-• 1-2 points required for PP4; at minimum, elevated urine creatine/creatinine level on one occasion.
-
-
-
-
-For PP4, assign points for each type of data present, and then add up the points.
-
-
-
-
-PP4 = 1-2 points, PP4_Moderate = 3 points, PP4_Strong = 4 points
-
-
-Two or more data types are recommended to reach moderate and required to reach strong.
-
-
-An individual used to assign PP4, at any weight, cannot be also included for PS4 count. If multiple unrelated probands with the variant have been identified, it is recommended that the case with the highest PP4 points is assigned the appropriate weight for PP4, and the other cases are used for PS4.
-
-
-Variant must meet PM2_Supporting for PP4 to apply at any strength.
-
-
-For PP4 to be applied at strong, full SLC6A8 gene sequencing, including all coding exons and intron/exon boundaries, must have been carried out. If not, consider downgrading.",Disease-specific
-SLC6A8 (HGNC:11055),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SLC6A8 (HGNC:11055),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-SLC6A8 (HGNC:11055),BA1,Stand Alone,Allele frequency >0.0020 (0.2%) OR ≥10 hemizygotes in gnomAD,Disease-specific
-SLC6A8 (HGNC:11055),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-SLC6A8 (HGNC:11055),BS1,Strong,Allele frequency > 0.0002 (0.02%) OR ≥ 5 hemizygotes in gnomAD,Disease-specific
-SLC6A8 (HGNC:11055),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-SLC6A8 (HGNC:11055),BS2,Strong,Observed in the homozygous state in a healthy adult,None
-SLC6A8 (HGNC:11055),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-SLC6A8 (HGNC:11055),BS3,Supporting,"Creatine transport assay demonstrating ≥50% normal transport activity using physiological creatine concentrations (≤125μM creatine).
-
-
-RT-PCR evidence demonstrating no observable effect of splicing.
-
-
-Expression assay demonstrating wild type transcript levels","Strength,Disease-specific"
-SLC6A8 (HGNC:11055),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-SLC6A8 (HGNC:11055),BS4,Strong,Lack of segregation in affected members of a family.,None
-SLC6A8 (HGNC:11055),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-SLC6A8 (HGNC:11055),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-SLC6A8 (HGNC:11055),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-SLC6A8 (HGNC:11055),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SLC6A8 (HGNC:11055),BP4,Supporting,"REVEL score <0.2 for missense variants
-
-
-In frame deletion or insertion predicted benign by PROVEAN, MutPred indel, and MutationTaster.
-
-
-No predicted impact on splicing by SpliceAI and varSEAK.",None
-SLC6A8 (HGNC:11055),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-SLC6A8 (HGNC:11055),BP5,Supporting,"Variant found in a case with an alternate molecular basis for disease.
-BP5 applicable as described; the case must have specific features of creatine transporter deficiency, such as low creatine on brain magnetic resonance spectroscopy, or elevated urine creatine in order to apply this criterion. Presence of developmental delay and seizures is not sufficient.",None
-SLC6A8 (HGNC:11055),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SLC6A8 (HGNC:11055),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-SLC6A8 (HGNC:11055),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,None
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCoagulationFactorDeficiencyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforF8Version1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCoagulationFactorDeficiencyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforF8Version1.0.0_version=1.0.0.csv
deleted file mode 100644
index 2c14fc44f044f2cbca6ca8c458e13e0d25e01454..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCoagulationFactorDeficiencyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforF8Version1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,122 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-F8 (HGNC:3546),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-F8 (HGNC:3546),PVS1,Very Strong,Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree.,General recommendation
-F8 (HGNC:3546),PVS1,Strong,Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree.,General recommendation
-F8 (HGNC:3546),PVS1,Moderate,Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree.,General recommendation
-F8 (HGNC:3546),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-F8 (HGNC:3546),PS1,Strong,"This evidence code can be applied when there is 1 pathogenic variant or 2 likely pathogenic variants at the same residue based on 
-F8
- gene rule specifications from the Coagulation Factor Deficiency VCEP and where 
-in silico
- predictors do not suggest a splicing defect.",General recommendation
-F8 (HGNC:3546),PS1,Moderate,"This evidence code can be applied when there is 1 likely pathogenic variants at the same residue based on 
-F8
- gene rule specifications from the Coagulation Factor Deficiency VCEP and where 
-in silico
- predictors do not suggesting a splicing defect.",General recommendation
-F8 (HGNC:3546),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-F8 (HGNC:3546),PS2,Very Strong,Use the SVI recommendations for de novo cases; 4 points. Use de novo guidance below to determine point value.,Disease-specific
-F8 (HGNC:3546),PS2,Strong,Use the SVI recommendations for de novo cases; 2 points. Use de novo guidance below to determine point value.,Disease-specific
-F8 (HGNC:3546),PS2,Moderate,Use the SVI recommendations for de novo cases; 1 point. Use de novo guidance below to determine point value.,Disease-specific
-F8 (HGNC:3546),PS2,Supporting,Use the SVI recommendations for de novo cases; 0.5 point. Use de novo guidance below to determine point value.,Disease-specific
-F8 (HGNC:3546),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-F8 (HGNC:3546),PS3,Strong,Abnormal factor VIII activity (<40 IU/dL or 40%) via one-stage or two-stage chromogenic assay in a cell line and/or mouse model.,Disease-specific
-F8 (HGNC:3546),PS3,Supporting,Absent or significantly reduced factor VIII antigen levels compared to wildtype in a cell line by quantitative assay.,Disease-specific
-F8 (HGNC:3546),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-F8 (HGNC:3546),PS4,Very Strong,≥8 probands meet criteria described below,Disease-specific
-F8 (HGNC:3546),PS4,Strong,4-7 probands meet criteria described below,Disease-specific
-F8 (HGNC:3546),PS4,Moderate,2-3 probands meet criteria described below,Disease-specific
-F8 (HGNC:3546),PS4,Supporting,1 proband meets criteria described below,Disease-specific
-F8 (HGNC:3546),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-F8 (HGNC:3546),PM1,Strong,"This code can be applied at the strong level for variants involving the following residues: R391-S392, R759-S760, E1701-Q1705, R1708-S1709, Y1683, Y1689, Y737, Y742.",Gene-specific
-F8 (HGNC:3546),PM1,Moderate,"This code can be applied at the moderate level for variants involving the following residues: 
-
-
-Residues affecting secretion: Arg1667, Arg1332
-
-
-FXa-binding residues: Gly2267-Gly2304 (with the exception of Ser2283)",Gene-specific
-F8 (HGNC:3546),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-F8 (HGNC:3546),PM2,Supporting,"Variant must be absent in males in population databases, such as gnomAD.",Disease-specific
-F8 (HGNC:3546),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-F8 (HGNC:3546),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-F8 (HGNC:3546),PM4,Moderate,Use code with no specification.,None
-F8 (HGNC:3546),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-F8 (HGNC:3546),PM5,Moderate,"This evidence code can be applied when there is 1 pathogenic variant or 2 likely pathogenic variants at the same residue based on the 
-F8
- rule specifications from the Coagulation Factor Deficiency VCEP and where 
-in silico
- predictors do not suggest a splicing defect.",Gene-specific
-F8 (HGNC:3546),PM5,Supporting,"This evidence code can be applied when there is 1 likely pathogenic variant at the same residue based on the 
-F8
- rule specifications from the Coagulation Factor Deficiency VCEP and where 
-in silico
- predictors do not suggest a splicing defect.",Gene-specific
-F8 (HGNC:3546),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-F8 (HGNC:3546),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-F8 (HGNC:3546),PP1,Strong,The code is application when there are ≥4 meioses across ≥2 families.,Disease-specific
-F8 (HGNC:3546),PP1,Moderate,The code is application when there are at least 3 meioses across one or more families.,Disease-specific
-F8 (HGNC:3546),PP1,Supporting,"The code is application when there are 2 meioses in one family 
-OR
- 1 meiosis between 2 affected siblings.",Disease-specific
-F8 (HGNC:3546),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-F8 (HGNC:3546),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-F8 (HGNC:3546),PP3,Supporting,Code can be applied for variants where the REVEL score is greater than or equal to 0.6 or a SpliceAI score of greater than or equal to 0.5.,Gene-specific
-F8 (HGNC:3546),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-F8 (HGNC:3546),PP4,Moderate,Proband must meet hemophilia A phenotype criteria AND have full gene sequencing and deletion/duplication analysis.,Disease-specific
-F8 (HGNC:3546),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-F8 (HGNC:3546),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-F8 (HGNC:3546),BA1,Stand Alone,MAF cutoff of greater or equal to 0.0333% (or 0.000333).,Gene-specific
-F8 (HGNC:3546),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-F8 (HGNC:3546),BS1,Strong,MAF cutoff of greater than or equal to 0.00333% (or 0.0000333).,Gene-specific
-F8 (HGNC:3546),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-F8 (HGNC:3546),BS2,Strong,"This evidence code can be used when a 
-F8
- variant is observed in a male with a normal factor VIII activity level (<40% IU) using a one stage and/or a chromogenic assay.",Disease-specific
-F8 (HGNC:3546),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-F8 (HGNC:3546),BS3,Strong,"This code can be used for 
-F8
- gene variants studied in a cell line or mouse model setting that confer a normal factor VIII activity level AND normal factor VIII antigen level OR normal Western Blot.",Disease-specific
-F8 (HGNC:3546),BS3,Supporting,"This code can be used for 
-F8
- gene variants studied in a cell line or mouse model setting that confer the following results:                    
-
-
-
-
-Normal factor VIII activity level, OR
-
-
-Abnormal factor VIII activity level with abnormal 2N binding assay suggesting a diagnosis of VWD Normandy (VWD 2N) instead of hemophilia A.",Disease-specific
-F8 (HGNC:3546),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-F8 (HGNC:3546),BS4,Strong,"This evidence code can be used when a 
-F8
- variant is observed in a male with a family history of hemophilia A and has a normal factor VIII activity level.",Disease-specific
-F8 (HGNC:3546),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-F8 (HGNC:3546),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-F8 (HGNC:3546),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-F8 (HGNC:3546),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-F8 (HGNC:3546),BP4,Supporting,This code can be applied for variants reaching a REVEL score of 0.3 or below AND a Splice AI score of less than or equal to 0.05.,Gene-specific
-F8 (HGNC:3546),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-F8 (HGNC:3546),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-F8 (HGNC:3546),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-F8 (HGNC:3546),BP7,Supporting,Splice AI should be used to suggest no splicing impact. Splicing prediction score of less than or equal to 0.05 is required. Conservation should be assess using PhyloP (cutoff less than 0.1) and PhastCons (cutoff less than 0.5).,Gene-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCoagulationFactorDeficiencyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforF9Version1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCoagulationFactorDeficiencyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforF9Version1.0.0_version=1.0.0.csv
deleted file mode 100644
index 435adb42cafb7a68c9742b535d1b8e0727c51323..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCoagulationFactorDeficiencyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforF9Version1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,111 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-F9 (HGNC:3551),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-F9 (HGNC:3551),PVS1,Very Strong,Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree.,Gene-specific
-F9 (HGNC:3551),PVS1,Strong,Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree.,Gene-specific
-F9 (HGNC:3551),PVS1,Moderate,Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree.,Gene-specific
-F9 (HGNC:3551),PVS1,Supporting,Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree.,Gene-specific
-F9 (HGNC:3551),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-F9 (HGNC:3551),PS1,Strong,"This evidence code can be applied when there is 1 pathogenic variant or 2 likely pathogenic variants at the same residue based on 
-F9
- gene rule specifications from the Coagulation Factor Deficiency VCEP and where 
-in silico
- predictors do not suggest a splicing defect.",General recommendation
-F9 (HGNC:3551),PS1,Moderate,"This evidence code can be applied when there is 1 likely pathogenic variants at the same residue based on 
-F9
- gene rule specifications from the Coagulation Factor Deficiency VCEP and where 
-in silico
- predictors do not suggest a splicing defect.",General recommendation
-F9 (HGNC:3551),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-F9 (HGNC:3551),PS2,Very Strong,Use the SVI recommendations for de novo cases; 4 points. Use de novo guidance below to determine point value.,Disease-specific
-F9 (HGNC:3551),PS2,Strong,Use the SVI recommendations for de novo cases; 2 points. Use de novo guidance below to determine point value.,Disease-specific
-F9 (HGNC:3551),PS2,Moderate,Use the SVI recommendations for de novo cases; 1 point. Use de novo guidance below to determine point value.,Disease-specific
-F9 (HGNC:3551),PS2,Supporting,Use the SVI recommendations for de novo cases; 0.5 point. Use de novo guidance below to determine point value.,Disease-specific
-F9 (HGNC:3551),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-F9 (HGNC:3551),PS3,Strong,Abnormal factor IX activity level (<40 IU/dL or 40%) in a cell line and/or mouse model.,Disease-specific
-F9 (HGNC:3551),PS3,Moderate,Abnormal factor IX activity level (<40 IU/dL or 40%) studied in an animal model setting other than mouse (i.e. – bovine factor IX activity levels compared to factor X levels).,Disease-specific
-F9 (HGNC:3551),PS3,Supporting,Absent or significantly reduced factor IX antigen level compared to wildtype using conformation-specific reporter assay in cell lines.,Disease-specific
-F9 (HGNC:3551),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-F9 (HGNC:3551),PS4,Very Strong,≥8 probands meet criteria described below,Disease-specific
-F9 (HGNC:3551),PS4,Strong,4-7 probands meet criteria described below,Disease-specific
-F9 (HGNC:3551),PS4,Moderate,2-3 probands meet criteria described below,Disease-specific
-F9 (HGNC:3551),PS4,Supporting,1 proband meets criteria described below,Disease-specific
-F9 (HGNC:3551),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-F9 (HGNC:3551),PM1,Strong,"This code can be used for variants affecting any of the 3 catalytic residues (H267, D315 or S411) and 2 activation residues (R191-A192 and R226-V227) in the 
-F9
- gene (PMID: 12554099).",Gene-specific
-F9 (HGNC:3551),PM1,Moderate,"This code should be applied when the variant is within exons 3, 4 or 5.",Gene-specific
-F9 (HGNC:3551),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-F9 (HGNC:3551),PM2,Supporting,"Variant must be absent in males in population databases, such as gnomAD.",Disease-specific
-F9 (HGNC:3551),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-F9 (HGNC:3551),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-F9 (HGNC:3551),PM4,Moderate,Use code with no specification.,None
-F9 (HGNC:3551),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-F9 (HGNC:3551),PM5,Moderate,"This evidence code can be applied when there is 1 pathogenic variant or 2 likely pathogenic variants at the same residue based on 
-F9
- rule specification from the Coagulation Factor Deficiency VCEP and where 
-in silico
- predictors do not suggest a splicing defect.",Gene-specific
-F9 (HGNC:3551),PM5,Supporting,"This evidence code can be applied when there is 1 likely pathogenic variant at the same residue based on 
-F9
- rule specifications Coagulation Factor Deficiency VCEP and where 
-in silico
- predictors do not suggest a splicing defect. A “highly suspicious” VUS is defined as a variant that is 1 supporting code away from reaching a likely pathogenic classification.",Gene-specific
-F9 (HGNC:3551),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-F9 (HGNC:3551),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-F9 (HGNC:3551),PP1,Strong,This code is applicable when there ≥4 meioses across ≥2 families.,Disease-specific
-F9 (HGNC:3551),PP1,Moderate,This code is applicable when there are at least 3 meioses across one or more families.,Disease-specific
-F9 (HGNC:3551),PP1,Supporting,"This code is applicable when there 2 meioses in one family 
-OR
- 1 meiosis between 2 affected siblings.",Disease-specific
-F9 (HGNC:3551),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-F9 (HGNC:3551),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-F9 (HGNC:3551),PP3,Supporting,Code can be applied for variants where the REVEL score is greater than or equal to 0.6 or a SpliceAI score of greater than or equal to 0.5.,Gene-specific
-F9 (HGNC:3551),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-F9 (HGNC:3551),PP4,Moderate,Proband must meet hemophilia B phenotype criteria AND have full gene sequencing and deletion/duplication analysis.,Disease-specific
-F9 (HGNC:3551),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-F9 (HGNC:3551),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-F9 (HGNC:3551),BA1,Stand Alone,MAF cutoff of greater than or equal to 0.0000556 (or 0.00556%).,Gene-specific
-F9 (HGNC:3551),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-F9 (HGNC:3551),BS1,Strong,MAF cutoff of greater than or equal to 0.00000556 (or 0.000556%).,Gene-specific
-F9 (HGNC:3551),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-F9 (HGNC:3551),BS2,Strong,"This evidence code can be used when a 
-F9
- variant is observed in a male with a normal factor IX activity level (<40% IU).",Disease-specific
-F9 (HGNC:3551),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-F9 (HGNC:3551),BS3,Strong,"This code can be used for 
-F9
- gene variants studied in a cell line or mouse model setting that confer a normal factor IX activity AND normal factor IX antigen levels 
-OR
- normal Western Blot.",Disease-specific
-F9 (HGNC:3551),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-F9 (HGNC:3551),BS4,Strong,"This evidence code can be used when a 
-F9
- variant is observed in a male with a family history of hemophilia B and has a normal factor IX activity level.",Disease-specific
-F9 (HGNC:3551),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-F9 (HGNC:3551),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-F9 (HGNC:3551),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-F9 (HGNC:3551),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-F9 (HGNC:3551),BP4,Supporting,This code can be applied for variants reaching a REVEL score of 0.3 or below AND a Splice AI score of less than or equal to 0.01.,Gene-specific
-F9 (HGNC:3551),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-F9 (HGNC:3551),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-F9 (HGNC:3551),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-F9 (HGNC:3551),BP7,Supporting,Splicing prediction score of less than or equal to 0.01 is required. Conservation should be assess using PhyloP (cutoff less than 0.1) and PhastCons (cutoff less than 0.5).,Gene-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforACTA1Version1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforACTA1Version1.0.0_version=1.0.0.csv
deleted file mode 100644
index 82d90d74d542eaf7f5ae826df6ba6b564b93657f..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforACTA1Version1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,180 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-ACTA1 (HGNC:129),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-ACTA1 (HGNC:129),PVS1,Very Strong,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
-
-
-
-
-Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
-
-
-Use caution interpreting LOF variants at the extreme 3’ end of a gene.
-
-
-Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
-
-
-Use caution in the presence of multiple transcripts.",Gene-specific
-ACTA1 (HGNC:129),PVS1,Strong,See PVS1 flowchart,Gene-specific
-ACTA1 (HGNC:129),PVS1,Moderate,See PVS1 flowchart,Gene-specific
-ACTA1 (HGNC:129),PVS1,Supporting,See PVS1 flowchart,Gene-specific
-ACTA1 (HGNC:129),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-ACTA1 (HGNC:129),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",No change
-ACTA1 (HGNC:129),PS1,Moderate,No change - use as originally described,No change
-ACTA1 (HGNC:129),PS1,Supporting,No change - use as originally described,No change
-ACTA1 (HGNC:129),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-ACTA1 (HGNC:129),PS2,Very Strong,No change - use as originally described,No change
-ACTA1 (HGNC:129),PS2,Strong,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",No change
-ACTA1 (HGNC:129),PS2,Moderate,No change - use as originally described,No change
-ACTA1 (HGNC:129),PS2,Supporting,No change - use as originally described,No change
-ACTA1 (HGNC:129),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-ACTA1 (HGNC:129),PS3,Strong,"Strong may only be considered for variant-specific mouse models. Currently, no other assays are applicable at this strength.",Disease-specific
-ACTA1 (HGNC:129),PS3,Supporting,"There are no specific functional assays listed for the ACTA1 AR specifications; all should be used for AD specifications. However, it is acceptable to use PS3_Supporting for functional analyses if
-
-
-
-
-The assay has been validated by a known pathogenic and benign variant AND
-
-
-There is plausible reason that the function the assay is testing relates to the phenotype AND
-
-
-The assay conditions are likely to mimic the physiological environment.",Gene-specific
-ACTA1 (HGNC:129),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",NA
-ACTA1 (HGNC:129),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-ACTA1 (HGNC:129),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-ACTA1 (HGNC:129),PM2,Supporting,"PM2_Supporting may be applied if the minor allele frequency in population databases of at least 2000 alleles is 
-
-
-≤ 0.000005 for autosomal recessive","Disease-specific,Gene-specific"
-ACTA1 (HGNC:129),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-ACTA1 (HGNC:129),PM3,Very Strong,4.0 points per the PM3 chart,Disease-specific
-ACTA1 (HGNC:129),PM3,Strong,2.0 points per the PM3 chart,Gene-specific
-ACTA1 (HGNC:129),PM3,Moderate,"For recessive disorders, detected in trans with a pathogenic variant Note: This requires testing of parents (or offspring) to determine phase.
-
-
-1.0 points per the PM3 chart",Gene-specific
-ACTA1 (HGNC:129),PM3,Supporting,0.5 points per the PM3 chart,Gene-specific
-ACTA1 (HGNC:129),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-ACTA1 (HGNC:129),PM4,Strong,No change - use as originally described,No change
-ACTA1 (HGNC:129),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,No change
-ACTA1 (HGNC:129),PM4,Supporting,No change - use as originally described,No change
-ACTA1 (HGNC:129),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-ACTA1 (HGNC:129),PM5,Strong,No change - use as originally described,No change
-ACTA1 (HGNC:129),PM5,Moderate,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",No change
-ACTA1 (HGNC:129),PM5,Supporting,No change - use as originally described,No change
-ACTA1 (HGNC:129),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-ACTA1 (HGNC:129),PM6,Strong,No change - use as originally described,No change
-ACTA1 (HGNC:129),PM6,Moderate,"Assumed de novo, but without confirmation of paternity and maternity.",No change
-ACTA1 (HGNC:129),PM6,Supporting,No change - use as originally described,No change
-ACTA1 (HGNC:129),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-ACTA1 (HGNC:129),PP1,Strong,See segregation chart,General recommendation
-ACTA1 (HGNC:129),PP1,Moderate,See segregation chart,General recommendation
-ACTA1 (HGNC:129),PP1,Supporting,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. Note: May be used as stronger evidence with increasing segregation data.
-
-
-See segregation chart",General recommendation
-ACTA1 (HGNC:129),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-ACTA1 (HGNC:129),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-ACTA1 (HGNC:129),PP3,Supporting,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.
-
-
-PP3 is met if the REVEL score ≥ 0.7 or if the variant is predicted to impact splicing using SpliceAI score ≥0.5",General recommendation
-ACTA1 (HGNC:129),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-ACTA1 (HGNC:129),PP4,Strong,"PP4 follows the published SVI guidance from Biesecker et al 2023 (PMID:38103548). For ACTA1, a conservative estimate of the diagnostic yield is 33%, which corresponds to +2 points and a moderate strength in Table 2 of this guidance. However, if the proband meets PP4_Moderate criteria and has had a comprehensive myopathy panel, exome, or genome testing that is negative for all other causes of myopathy, PP4 can be applied at strong, per the SVI guidance. 
-
-
-The combination of PP1 and PP4 is capped at strong.","Disease-specific,Gene-specific"
-ACTA1 (HGNC:129),PP4,Moderate,"PP4 follows the published SVI guidance from Biesecker et al 2023 (PMID:38103548). For ACTA1, a conservative estimate of the diagnostic yield is 33%, which corresponds to +2 points and a moderate strength in Table 2 of this guidance. 
-
-
-PP4_Moderate is met with the presence of any of these features
-
-
-Presence on Muscle Biopsy of:
-
-
-
-
-Accumulated thin filaments
-
-
-Intranuclear rods
-
-
-Cores, fiber type disproportion
-
-
-Zebra bodies","Disease-specific,Gene-specific"
-ACTA1 (HGNC:129),PP4,Supporting,"If a biopsy demonstrates a presence of nemaline rods, this is suggestive of ACTA1-related congenital myopathy and can be given PP4 at a supporting level.","Disease-specific,Gene-specific"
-ACTA1 (HGNC:129),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-ACTA1 (HGNC:129),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-ACTA1 (HGNC:129),BA1,Stand Alone,"The minor allele frequency using the filtering allele frequency of either exomes or genomes in gnomAD is 
-≥0.0025 for AR variants
-. All continental populations in gnomAD used should have at least 2000 alleles and >1 observation. 
-
-
-BA1 exclusion variants
- (well-known pathogenic variants that are above the specified BA1 threshold) are as follows: 
-
-
-NM_001100.4(ACTA1):c.541del (p.Asp181fs)
-
-
-NM_001100.4(ACTA1):c.121C>T(p.Arg41*)",Gene-specific
-ACTA1 (HGNC:129),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-ACTA1 (HGNC:129),BS1,Strong,"The minor allele frequency using the filtering allele frequency of either exomes or genomes in gnomAD is 
-≥0.00025 for AR
- 
-variants
-. All continental populations used in gnomAD should have at least 2000 alleles and >1 observation.",Gene-specific
-ACTA1 (HGNC:129),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-ACTA1 (HGNC:129),BS2,Strong,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",No change
-ACTA1 (HGNC:129),BS2,Moderate,No change - use as originally described,No change
-ACTA1 (HGNC:129),BS2,Supporting,No change - use as originally described,No change
-ACTA1 (HGNC:129),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-ACTA1 (HGNC:129),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-ACTA1 (HGNC:129),BS4,Strong,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",No change
-ACTA1 (HGNC:129),BS4,Moderate,No change - use as originally described,No change
-ACTA1 (HGNC:129),BS4,Supporting,No change - use as originally described,No change
-ACTA1 (HGNC:129),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-ACTA1 (HGNC:129),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-ACTA1 (HGNC:129),BP2,Supporting,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,No change
-ACTA1 (HGNC:129),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-ACTA1 (HGNC:129),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-ACTA1 (HGNC:129),BP4,Supporting,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.
-
-
-BP4 is met if the REVEL score ≤ 0.15 or if the variant is not predicted to impact splicing using SpliceAI.",General recommendation
-ACTA1 (HGNC:129),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-ACTA1 (HGNC:129),BP5,Supporting,Variant found in a case with an alternate molecular basis for disease.,No change
-ACTA1 (HGNC:129),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-ACTA1 (HGNC:129),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-ACTA1 (HGNC:129),BP7,Supporting,A synonymous variant for which SpliceAI predicts no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforACTA1Version2.0.0_version=2.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforACTA1Version2.0.0_version=2.0.0.csv
deleted file mode 100644
index 93e1a9ec85a0996123109f02eb2b295982b4cc21..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforACTA1Version2.0.0_version=2.0.0.csv
+++ /dev/null
@@ -1,163 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-ACTA1 (HGNC:129),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-ACTA1 (HGNC:129),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-ACTA1 (HGNC:129),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",No change
-ACTA1 (HGNC:129),PS1,Moderate,No change - use as originally described,No change
-ACTA1 (HGNC:129),PS1,Supporting,No change - use as originally described,No change
-ACTA1 (HGNC:129),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-ACTA1 (HGNC:129),PS2,Very Strong,No change - use as originally described,No change
-ACTA1 (HGNC:129),PS2,Strong,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",No change
-ACTA1 (HGNC:129),PS2,Moderate,No change - use as originally described,No change
-ACTA1 (HGNC:129),PS2,Supporting,No change - use as originally described,No change
-ACTA1 (HGNC:129),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-ACTA1 (HGNC:129),PS3,Strong,"Strong may only be considered for variant-specific mouse models. Currently, no other assays are applicable at this strength.",Disease-specific
-ACTA1 (HGNC:129),PS3,Moderate,The two assays from PS3_Supporting may be stacked to reach a Moderate Strength,Gene-specific
-ACTA1 (HGNC:129),PS3,Supporting,"Three specific assays are currently suggested to be applied at Supporting:
-
-
-
-
-Actin Localization: An abnormal readout consists of integration of actin into cytoplasmic or intranuclear aggregates or rods.
-
-
-Actin Polymerization: An abnormal readout consists of a significant reduction in levels of actin in insoluble fraction or absent or short polymerized actin filaments compared to WT.
-
-
-Actin Motility Assay: An abnormal readout consists of percent motility, velocity, and force generation statistically different from WT.
-
-
-
-
-If not listed above, it is acceptable to use PS3_Supporting for other functional analyses if
-
-
-
-
-The assay has been validated by a known pathogenic and benign variant AND
-
-
-There is plausible reason that the function the assay is testing relates to the phenotype AND
-
-
-The assay conditions are likely to mimic the physiological environment.",Gene-specific
-ACTA1 (HGNC:129),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-ACTA1 (HGNC:129),PS4,Strong,8 case observations,Gene-specific
-ACTA1 (HGNC:129),PS4,Moderate,4 case observations,Gene-specific
-ACTA1 (HGNC:129),PS4,Supporting,2 case observations,Gene-specific
-ACTA1 (HGNC:129),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-ACTA1 (HGNC:129),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-ACTA1 (HGNC:129),PM2,Supporting,"PM2_Supporting may be applied if the minor allele frequency in population databases of at least 2000 alleles is 
-
-
-absent (1 allele allowed) for autosomal dominant","Disease-specific,Gene-specific"
-ACTA1 (HGNC:129),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-ACTA1 (HGNC:129),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-ACTA1 (HGNC:129),PM4,Strong,No change - use as originally described,No change
-ACTA1 (HGNC:129),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,No change
-ACTA1 (HGNC:129),PM4,Supporting,No change - use as originally described,No change
-ACTA1 (HGNC:129),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-ACTA1 (HGNC:129),PM5,Strong,No change - use as originally described,No change
-ACTA1 (HGNC:129),PM5,Moderate,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",No change
-ACTA1 (HGNC:129),PM5,Supporting,No change - use as originally described,No change
-ACTA1 (HGNC:129),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-ACTA1 (HGNC:129),PM6,Strong,No change - use as originally described,No change
-ACTA1 (HGNC:129),PM6,Moderate,"Assumed de novo, but without confirmation of paternity and maternity.",No change
-ACTA1 (HGNC:129),PM6,Supporting,No change - use as originally described,No change
-ACTA1 (HGNC:129),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-ACTA1 (HGNC:129),PP1,Strong,See segregation chart,General recommendation
-ACTA1 (HGNC:129),PP1,Moderate,See segregation chart,General recommendation
-ACTA1 (HGNC:129),PP1,Supporting,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. Note: May be used as stronger evidence with increasing segregation data.
-
-
-See segregation chart",General recommendation
-ACTA1 (HGNC:129),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,
-ACTA1 (HGNC:129),PP2,Supporting,ACTA1 is a gene that is constrained for missense variation (gnomAD v4.1 z=6.09). PP2 may be used for missense variants with an autosomal dominant mode of inheritance.,Gene-specific
-ACTA1 (HGNC:129),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-ACTA1 (HGNC:129),PP3,Supporting,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.
-
-
-PP3 is met if the REVEL score ≥ 0.7 or if the variant is predicted to impact splicing using SpliceAI score ≥0.5",General recommendation
-ACTA1 (HGNC:129),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-ACTA1 (HGNC:129),PP4,Strong,"PP4 follows the published SVI guidance from Biesecker et al 2023 (PMID:38103548). For ACTA1, a conservative estimate of the diagnostic yield is 33%, which corresponds to +2 points and a moderate strength in Table 2 of this guidance. However, if the proband meets PP4_Moderate criteria and has had a comprehensive myopathy panel, exome, or genome testing that is negative for all other causes of myopathy, PP4 can be applied at strong, per the SVI guidance.   
-
-
-The combination of PP1 and PP4 is capped at strong.","Disease-specific,Gene-specific"
-ACTA1 (HGNC:129),PP4,Moderate,"PP4 follows the published SVI guidance from Biesecker et al 2023 (PMID:38103548). For ACTA1, a conservative estimate of the diagnostic yield is 33%, which corresponds to +2 points and a moderate strength in Table 2 of this guidance. 
-
-
-PP4_Moderate is met with the presence of any of these features
-
-
-Presence on Muscle Biopsy of:
-
-
-
-
-Accumulated thin filaments
-
-
-Intranuclear rods
-
-
-Cores, fiber type disproportion
-
-
-Zebra bodies","Disease-specific,Gene-specific"
-ACTA1 (HGNC:129),PP4,Supporting,"If a biopsy demonstrates a presence of nemaline rods, this is suggestive of ACTA1-related congenital myopathy and can be given PP4 at a supporting level.","Disease-specific,Gene-specific"
-ACTA1 (HGNC:129),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-ACTA1 (HGNC:129),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-ACTA1 (HGNC:129),BA1,Stand Alone,"The minor allele frequency using the filtering allele frequency of either exomes or genomes in gnomAD is 
-≥0.0000781 for AD variants
-. All continental populations in gnomAD used should have at least 2000 alleles and >1 observation.",Gene-specific
-ACTA1 (HGNC:129),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-ACTA1 (HGNC:129),BS1,Strong,"The minor allele frequency using the filtering allele frequency of either exomes or genomes in gnomAD is 
-≥0.00000781 for AD variants
-. All continental populations used in gnomAD should have at least 2000 alleles and >1 observation.",Gene-specific
-ACTA1 (HGNC:129),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-ACTA1 (HGNC:129),BS2,Strong,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",No change
-ACTA1 (HGNC:129),BS2,Moderate,No change - use as originally described,No change
-ACTA1 (HGNC:129),BS2,Supporting,No change - use as originally described,No change
-ACTA1 (HGNC:129),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-ACTA1 (HGNC:129),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-ACTA1 (HGNC:129),BS4,Strong,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",No change
-ACTA1 (HGNC:129),BS4,Moderate,No change - use as originally described,No change
-ACTA1 (HGNC:129),BS4,Supporting,No change - use as originally described,No change
-ACTA1 (HGNC:129),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-ACTA1 (HGNC:129),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-ACTA1 (HGNC:129),BP2,Supporting,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,No change
-ACTA1 (HGNC:129),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-ACTA1 (HGNC:129),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-ACTA1 (HGNC:129),BP4,Supporting,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.
-
-
-BP4 is met if the REVEL score ≤ 0.15 or if the variant is not predicted to impact splicing using SpliceAI.",General recommendation
-ACTA1 (HGNC:129),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-ACTA1 (HGNC:129),BP5,Supporting,Variant found in a case with an alternate molecular basis for disease.,No change
-ACTA1 (HGNC:129),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-ACTA1 (HGNC:129),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-ACTA1 (HGNC:129),BP7,Supporting,A synonymous variant for which SpliceAI predicts no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDNM2Version1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDNM2Version1.0.0_version=1.0.0.csv
deleted file mode 100644
index 1aa57b6180a2fa86d774438c9b6e97d56d9b8b84..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDNM2Version1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,161 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-DNM2 (HGNC:2974),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-DNM2 (HGNC:2974),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-DNM2 (HGNC:2974),PS1,Strong,Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.,No change
-DNM2 (HGNC:2974),PS1,Moderate,No change - use as originally described,No change
-DNM2 (HGNC:2974),PS1,Supporting,No change - use as originally described,No change
-DNM2 (HGNC:2974),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-DNM2 (HGNC:2974),PS2,Very Strong,No change - use as originally described,No change
-DNM2 (HGNC:2974),PS2,Strong,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",No change
-DNM2 (HGNC:2974),PS2,Moderate,No change - use as originally described,No change
-DNM2 (HGNC:2974),PS2,Supporting,No change - use as originally described,No change
-DNM2 (HGNC:2974),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-DNM2 (HGNC:2974),PS3,Strong,"Strong may only be considered for variant-specific mouse models. Currently, no other assays are applicable at this strength.",Disease-specific
-DNM2 (HGNC:2974),PS3,Moderate,The two assays from PS3_Supporting may be stacked to reach a Moderate Strength,Gene-specific
-DNM2 (HGNC:2974),PS3,Supporting,"Two specific assays are currently suggested to be applied at Supporting:
-
-
-
-
-Oligomerization: An abnormal readout consists of integration of increased dynamin stability compared to WT dynamin.
-
-
-GTPase activity: An abnormal readout consists of increased GTPase activity or increased stability compared to wild type dynamin.
-
-
-
-
-If not listed above, it is acceptable to use PS3_Supporting for other functional analyses if
-
-
-
-
-The assay has been validated by a known pathogenic and benign variant AND
-
-
-There is plausible reason that the function the assay is testing relates to the phenotype AND
-
-
-The assay conditions are likely to mimic the physiological environment.",Gene-specific
-DNM2 (HGNC:2974),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-DNM2 (HGNC:2974),PS4,Strong,"Specific phenotypes for proband counting include:
-
-
-A Congenital myopathy panel should be run and negative for other variants (must include BIN1, RYR1, MTM1) AND at least two of these features:
-
-
-
-
-Presence on Muscle Biopsy of: Oxidative activity and/or radial stranding with spokes on a wheel appearance with centrally nucleated muscle fibers
-
-
-Distal weakness
-
-
-Characteristic muscle imaging (See Figure 9 of Saade et al 2019 PMID: 31060725 for example)
-
-
-Ophthalmoparesis and Ptosis (both of these must be observed to count this as one phenotype criteria)
-
-
-
-
-At least 1 point, please see PS4 chart",Gene-specific
-DNM2 (HGNC:2974),PS4,Moderate,"0.5 points, please see PS4 chart",Gene-specific
-DNM2 (HGNC:2974),PS4,Supporting,"0.25 points, please see PS4 chart",Gene-specific
-DNM2 (HGNC:2974),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-DNM2 (HGNC:2974),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-DNM2 (HGNC:2974),PM2,Supporting,PM2_Supporting may be applied if the minor allele frequency in population databases of at least 2000 alleles is absent (1 allele allowed),"Disease-specific,Gene-specific"
-DNM2 (HGNC:2974),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-DNM2 (HGNC:2974),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-DNM2 (HGNC:2974),PM4,Strong,No change - use as originally described,No change
-DNM2 (HGNC:2974),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,No change
-DNM2 (HGNC:2974),PM4,Supporting,No change - use as originally described,No change
-DNM2 (HGNC:2974),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-DNM2 (HGNC:2974),PM5,Strong,No change - use as originally described,No change
-DNM2 (HGNC:2974),PM5,Moderate,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",No change
-DNM2 (HGNC:2974),PM5,Supporting,No change - use as originally described,No change
-DNM2 (HGNC:2974),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-DNM2 (HGNC:2974),PM6,Strong,No change - use as originally described,No change
-DNM2 (HGNC:2974),PM6,Moderate,"Assumed de novo, but without confirmation of paternity and maternity.",No change
-DNM2 (HGNC:2974),PM6,Supporting,No change - use as originally described,No change
-DNM2 (HGNC:2974),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-DNM2 (HGNC:2974),PP1,Strong,At least five segregations,General recommendation
-DNM2 (HGNC:2974),PP1,Moderate,Four segregations,General recommendation
-DNM2 (HGNC:2974),PP1,Supporting,At least 2 segregations,General recommendation
-DNM2 (HGNC:2974),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,
-DNM2 (HGNC:2974),PP2,Supporting,DNM2 is a gene that is constrained for missense variation (gnomAD v4.1 z=4.87). PP2 may be used for missense variants.,Gene-specific
-DNM2 (HGNC:2974),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-DNM2 (HGNC:2974),PP3,Supporting,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.
-
-
-PP3 is met if the REVEL score ≥ 0.7 or if the variant is predicted to impact splicing using SpliceAI score ≥0.5",General recommendation
-DNM2 (HGNC:2974),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-DNM2 (HGNC:2974),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-DNM2 (HGNC:2974),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-DNM2 (HGNC:2974),BA1,Stand Alone,"The minor allele frequency using the filtering allele frequency of either exomes or genomes in gnomAD is 
-≥0.0000015
-. All continental populations used in gnomAD should have at least 2000 alleles and >1 observation.","Disease-specific,Gene-specific"
-DNM2 (HGNC:2974),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-DNM2 (HGNC:2974),BS1,Strong,"The minor allele frequency using the filtering allele frequency of either exomes or genomes in gnomAD is 
-≥0.00000015
-. All continental populations used in gnomAD should have at least 2000 alleles and >1 observation.","Disease-specific,Gene-specific"
-DNM2 (HGNC:2974),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-DNM2 (HGNC:2974),BS2,Strong,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",No change
-DNM2 (HGNC:2974),BS2,Moderate,No change - use as originally described,No change
-DNM2 (HGNC:2974),BS2,Supporting,No change - use as originally described,No change
-DNM2 (HGNC:2974),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-DNM2 (HGNC:2974),BS3,Supporting,"BS3_Supporting is met if 
-both
- of these assays have WT readouts:
-
-
-Oligomerization Assay: DNM2 assembly/disassembly dynamics similar to wild type DNM2
-
-
-GTPase Activity Assay: GTPase activity and stability similar to wild type DNM2",Gene-specific
-DNM2 (HGNC:2974),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-DNM2 (HGNC:2974),BS4,Strong,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",No change
-DNM2 (HGNC:2974),BS4,Moderate,No change - use as originally described,No change
-DNM2 (HGNC:2974),BS4,Supporting,No change - use as originally described,No change
-DNM2 (HGNC:2974),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-DNM2 (HGNC:2974),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-DNM2 (HGNC:2974),BP2,Strong,No change - use as originally described,No change
-DNM2 (HGNC:2974),BP2,Moderate,No change - use as originally described,No change
-DNM2 (HGNC:2974),BP2,Supporting,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,No change
-DNM2 (HGNC:2974),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-DNM2 (HGNC:2974),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-DNM2 (HGNC:2974),BP4,Supporting,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.
-
-
-BP4 is met if the REVEL score ≤ 0.15 or if the variant is not predicted to impact splicing using SpliceAI.",General recommendation
-DNM2 (HGNC:2974),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-DNM2 (HGNC:2974),BP5,Strong,No change - use as originally described,No change
-DNM2 (HGNC:2974),BP5,Moderate,No change - use as originally described,No change
-DNM2 (HGNC:2974),BP5,Supporting,Variant found in a case with an alternate molecular basis for disease.,No change
-DNM2 (HGNC:2974),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-DNM2 (HGNC:2974),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-DNM2 (HGNC:2974),BP7,Supporting,A synonymous variant for which SpliceAI predicts no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMTM1Version1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMTM1Version1.0.0_version=1.0.0.csv
deleted file mode 100644
index ad89c07cc501a878b2af5e4d4df293b641cd1fb2..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMTM1Version1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,182 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-MTM1 (HGNC:7448),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-MTM1 (HGNC:7448),PVS1,Very Strong,See PVS1 flowchart,Gene-specific
-MTM1 (HGNC:7448),PVS1,Strong,See PVS1 flowchart,Gene-specific
-MTM1 (HGNC:7448),PVS1,Moderate,See PVS1 flowchart,Gene-specific
-MTM1 (HGNC:7448),PVS1,Supporting,See PVS1 flowchart,Gene-specific
-MTM1 (HGNC:7448),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MTM1 (HGNC:7448),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",No change
-MTM1 (HGNC:7448),PS1,Moderate,No change - use as originally described,No change
-MTM1 (HGNC:7448),PS1,Supporting,No change - use as originally described,No change
-MTM1 (HGNC:7448),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-MTM1 (HGNC:7448),PS2,Very Strong,No change - use as originally described,No change
-MTM1 (HGNC:7448),PS2,Strong,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",No change
-MTM1 (HGNC:7448),PS2,Moderate,No change - use as originally described,No change
-MTM1 (HGNC:7448),PS2,Supporting,No change - use as originally described,No change
-MTM1 (HGNC:7448),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-MTM1 (HGNC:7448),PS3,Strong,"Strong may only be considered for variant-specific mouse models. Currently, no other assays are applicable at this strength.",Disease-specific
-MTM1 (HGNC:7448),PS3,Moderate,"Where indicated, some of the assays from PS3_Supporting may be stacked to reach a Moderate Strength",Gene-specific
-MTM1 (HGNC:7448),PS3,Supporting,"Five specific assays are currently suggested to be applied at Supporting:
-
-
-
-
-Phosphatase Activity: An abnormal readout consists of reduced phosphatase activity (measured via levels of PtdIns and PtdIns5p or increased levels of precursors)
-
-
-Myotubularin Localization
-**
-: An abnormal readout consists of altered localization (presence in spots/aggregates/extensions, loss of cytoplasmic localization)
-
-
-Myotubularin Translocation
-**
-: An abnormal readout consists of loss of MTM1 recruitment to late endosomal compartment following EGF stimulation
-
-
-Intracellular Trafficking (Trafficking of endosomal cargo is thought to require phosphoinositide conversion and may be disrupted by defective MTM1 activity): An abnormal readout consists of reduced localization/trafficking of receptor proteins
-
-
-Protein and Lipid Association: An abnormal readout consists of decreased association with known binding partner (BIN1, Desmin, hVPS34-PI 3-Kinase, MTMR12, Phosphoinositide, or EEA Membrane association)
-
-
-
-
-**These two assays should not be stacked because they may not be assessing independent biological function
-
-
-If not listed above, it is acceptable to use PS3_Supporting for other functional analyses if
-
-
-
-
-The assay has been validated by a known pathogenic and benign variant AND
-
-
-There is plausible reason that the function the assay is testing relates to the phenotype AND
-
-
-The assay conditions are likely to mimic the physiological environment.",Gene-specific
-MTM1 (HGNC:7448),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-MTM1 (HGNC:7448),PS4,Strong,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance. Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.
-
-
-In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.
-
-
-5+ cases","Disease-specific,Gene-specific"
-MTM1 (HGNC:7448),PS4,Moderate,3-4 cases,"Disease-specific,Gene-specific"
-MTM1 (HGNC:7448),PS4,Supporting,2 cases,"Disease-specific,Gene-specific"
-MTM1 (HGNC:7448),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-MTM1 (HGNC:7448),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-MTM1 (HGNC:7448),PM2,Supporting,PM2_Supporting may be applied if the minor allele frequency in population databases of at least 2000 alleles is absent (1 observation allowed in females only),"Disease-specific,Gene-specific"
-MTM1 (HGNC:7448),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-MTM1 (HGNC:7448),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-MTM1 (HGNC:7448),PM4,Strong,No change - use as originally described,No change
-MTM1 (HGNC:7448),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,No change
-MTM1 (HGNC:7448),PM4,Supporting,No change - use as originally described,No change
-MTM1 (HGNC:7448),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MTM1 (HGNC:7448),PM5,Strong,No change - use as originally described,No change
-MTM1 (HGNC:7448),PM5,Moderate,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",No change
-MTM1 (HGNC:7448),PM5,Supporting,No change - use as originally described,No change
-MTM1 (HGNC:7448),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-MTM1 (HGNC:7448),PM6,Strong,No change - use as originally described,No change
-MTM1 (HGNC:7448),PM6,Moderate,"Assumed de novo, but without confirmation of paternity and maternity.",No change
-MTM1 (HGNC:7448),PM6,Supporting,No change - use as originally described,No change
-MTM1 (HGNC:7448),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-MTM1 (HGNC:7448),PP1,Strong,At least five segregations,General recommendation
-MTM1 (HGNC:7448),PP1,Moderate,3-4 segregations,General recommendation
-MTM1 (HGNC:7448),PP1,Supporting,2 segregations,General recommendation
-MTM1 (HGNC:7448),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-MTM1 (HGNC:7448),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-MTM1 (HGNC:7448),PP3,Supporting,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.
-
-
-PP3 is met if the REVEL score ≥ 0.7 or if the variant is predicted to impact splicing using SpliceAI score ≥0.5",General recommendation
-MTM1 (HGNC:7448),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-MTM1 (HGNC:7448),PP4,Supporting,"Affected Males (must be negative for BIN1, RYR1, and DNM2 variants)
-
-
-
-
-Muscle biopsy with rounded muscle fibers with a single centrally located nucleus surrounded by a halo devoid of contractile elements, but containing mitochondria
-
-
-
-
-Carrier Females (a panel test for neuromuscular disease to rule out other causes)
-
-
-
-
-Observation of myopathy (may be asymmetric) AND at least 1 other feature
-
-
-Unilateral skeletal asymmetry
-
-
-Narrow, elongated face
-
-
-High arched palate","Disease-specific,Gene-specific"
-MTM1 (HGNC:7448),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MTM1 (HGNC:7448),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-MTM1 (HGNC:7448),BA1,Stand Alone,"The minor allele frequency using the filtering allele frequency of either exomes or genomes in gnomAD is 
-≥0.000016
-. All continental gnomAD populations used should have at least 2000 alleles and >1 observation.","Disease-specific,Gene-specific"
-MTM1 (HGNC:7448),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-MTM1 (HGNC:7448),BS1,Strong,"The minor allele frequency using the filtering allele frequency of either exomes or genomes in gnomAD is 
-≥0.0000016
-. All continental gnomAD populations used should have at least 2000 alleles and >1 observation.","Disease-specific,Gene-specific"
-MTM1 (HGNC:7448),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-MTM1 (HGNC:7448),BS2,Strong,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",No change
-MTM1 (HGNC:7448),BS2,Moderate,No change - use as originally described,No change
-MTM1 (HGNC:7448),BS2,Supporting,No change - use as originally described,No change
-MTM1 (HGNC:7448),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-MTM1 (HGNC:7448),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-MTM1 (HGNC:7448),BS4,Strong,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",No change
-MTM1 (HGNC:7448),BS4,Moderate,No change - use as originally described,No change
-MTM1 (HGNC:7448),BS4,Supporting,No change - use as originally described,No change
-MTM1 (HGNC:7448),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-MTM1 (HGNC:7448),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-MTM1 (HGNC:7448),BP2,Strong,No change - use as originally described,No change
-MTM1 (HGNC:7448),BP2,Moderate,No change - use as originally described,No change
-MTM1 (HGNC:7448),BP2,Supporting,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,No change
-MTM1 (HGNC:7448),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-MTM1 (HGNC:7448),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-MTM1 (HGNC:7448),BP4,Supporting,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.
-
-
-BP4 is met if the REVEL score ≤ 0.15 or if the variant is not predicted to impact splicing using SpliceAI.",General recommendation
-MTM1 (HGNC:7448),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-MTM1 (HGNC:7448),BP5,Strong,No change - use as originally described,No change
-MTM1 (HGNC:7448),BP5,Moderate,No change - use as originally described,No change
-MTM1 (HGNC:7448),BP5,Supporting,Variant found in a case with an alternate molecular basis for disease.,No change
-MTM1 (HGNC:7448),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MTM1 (HGNC:7448),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-MTM1 (HGNC:7448),BP7,Supporting,A synonymous variant for which SpliceAI predicts no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforNEBVersion1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforNEBVersion1.0.0_version=1.0.0.csv
deleted file mode 100644
index 6e26b68a3eb9c305a8ebc668f1bde513b12a1a07..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforNEBVersion1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,218 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-NEB (HGNC:7720),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-NEB (HGNC:7720),PVS1,Very Strong,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Caveats:
-
-
-
-
-Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
-
-
-Use caution interpreting LOF variants at the extreme 3’ end of a gene.
-
-
-Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
-
-
-Use caution in the presence of multiple transcripts.
-
-
-
-
-Specified critical regions in NEB that should also receive PVS1 are listed below and in the PVS1 flowchart:
-
-
-In-frame deletions due to the repetitive nature of NEB, particularly in exon 55, are deleterious and pathogenic (Anderson 2004 PMID:15221447, Lehtokari 2009 PMID:19232495). 
-
-
-Exons 161-183 (Pelin 1999 PMID:10051637).",Gene-specific
-NEB (HGNC:7720),PVS1,Strong,"In-frame deletions due to the repetitive nature of NEB, particularly in exon 55, are deleterious and pathogenic (Anderson 2004 PMID:15221447, Lehtokari 2009 PMID:19232495). The majority of NEB exons are in frame (exons 3-180, 182); thus, skipping of in-frame exons should be scored at PVS1_Strong.",Gene-specific
-NEB (HGNC:7720),PVS1,Moderate,See PVS1 flowchart,Gene-specific
-NEB (HGNC:7720),PVS1,Supporting,See PVS1 flowchart,Gene-specific
-NEB (HGNC:7720),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-NEB (HGNC:7720),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",No change
-NEB (HGNC:7720),PS1,Moderate,No change - use as originally described,No change
-NEB (HGNC:7720),PS1,Supporting,No change - use as originally described,No change
-NEB (HGNC:7720),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-NEB (HGNC:7720),PS2,Strong,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",No change
-NEB (HGNC:7720),PS2,Moderate,No change - use as originally described,No change
-NEB (HGNC:7720),PS2,Supporting,No change - use as originally described,No change
-NEB (HGNC:7720),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-NEB (HGNC:7720),PS3,Strong,"Strong may only be considered for variant-specific mouse models. Currently, no other assays are applicable at this strength.",Disease-specific
-NEB (HGNC:7720),PS3,Moderate,The two assays from PS3_Supporting may be stacked to reach a Moderate Strength,Gene-specific
-NEB (HGNC:7720),PS3,Supporting,"Two specific assays are currently suggested to be applied at Supporting:
-
-
-
-
-Thin filament structure: An abnormal readout consists of a significant difference in intensity reflections of X-ray diffraction patterns generated by muscle fibers from patient biopsies compared to WT.
-
-
-In vitro
- motility: An abnormal readout consists of a significant difference in speed of single fibers derived from patient muscle compared to WT.
-
-
-
-
-If not listed above, it is acceptable to use PS3_Supporting for other functional analyses if
-
-
-
-
-The assay has been validated by a known pathogenic and benign variant AND
-
-
-There is plausible reason that the function the assay is testing relates to the phenotype AND
-
-
-The assay conditions are likely to mimic the physiological environment.",Gene-specific
-NEB (HGNC:7720),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-NEB (HGNC:7720),PS4,Strong,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance. 
-
-
-NEB is associated with Autosomal Recessive disease; PS4 can only be used for case-control studies and not proband counting. Please use PM3 for individual case observations.","Disease-specific,Gene-specific"
-NEB (HGNC:7720),PS4,Moderate,NEB is associated with Autosomal Recessive disease; PS4 can only be used for case-control studies and not proband counting. Please use PM3 for individual case observations.,Gene-specific
-NEB (HGNC:7720),PS4,Supporting,NEB is associated with Autosomal Recessive disease; PS4 can only be used for case-control studies and not proband counting. Please use PM3 for individual case observations.,Gene-specific
-NEB (HGNC:7720),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-NEB (HGNC:7720),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-NEB (HGNC:7720),PM2,Supporting,PM2_Supporting may be applied if the minor allele frequency in population databases of at least 2000 alleles is ≤ 0.0000559. 1 allele is allowed.,"Disease-specific,Gene-specific"
-NEB (HGNC:7720),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-NEB (HGNC:7720),PM3,Very Strong,4.0 points per the PM3 chart,Disease-specific
-NEB (HGNC:7720),PM3,Strong,2.0 points per the PM3 chart,Disease-specific
-NEB (HGNC:7720),PM3,Moderate,"For recessive disorders, detected in trans with a pathogenic variant Note: This requires testing of parents (or offspring) to determine phase.
-
-
-1.0 points per the PM3 chart",Disease-specific
-NEB (HGNC:7720),PM3,Supporting,0.5 points per the PM3 chart,Disease-specific
-NEB (HGNC:7720),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-NEB (HGNC:7720),PM4,Strong,"In-frame deletions due to the repetitive nature of NEB, particularly in exon 55, are deleterious and pathogenic (Anderson 2004 PMID:15221447, Lehtokari 2009 PMID:19232495).",Gene-specific
-NEB (HGNC:7720),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,No change
-NEB (HGNC:7720),PM4,Supporting,No change - use as originally described,No change
-NEB (HGNC:7720),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-NEB (HGNC:7720),PM5,Strong,No change - use as originally described,No change
-NEB (HGNC:7720),PM5,Moderate,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",No change
-NEB (HGNC:7720),PM5,Supporting,No change - use as originally described,No change
-NEB (HGNC:7720),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-NEB (HGNC:7720),PM6,Strong,No change - use as originally described,No change
-NEB (HGNC:7720),PM6,Moderate,"Assumed de novo, but without confirmation of paternity and maternity.",No change
-NEB (HGNC:7720),PM6,Supporting,No change - use as originally described,No change
-NEB (HGNC:7720),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-NEB (HGNC:7720),PP1,Strong,See segregation chart,General recommendation
-NEB (HGNC:7720),PP1,Moderate,See segregation chart,General recommendation
-NEB (HGNC:7720),PP1,Supporting,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. Note: May be used as stronger evidence with increasing segregation data.
-
-
-See segregation chart",General recommendation
-NEB (HGNC:7720),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-NEB (HGNC:7720),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-NEB (HGNC:7720),PP3,Supporting,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.
-
-
-PP3 is met if the REVEL score ≥ 0.7 or if the variant is predicted to impact splicing using SpliceAI score ≥0.5",General recommendation
-NEB (HGNC:7720),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-NEB (HGNC:7720),PP4,Supporting,"PP4 is met with the presence of any of these features
-
-
-Presence on Muscle Biopsy of:
-
-
-
-
-Nemaline rods
-
-
-Shorter thin filaments
-
-
-
-
-Functional assays performed upon patient muscle biopsy indicate:
-
-
-
-
-Significantly altered Calcium sensitivity
-
-
-Significantly altered muscle mechanics (altered force-sarcomere length or reduced contractile strength and force generation)","Disease-specific,Gene-specific"
-NEB (HGNC:7720),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-NEB (HGNC:7720),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-NEB (HGNC:7720),BA1,Stand Alone,"The minor allele frequency using the filtering allele frequency of either exomes or genomes in gnomAD is ≥0.00559. All populations used should have at least 2000 alleles and >1 observation. The Ashkenazi Jewish, European Finnish, and Other populations in gnomAD will not be used for BA1 application.
-
-
-BA1 exclusion variants
- (well-known pathogenic variants that are above the specified BA1 threshold) are as follows: 
-
-
-Exon 55 deletion common in the AJ population (NM_001271208.2:c.7431+1919_7536+374del)
-
-
-NM_001271208.2:c.19097G>T (p.Ser6366Ile)
-
-
-NM_001271208.2:c.22249A>C (p.Thr7417Pro)","Disease-specific,Gene-specific"
-NEB (HGNC:7720),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-NEB (HGNC:7720),BS1,Strong,The minor allele frequency using the filtering allele frequency of either exomes or genomes in gnomAD is ≥0.000237 in continental populations. All populations used should have at least 2000 alleles and >1 observation.,"Disease-specific,Gene-specific"
-NEB (HGNC:7720),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-NEB (HGNC:7720),BS2,Strong,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",No change
-NEB (HGNC:7720),BS2,Moderate,No change - use as originally described,No change
-NEB (HGNC:7720),BS2,Supporting,No change - use as originally described,No change
-NEB (HGNC:7720),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-NEB (HGNC:7720),BS3,Moderate,The two assays from BS3_Supporting may be stacked to reach a Moderate Strength,Gene-specific
-NEB (HGNC:7720),BS3,Supporting,"Two specific assays are currently suggested to be applied at Supporting:
-
-
-
-
-Thin filament structure: A normal readout consists of no significant difference in intensity reflections of X-ray diffraction patterns generated by muscle fibers from patient biopsies compared to WT.
-
-
-In vitro
- motility: A normal readout consists of no a significant difference in speed of single fibers derived from patient muscle compared to WT.",Gene-specific
-NEB (HGNC:7720),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-NEB (HGNC:7720),BS4,Strong,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",No change
-NEB (HGNC:7720),BS4,Moderate,No change - use as originally described,No change
-NEB (HGNC:7720),BS4,Supporting,No change - use as originally described,No change
-NEB (HGNC:7720),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-NEB (HGNC:7720),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-NEB (HGNC:7720),BP2,Strong,No change - use as originally described,No change
-NEB (HGNC:7720),BP2,Moderate,No change - use as originally described,No change
-NEB (HGNC:7720),BP2,Supporting,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,No change
-NEB (HGNC:7720),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-NEB (HGNC:7720),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-NEB (HGNC:7720),BP4,Supporting,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.
-
-
-BP4 is met if the REVEL score ≤ 0.15 or if the variant is not predicted to impact splicing using SpliceAI.",General recommendation
-NEB (HGNC:7720),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-NEB (HGNC:7720),BP5,Strong,No change - use as originally described,No change
-NEB (HGNC:7720),BP5,Moderate,No change - use as originally described,No change
-NEB (HGNC:7720),BP5,Supporting,Variant found in a case with an alternate molecular basis for disease.,No change
-NEB (HGNC:7720),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-NEB (HGNC:7720),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-NEB (HGNC:7720),BP7,Supporting,A synonymous variant for which SpliceAI predicts no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRYR1Version1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRYR1Version1.0.0_version=1.0.0.csv
deleted file mode 100644
index 486edb328862ec82c353a25849ce57b4f07d7e4b..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRYR1Version1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,187 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-RYR1 (HGNC:10483),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-RYR1 (HGNC:10483),PVS1,Very Strong,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
-
-
-
-
-Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
-
-
-Use caution interpreting LOF variants at the extreme 3’ end of a gene.
-
-
-Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
-
-
-Use caution in the presence of multiple transcripts.","Disease-specific,Gene-specific"
-RYR1 (HGNC:10483),PVS1,Strong,"In-frame deletions or in frame exon-skipping variants in the pore/transmembrane region of RYR1 should be scored at PVS1_strong. (Amino acids 4800-4950, Exons 100-103)",Gene-specific
-RYR1 (HGNC:10483),PVS1,Moderate,See PVS1 flowchart,"Disease-specific,Gene-specific"
-RYR1 (HGNC:10483),PVS1,Supporting,See PVS1 flowchart,"Disease-specific,Gene-specific"
-RYR1 (HGNC:10483),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RYR1 (HGNC:10483),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",No change
-RYR1 (HGNC:10483),PS1,Moderate,No change - use as originally described,No change
-RYR1 (HGNC:10483),PS1,Supporting,No change - use as originally described,No change
-RYR1 (HGNC:10483),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-RYR1 (HGNC:10483),PS2,Very Strong,No change - use as originally described,No change
-RYR1 (HGNC:10483),PS2,Strong,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",No change
-RYR1 (HGNC:10483),PS2,Moderate,No change - use as originally described,No change
-RYR1 (HGNC:10483),PS2,Supporting,No change - use as originally described,No change
-RYR1 (HGNC:10483),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-RYR1 (HGNC:10483),PS3,Strong,"Strong may only be considered for variant-specific mouse models. Currently, no other assays are applicable at this strength.",Disease-specific
-RYR1 (HGNC:10483),PS3,Supporting,"There are no specified functional assay for AR RYR1-related myopathy. However, it is acceptable to use PS3_Supporting for other functional analyses if
-
-
-
-
-The assay has been validated by a known pathogenic and benign variant AND
-
-
-There is plausible reason that the function the assay is testing relates to the phenotype AND
-
-
-The assay conditions are likely to mimic the physiological environment.",Gene-specific
-RYR1 (HGNC:10483),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",NA
-RYR1 (HGNC:10483),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-RYR1 (HGNC:10483),PM1,Moderate,The pore/transmembrane region of RYR1 is critical for protein function and missense variants that fall within this region (amino acids 4800-4950),"Disease-specific,Gene-specific"
-RYR1 (HGNC:10483),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-RYR1 (HGNC:10483),PM2,Supporting,"PM2_Supporting may be applied if the minor allele frequency in population databases of at least 2000 alleles is 
-
-
- ≤ 0.00000697 for autosomal recessive","Disease-specific,Gene-specific"
-RYR1 (HGNC:10483),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-RYR1 (HGNC:10483),PM3,Very Strong,4.0 points per the PM3 chart,"Disease-specific,Gene-specific"
-RYR1 (HGNC:10483),PM3,Strong,2.0 points per the PM3 chart,"Disease-specific,Gene-specific"
-RYR1 (HGNC:10483),PM3,Moderate,"For recessive disorders, detected in trans with a pathogenic variant Note: This requires testing of parents (or offspring) to determine phase.
-
-
-1.0 points per the PM3 chart","Disease-specific,Gene-specific"
-RYR1 (HGNC:10483),PM3,Supporting,0.5 points per the PM3 chart,"Disease-specific,Gene-specific"
-RYR1 (HGNC:10483),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-RYR1 (HGNC:10483),PM4,Strong,No change - use as originally described,No change
-RYR1 (HGNC:10483),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,No change
-RYR1 (HGNC:10483),PM4,Supporting,No change - use as originally described,No change
-RYR1 (HGNC:10483),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RYR1 (HGNC:10483),PM5,Strong,No change - use as originally described,No change
-RYR1 (HGNC:10483),PM5,Moderate,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",No change
-RYR1 (HGNC:10483),PM5,Supporting,No change - use as originally described,No change
-RYR1 (HGNC:10483),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-RYR1 (HGNC:10483),PM6,Strong,No change - use as originally described,No change
-RYR1 (HGNC:10483),PM6,Moderate,"Assumed de novo, but without confirmation of paternity and maternity.",No change
-RYR1 (HGNC:10483),PM6,Supporting,No change - use as originally described,No change
-RYR1 (HGNC:10483),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-RYR1 (HGNC:10483),PP1,Strong,See segregation chart,General recommendation
-RYR1 (HGNC:10483),PP1,Moderate,See segregation chart,General recommendation
-RYR1 (HGNC:10483),PP1,Supporting,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. Note: May be used as stronger evidence with increasing segregation data.
-
-
-See segregation chart",General recommendation
-RYR1 (HGNC:10483),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-RYR1 (HGNC:10483),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-RYR1 (HGNC:10483),PP3,Supporting,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.
-
-
-PP3 is met if the REVEL score ≥ 0.7 or if the variant is predicted to impact splicing using SpliceAI score ≥0.5",General recommendation
-RYR1 (HGNC:10483),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-RYR1 (HGNC:10483),PP4,Supporting,"To meet PP4, a congenital myopathy testing panel should be performed without identification of other causative variants and AT LEAST TWO of these features should be present
-
-
-
-
-Presence on Muscle Biopsy of:
- mini cores or central cores (histology or electron microscopy)
-
-
-Exercise, heat, or anesthetic induced rhabdomyolysis
-
-
-Ophthalmoplegia
-
-
-Characteristic muscle imaging (see Figure 8, Saade et al 2019 PMID: 31060725)","Disease-specific,Gene-specific"
-RYR1 (HGNC:10483),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RYR1 (HGNC:10483),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-RYR1 (HGNC:10483),BA1,Stand Alone,"The minor allele frequency using the filtering allele frequency of either exomes or genomes of continental populations in gnomAD is 
-≥0.00697
- 
-for AR variants
-. All populations used should have at least 2000 alleles and >1 observation. 
-
-
-BA1 exclusion variants
- (well-known pathogenic variants that are above the specified BA1 or BS1 threshold) are as follows: 
-
-
-NM_000540.3:c.6721C>T (p.Arg2241Ter)
-
-
-NM_000540.3:c.10348-6C>G","Disease-specific,Gene-specific"
-RYR1 (HGNC:10483),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-RYR1 (HGNC:10483),BS1,Strong,"The minor allele frequency using the filtering allele frequency of either exomes or genomes of continental populations in gnomAD is 
-≥0.0000006 for AR
- 
-variants
-. All populations used should have at least 2000 alleles and >1 observation. 
-
-
-BA1/BS1 exclusion variants
- (well-known pathogenic variants that are above the specified BA1 or BS1 threshold) are as follows: 
-
-
-NM_000540.3:c.6721C>T (p.Arg2241Ter)
-
-
-NM_000540.3:c.10348-6C>G","Disease-specific,Gene-specific"
-RYR1 (HGNC:10483),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-RYR1 (HGNC:10483),BS2,Strong,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",No change
-RYR1 (HGNC:10483),BS2,Moderate,No change - use as originally described,No change
-RYR1 (HGNC:10483),BS2,Supporting,No change - use as originally described,No change
-RYR1 (HGNC:10483),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-RYR1 (HGNC:10483),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-RYR1 (HGNC:10483),BS4,Strong,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",No change
-RYR1 (HGNC:10483),BS4,Moderate,No change - use as originally described,No change
-RYR1 (HGNC:10483),BS4,Supporting,No change - use as originally described,No change
-RYR1 (HGNC:10483),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-RYR1 (HGNC:10483),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-RYR1 (HGNC:10483),BP2,Strong,No change - use as originally described,No change
-RYR1 (HGNC:10483),BP2,Moderate,No change - use as originally described,No change
-RYR1 (HGNC:10483),BP2,Supporting,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,No change
-RYR1 (HGNC:10483),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-RYR1 (HGNC:10483),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-RYR1 (HGNC:10483),BP4,Supporting,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.
-
-
-BP4 is met if the REVEL score ≤ 0.15 or if the variant is not predicted to impact splicing using SpliceAI.",General recommendation
-RYR1 (HGNC:10483),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-RYR1 (HGNC:10483),BP5,Strong,No change - use as originally described,No change
-RYR1 (HGNC:10483),BP5,Moderate,No change - use as originally described,No change
-RYR1 (HGNC:10483),BP5,Supporting,Variant found in a case with an alternate molecular basis for disease.,No change
-RYR1 (HGNC:10483),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RYR1 (HGNC:10483),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-RYR1 (HGNC:10483),BP7,Supporting,A synonymous variant for which SpliceAI predicts no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRYR1Version2.0.0_version=2.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRYR1Version2.0.0_version=2.0.0.csv
deleted file mode 100644
index ea0ea1eed3f14409e39fc369e4a0e64029bb19f8..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRYR1Version2.0.0_version=2.0.0.csv
+++ /dev/null
@@ -1,185 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-RYR1 (HGNC:10483),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-RYR1 (HGNC:10483),PVS1,Very Strong,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
-
-
-
-
-Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
-
-
-Use caution interpreting LOF variants at the extreme 3’ end of a gene.
-
-
-Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
-
-
-Use caution in the presence of multiple transcripts.","Disease-specific,Gene-specific"
-RYR1 (HGNC:10483),PVS1,Strong,"In-frame deletions or in frame exon-skipping variants in the pore/transmembrane region of RYR1 should be scored at PVS1_strong. (Amino acids 4800-4950, Exons 100-103)",Gene-specific
-RYR1 (HGNC:10483),PVS1,Moderate,See PVS1 flowchart,"Disease-specific,Gene-specific"
-RYR1 (HGNC:10483),PVS1,Supporting,See PVS1 flowchart,"Disease-specific,Gene-specific"
-RYR1 (HGNC:10483),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RYR1 (HGNC:10483),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",No change
-RYR1 (HGNC:10483),PS1,Moderate,No change - use as originally described,No change
-RYR1 (HGNC:10483),PS1,Supporting,No change - use as originally described,No change
-RYR1 (HGNC:10483),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-RYR1 (HGNC:10483),PS2,Very Strong,No change - use as originally described,No change
-RYR1 (HGNC:10483),PS2,Strong,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",No change
-RYR1 (HGNC:10483),PS2,Moderate,No change - use as originally described,No change
-RYR1 (HGNC:10483),PS2,Supporting,No change - use as originally described,No change
-RYR1 (HGNC:10483),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-RYR1 (HGNC:10483),PS3,Strong,"Strong may only be considered for variant-specific mouse models. Currently, no other assays are applicable at this strength.",Disease-specific
-RYR1 (HGNC:10483),PS3,Supporting,"There are no specified functional assay for AR RYR1-related myopathy. However, it is acceptable to use PS3_Supporting for other functional analyses if
-
-
-
-
-The assay has been validated by a known pathogenic and benign variant AND
-
-
-There is plausible reason that the function the assay is testing relates to the phenotype AND
-
-
-The assay conditions are likely to mimic the physiological environment.",Gene-specific
-RYR1 (HGNC:10483),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",NA
-RYR1 (HGNC:10483),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-RYR1 (HGNC:10483),PM1,Moderate,The pore/transmembrane region of RYR1 is critical for protein function and missense variants that fall within this region (amino acids 4800-4950),"Disease-specific,Gene-specific"
-RYR1 (HGNC:10483),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-RYR1 (HGNC:10483),PM2,Supporting,"PM2_Supporting may be applied if the minor allele frequency in population databases of at least 2000 alleles is 
-
-
- ≤ 0.00000697 for autosomal recessive","Disease-specific,Gene-specific"
-RYR1 (HGNC:10483),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-RYR1 (HGNC:10483),PM3,Very Strong,4.0 points per the PM3 chart,"Disease-specific,Gene-specific"
-RYR1 (HGNC:10483),PM3,Strong,2.0 points per the PM3 chart,"Disease-specific,Gene-specific"
-RYR1 (HGNC:10483),PM3,Moderate,"For recessive disorders, detected in trans with a pathogenic variant Note: This requires testing of parents (or offspring) to determine phase.
-
-
-1.0 points per the PM3 chart","Disease-specific,Gene-specific"
-RYR1 (HGNC:10483),PM3,Supporting,0.5 points per the PM3 chart,"Disease-specific,Gene-specific"
-RYR1 (HGNC:10483),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-RYR1 (HGNC:10483),PM4,Strong,No change - use as originally described,No change
-RYR1 (HGNC:10483),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,No change
-RYR1 (HGNC:10483),PM4,Supporting,No change - use as originally described,No change
-RYR1 (HGNC:10483),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RYR1 (HGNC:10483),PM5,Strong,No change - use as originally described,No change
-RYR1 (HGNC:10483),PM5,Moderate,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",No change
-RYR1 (HGNC:10483),PM5,Supporting,No change - use as originally described,No change
-RYR1 (HGNC:10483),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-RYR1 (HGNC:10483),PM6,Strong,No change - use as originally described,No change
-RYR1 (HGNC:10483),PM6,Moderate,"Assumed de novo, but without confirmation of paternity and maternity.",No change
-RYR1 (HGNC:10483),PM6,Supporting,No change - use as originally described,No change
-RYR1 (HGNC:10483),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-RYR1 (HGNC:10483),PP1,Strong,See segregation chart,General recommendation
-RYR1 (HGNC:10483),PP1,Moderate,See segregation chart,General recommendation
-RYR1 (HGNC:10483),PP1,Supporting,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. Note: May be used as stronger evidence with increasing segregation data.
-
-
-See segregation chart",General recommendation
-RYR1 (HGNC:10483),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-RYR1 (HGNC:10483),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-RYR1 (HGNC:10483),PP3,Supporting,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.
-
-
-PP3 is met if the REVEL score ≥ 0.7 or if the variant is predicted to impact splicing using SpliceAI score ≥0.5",General recommendation
-RYR1 (HGNC:10483),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-RYR1 (HGNC:10483),PP4,Supporting,"To meet PP4, a congenital myopathy testing panel should be performed without identification of other causative variants and AT LEAST TWO of these features should be present
-
-
-
-
-Presence on Muscle Biopsy of:
- mini cores or central cores (histology or electron microscopy)
-
-
-Exercise, heat, or anesthetic induced rhabdomyolysis
-
-
-Ophthalmoplegia
-
-
-Characteristic muscle imaging (see Figure 8, Saade et al 2019 PMID: 31060725)","Disease-specific,Gene-specific"
-RYR1 (HGNC:10483),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RYR1 (HGNC:10483),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-RYR1 (HGNC:10483),BA1,Stand Alone,"The minor allele frequency using the filtering allele frequency of either exomes or genomes of continental populations in gnomAD is 
-≥0.00697
- 
-for AR variants
-. All populations used should have at least 2000 alleles and >1 observation. 
-
-
-BA1 exclusion variants
- (well-known pathogenic variants that are above the specified BA1 or BS1 threshold) are as follows: 
-
-
-NM_000540.3:c.6721C>T (p.Arg2241Ter)
-
-
-NM_000540.3:c.10348-6C>G","Disease-specific,Gene-specific"
-RYR1 (HGNC:10483),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-RYR1 (HGNC:10483),BS1,Strong,"The minor allele frequency using the filtering allele frequency of either exomes or genomes of continental populations in gnomAD is 
-≥0.000697 for AR variants
-. All populations used should have at least 2000 alleles and >1 observation. 
-
-
-BA1/BS1 exclusion variants
- (well-known pathogenic variants that are above the specified BA1 or BS1 threshold) are as follows: 
-
-
-NM_000540.3:c.6721C>T (p.Arg2241Ter)
-
-
-NM_000540.3:c.10348-6C>G","Disease-specific,Gene-specific"
-RYR1 (HGNC:10483),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-RYR1 (HGNC:10483),BS2,Strong,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",No change
-RYR1 (HGNC:10483),BS2,Moderate,No change - use as originally described,No change
-RYR1 (HGNC:10483),BS2,Supporting,No change - use as originally described,No change
-RYR1 (HGNC:10483),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-RYR1 (HGNC:10483),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-RYR1 (HGNC:10483),BS4,Strong,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",No change
-RYR1 (HGNC:10483),BS4,Moderate,No change - use as originally described,No change
-RYR1 (HGNC:10483),BS4,Supporting,No change - use as originally described,No change
-RYR1 (HGNC:10483),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-RYR1 (HGNC:10483),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-RYR1 (HGNC:10483),BP2,Strong,No change - use as originally described,No change
-RYR1 (HGNC:10483),BP2,Moderate,No change - use as originally described,No change
-RYR1 (HGNC:10483),BP2,Supporting,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,No change
-RYR1 (HGNC:10483),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-RYR1 (HGNC:10483),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-RYR1 (HGNC:10483),BP4,Supporting,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.
-
-
-BP4 is met if the REVEL score ≤ 0.15 or if the variant is not predicted to impact splicing using SpliceAI.",General recommendation
-RYR1 (HGNC:10483),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-RYR1 (HGNC:10483),BP5,Strong,No change - use as originally described,No change
-RYR1 (HGNC:10483),BP5,Moderate,No change - use as originally described,No change
-RYR1 (HGNC:10483),BP5,Supporting,Variant found in a case with an alternate molecular basis for disease.,No change
-RYR1 (HGNC:10483),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RYR1 (HGNC:10483),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-RYR1 (HGNC:10483),BP7,Supporting,A synonymous variant for which SpliceAI predicts no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenDICER1andmiRNA-ProcessingGeneExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDICER1Version1.1.0_version=1.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenDICER1andmiRNA-ProcessingGeneExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDICER1Version1.1.0_version=1.1.0.csv
deleted file mode 100644
index 2504edaf4fc82059212d262d2b80ad0128c1b0e2..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenDICER1andmiRNA-ProcessingGeneExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDICER1Version1.1.0_version=1.1.0.csv
+++ /dev/null
@@ -1,205 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-DICER1 (HGNC:17098),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-DICER1 (HGNC:17098),PVS1,Very Strong,"Follow SVI guidance, using DICER1-specific information.
-Per the PVS1 workflow guidance provided in Tayoun et al. 2018 (PMID 30192042), the following will apply:
-
-
-
-
-Nonsense or frameshift variants:
-
-
-PVS1 applies to variants predicted to result in nonsense-mediated decay (NMD); the predicted NMD cutoff for DICER1 occurs at p.Pro1850.
-
-
-PVS1_Moderate applies to variants resulting in protein truncation 3’ of this cutoff
-
-
-Canonical splice variants (+/- 1,2 intronic positions): PVS1 applies with the following exceptions:
-
-
-Exon 10 SDS/SAS: PVS1_Strong (in-frame but exon includes >10% protein)
-
-
-Exons 5, 15, 18, 22 SDS/SAS: PVS1_Moderate (in-frame and each <10% of protein)
-
-
-Exon 27 SAS: PVS1_Moderate (final exon)
-
-
-Exon 1: no criteria (non-coding)
-
-
-Variants that disrupt the translation start site (p.M1?): no criteria applied given p.M1 is not highly conserved, there are three in-frame possible alternate start codons (p.Met11, p.Met17, p.Met24), and multiple lab cases of p.Met1? without
-DICER1 phenotype.
-SDS = splice donor site; SAS = splice acceptor site.
-Refer to PS3 weight guidelines when a variant meets criterion for application of both PVS1 and PS3.
-A disease-specific PVS1 decision tree incorporating the above bullets is also included at the end of this document as an additional curation tool.","Disease-specific,General recommendation"
-DICER1 (HGNC:17098),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-DICER1 (HGNC:17098),PS1,Strong,"For same AA change, must confirm there is no difference in splicing using RNA data or in-silico modeling data (concordance of MaxEntScan and SpliceAI). For non-canonical intronic splicing variants at same nucleotide should have equal or worse splicing impact.
-This rule code can only be used to compare variants asserted as pathogenic by the ClinGen DICER1 VCEP. Likely pathogenic changes do not apply.",General recommendation
-DICER1 (HGNC:17098),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-DICER1 (HGNC:17098),PS2,Very Strong,"≥4 de novo points.
-De novo points should be tallied using the simplified table for tallying
-proband points and used to determine the applied strength of PS2, consistent
-with SVI guidance. To avoid redundancy and increase consistency, the EP has
-opted to drop PM6 and exclusively use PS2 for de novo evidence.",Strength
-DICER1 (HGNC:17098),PS2,Strong,"≥2 but less than 4 de novo points.
-De novo points should be tallied using the simplified table for tallying
-proband points and used to determine the applied strength of PS2, consistent
-with SVI guidance. To avoid redundancy and increase consistency, the EP has
-opted to drop PM6 and exclusively use PS2 for de novo evidence.",Strength
-DICER1 (HGNC:17098),PS2,Moderate,"≥1 but less than 2 de novo points.
-De novo points should be tallied using the simplified table for tallying proband points and used to determine the applied strength of PS2, consistent with SVI guidance. To avoid redundancy and increase consistency, the EP has opted to drop PM6 and exclusively use PS2 for de novo evidence.",General recommendation
-DICER1 (HGNC:17098),PS2,Supporting,"≥0.5 but less than 1 de novo points.
-De novo points should be tallied using the simplified table for tallying
-proband points and used to determine the applied strength of PS2, consistent with SVI guidance. To avoid redundancy and increase consistency, the EP has opted to drop PM6 and exclusively use PS2 for de novo evidence.",Strength
-DICER1 (HGNC:17098),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-DICER1 (HGNC:17098),PS3,Strong,"RNA assay shows splicing impact that is out-of-frame, in-frame ≥193 residues, or in-frame with RNase IIIb disruption.
-(PS3_Moderate if PVS1_Strong is applied).
-This rule should be used and weighted appropriately for variants with functional evidence of a splicing impact and/or reduced DICER1 ability to cleave pre-miRNA. Follow SVI guidance regarding control numbers for functional studies. Do not apply PS3 at any strength if PVS1 is applied at full strength.",Disease-specific
-DICER1 (HGNC:17098),PS3,Moderate,"RNA assay shows in-frame splicing impact with change in protein length <193 residues AND RNase IIIb domain not disrupted.
-This rule should be used and weighted appropriately for variants with functional evidence of a splicing impact and/or reduced DICER1 ability to cleave pre-miRNA. Follow SVI guidance regarding control numbers for functional studies. Do not apply PS3 at any strength if PVS1 is applied at full strength.","Disease-specific,General recommendation"
-DICER1 (HGNC:17098),PS3,Supporting,"In vitro cleavage assay shows failure or severely reduced capacity to produce either 5p or 3p microRNAs from a premiRNA (positive and negative controls also performed). 
-This rule should be used and weighted appropriately for variants with functional evidence of a splicing impact and/or reduced DICER1 ability to cleave pre-miRNA. Follow SVI guidance regarding control numbers for functional studies. Do not apply PS3 at any strength if PVS1 is applied at full strength.","Disease-specific,Strength"
-DICER1 (HGNC:17098),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-DICER1 (HGNC:17098),PS4,Strong,"≥4 phenotype points.
-Unrelated probands may contribute up to 1 point each based on phenotype (see Tables 2 & 3 in ruleset)
-Caveats:
-
-
-
-
-Do not apply PS4 if variant meets BA1/BS1 criteria.
-
-
-Do not apply points for a phenotype in an individual with a likely pathogenic germline variant in a second gene that could have reasonably contributed to the phenotype (e.g. Wilms tumor in an individual with a P/LP WT1 variant).
-
-
-Do not apply points for a proband whose tumor sequencing is consistent with a likely sporadic event (i.e. sequencing reveals a somatic, VCEPcurated, non-hotspot, likely pathogenic DICER1 variant in addition to a somatic hotspot variant and the germline variant under assessment). Of note, DICER1 tumors that consistently or occasionally follow a classical 2- hit hypothesis (i.e. LOF of both alleles) are exempt from this caveat. For example, identification of a somatic pathogenic non-hotspot DICER1 variant in pineoblastoma (PMID: 25022261), pituitary blastoma (PMID: 24839956), and lung cysts or cystic nephroma lacking mesenchymal cells (PMIDs: 25500911, 25978641) should not exclude the proband from PS4.",General recommendation
-DICER1 (HGNC:17098),PS4,Moderate,"2 – 3.5 phenotype points.
-Unrelated probands may contribute up to 1 point each based on phenotype (see Tables 2 & 3 in ruleset)
-Caveats:
-
-
-
-
-Do not apply PS4 if variant meets BA1/BS1 criteria.
-
-
-Do not apply points for a phenotype in an individual with a likely pathogenic germline variant in a second gene that could have reasonably contributed to the phenotype (e.g. Wilms tumor in an individual with a P/LP WT1 variant).
-
-
-Do not apply points for a proband whose tumor sequencing is consistent with a likely sporadic event (i.e. sequencing reveals a somatic, VCEPcurated, non-hotspot, likely pathogenic DICER1 variant in addition to a somatic hotspot variant and the germline variant under assessment). Of note, DICER1 tumors that consistently or occasionally follow a classical 2- hit hypothesis (i.e. LOF of both alleles) are exempt from this caveat. For example, identification of a somatic pathogenic non-hotspot DICER1 variant in pineoblastoma (PMID: 25022261), pituitary blastoma (PMID: 24839956), and lung cysts or cystic nephroma lacking mesenchymal cells (PMIDs: 25500911, 25978641) should not exclude the proband from PS4.",Strength
-DICER1 (HGNC:17098),PS4,Supporting,"1 – 1.5 phenotype points.
-Unrelated probands may contribute up to 1 point each based on phenotype (see Tables 2 & 3 in ruleset)
-Caveats:
-
-
-
-
-Do not apply PS4 if variant meets BA1/BS1 criteria.
-
-
-Do not apply points for a phenotype in an individual with a likely pathogenic germline variant in a second gene that could have reasonably contributed to the phenotype (e.g. Wilms tumor in an individual with a P/LP WT1 variant).
-
-
-Do not apply points for a proband whose tumor sequencing is consistent with a likely sporadic event (i.e. sequencing reveals a somatic, VCEPcurated, non-hotspot, likely pathogenic DICER1 variant in addition to a somatic hotspot variant and the germline variant under assessment). Of note, DICER1 tumors that consistently or occasionally follow a classical 2- hit hypothesis (i.e. LOF of both alleles) are exempt from this caveat. For example, identification of a somatic pathogenic non-hotspot DICER1 variant in pineoblastoma (PMID: 25022261), pituitary blastoma (PMID: 24839956), and lung cysts or cystic nephroma lacking mesenchymal cells (PMIDs: 25500911, 25978641) should not exclude the proband from PS4.",Strength
-DICER1 (HGNC:17098),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-DICER1 (HGNC:17098),PM1,Moderate,"Putative missense variants at residues affecting metal ion-binding: codons p.S1344, p.E1705, p.D1709, p.D1713, p.G1809, p.D1810, p.E1813",Disease-specific
-DICER1 (HGNC:17098),PM1,Supporting,"Putative missense variants at residues in the RNase IIIb domain (p.Y1682 – p.S1846), besides the metal ion-binding residues (see PM1).",Strength
-DICER1 (HGNC:17098),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-DICER1 (HGNC:17098),PM2,Supporting,Allele frequency <0.000005 across gnomAD (non-cancer) with no more than one allele in any subpopulation and at least 20x coverage.,"Disease-specific,Strength"
-DICER1 (HGNC:17098),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-DICER1 (HGNC:17098),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-DICER1 (HGNC:17098),PM4,Moderate,In-frame indels with a residue within the RNase IIIb domain (p.Y1682 – p.S1846).,Disease-specific
-DICER1 (HGNC:17098),PM4,Supporting,In-frame indels outside of the RNase IIIb domain (p.Y1682 – p.S1846) and repeat regions (p.D606-p.D609; p.E1418-p.E1420; p.E1422-p.E1425).,Strength
-DICER1 (HGNC:17098),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-DICER1 (HGNC:17098),PM5,Moderate,Missense variant under evaluation should have equal or worse Grantham score. Splicing should be ruled out with either RNA data or agreement in splicing predictors (MaxEntScan and SpliceAI) that show no splicing effects. The other variant must be interpreted as pathogenic by the ClinGen DICER1 VCEP. Likely pathogenic changes do not apply. This rule cannot be applied in combination with PM1 or PS1.,General recommendation
-DICER1 (HGNC:17098),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-DICER1 (HGNC:17098),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-DICER1 (HGNC:17098),PP1,Strong,"≥7 meioses across ≥2 families.
-Phenotype-positive individuals should have high, moderate, or low-specificity phenotypes (see phenotype table). (Caveat: segregation with a single low-specificity phenotype across multiple individuals (e.g. familial Wilms tumor) does not fulfill PP1.)
-Do not apply PP1 if variant meets BA1/BS1 criteria.",Strength
-DICER1 (HGNC:17098),PP1,Moderate,"5 – 6 meioses across ≥1 family.
-Phenotype-positive individuals should have high, moderate, or low-specificity phenotypes (see phenotype table). (Caveat: segregation with a single low-specificity
-phenotype across multiple individuals (e.g. familial Wilms tumor) does not fulfill PP1.)
-Do not apply PP1 if variant meets BA1/BS1 criteria.",Strength
-DICER1 (HGNC:17098),PP1,Supporting,"3 – 4 meioses across ≥1 family.
-Phenotype-positive individuals should have high, moderate, or low-specificity phenotypes (see phenotype table). (Caveat: segregation with a single low-specificity phenotype across multiple individuals (e.g. familial Wilms tumor) does not fulfill PP1.) 
-Do not apply PP1 if variant meets BA1/BS1 criteria.",General recommendation
-DICER1 (HGNC:17098),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-DICER1 (HGNC:17098),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-DICER1 (HGNC:17098),PP3,Supporting,"For missense variants, REVEL score ≥ 0.75 OR agreement in splicing predictors predict splicing effects. For splicing variants, concordance of MaxEntScan and SpliceAI.",Disease-specific
-DICER1 (HGNC:17098),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-DICER1 (HGNC:17098),PP4,Supporting,"Somatic tumor testing identifies somatic hotspot second hit and no additional somatic LOF variants.
-Tumor testing (PMID: 30311369) of a neoplasm with known DICER1 association in a proband who carries the germline variant under evaluation reveals the
-following:
-
-
-
-
-A previously reported somatic second hit of DICER1 in an RNase IIIb-disrupting “hotspot” codon (p.S1344, p.E1705, p.D1709, p.D1713, p.G1809, p.D1810, or
-p.E1813) AND 
-
-
-Retention of the germline DICER1 variant under evaluation. 
-PP4 is NOT applicable if:
-
-
-The germline variant is a missense variant in one of the seven RNase IIIb “hotspot” codons (see PM1), OR
-
-
-Somatic sequencing reveals additional DICER1 non-hotspot variants (could be consistent with sporadic tumorigenesis).",Disease-specific
-DICER1 (HGNC:17098),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-DICER1 (HGNC:17098),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-DICER1 (HGNC:17098),BA1,Stand Alone,"Frequency >0.003 (0.3%) in gnomAD (non-cancer) subpopulations. Subpopulations must have >2,000 alleles tested and a minimum of 5 alleles present.",Disease-specific
-DICER1 (HGNC:17098),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-DICER1 (HGNC:17098),BS1,Strong,"Frequency >0.0003 (0.03%) in gnomAD (non-cancer) subpopulations. Subpopulations must have >2,000 alleles tested and a minimum of 5 alleles present.",Disease-specific
-DICER1 (HGNC:17098),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-DICER1 (HGNC:17098),BS2,Strong,"40+ unrelated females from a single source are tumor-free through age 50 (caveat: ratio of BS2-eligible females to PS4-eligible probands must be ≥ 40:1) 
-OR 2+ observations of homozygosity in healthy individuals
-OR 1+ observation(s) of homozygosity in a healthy individual with status confirmed by parental testing.",Disease-specific
-DICER1 (HGNC:17098),BS2,Supporting,"10+ unrelated females from a single source are tumor-free through age 50 (caveat: ratio of BS2-eligible females to PS4-eligible probands must be ≥ 10:1) 
-OR 2+ observations of homozygosity in individuals lacking clinical information",Disease-specific
-DICER1 (HGNC:17098),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-DICER1 (HGNC:17098),BS3,Strong,"This rule should be used and weighted appropriately for variants with functional evidence of no splicing impact and/or no reduced DICER1 ability to cleave pre-miRNA. Follow SVI guidance regarding control numbers for functional studies.
-For intronic or synonymous variants, no splicing impact observed via RNA assay. (Should be observed more than once.)",Disease-specific
-DICER1 (HGNC:17098),BS3,Supporting,"This rule should be used and weighted appropriately for variants with functional evidence of no splicing impact and/or no reduced DICER1 ability to cleave pre-miRNA. Follow SVI guidance regarding control numbers for functional studies.
-An in vitro cleavage assay must demonstrate the variant produces both 5p and 3p microRNAs from a pre-miRNA (positive and negative controls also performed). An example of an appropriate assay to which criteria could be applied is Wu et al. 2018 (PMID: 28862265).",Disease-specific
-DICER1 (HGNC:17098),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-DICER1 (HGNC:17098),BS4,Strong,"Family members should be phenotype-positive (must be high- or moderatespecificity phenotype; see phenotype table), genotype-negative 1st, 2nd, or 3rd degree relatives of the proband.",General recommendation
-DICER1 (HGNC:17098),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-DICER1 (HGNC:17098),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-DICER1 (HGNC:17098),BP2,Supporting,"≥1 observation in trans with P/LP DICER1 variant or ≥3
-observations in cis or phase unknown with 2+ different
-P/LP DICER1 variants.",Disease-specific
-DICER1 (HGNC:17098),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-DICER1 (HGNC:17098),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-DICER1 (HGNC:17098),BP4,Supporting,"For missense variants, REVEL score < 0.50 and agreement in splicing predictors that no splicing effects are predicted. For synonymous/intronic/non-coding variants concordance of MaxEntScan and SpliceAI.",Disease-specific
-DICER1 (HGNC:17098),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-DICER1 (HGNC:17098),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-DICER1 (HGNC:17098),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-DICER1 (HGNC:17098),BP7,Supporting,"Silent variant
-OR Intronic variant at or beyond +7 to -21 positions
-OR Other intronic or non-coding variant if the variant is the reference nucleotide in ≥1 primate and/or ≥4 mammalian species.
-Caveat: Variant must meet BP4 to apply BP7",General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenDICER1andmiRNA-ProcessingGeneExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDICER1Version1.2.0_version=1.2.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenDICER1andmiRNA-ProcessingGeneExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDICER1Version1.2.0_version=1.2.0.csv
deleted file mode 100644
index b26c0d30808ae2eb94052bae29d6d0d37e9720a6..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenDICER1andmiRNA-ProcessingGeneExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDICER1Version1.2.0_version=1.2.0.csv
+++ /dev/null
@@ -1,139 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-DICER1 (HGNC:17098),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-DICER1 (HGNC:17098),PVS1,Very Strong,"Follow SVI guidance, using DICER1-specific information. Per the PVS1 workflow guidance provided in Tayoun et al. 2018
-1
-, the following will apply:
-
-
-
-
-Nonsense or frameshift variants:
-
-
-PVS1 applies to variants predicted to result in nonsense-mediated decay (NMD); the predicted NMD cutoff for DICER1 occurs at p.Pro1850.
-
-
-PVS1_Moderate applies to variants resulting in protein truncation 3’ of this cutoff
-
-
-Canonical splice variants (+/- 1,2 intronic positions): PVS1 applies with the following exceptions:
-
-
-Exon 10 SDS/SAS: PVS1_Strong (in-frame but exon includes >10% protein)
-
-
-Exons 5, 15, 18, 22 SDS/SAS: PVS1_Moderate (in-frame and each <10% of protein)
-
-
-Exon 27 SAS: PVS1_Moderate (final exon)
-
-
-Exon 1: no criteria (non-coding)
-
-
-Variants that disrupt the translation start site (p.M1?): no criteria applied given p.M1 is not highly conserved, there are three in-frame possible alternate start codons (p.Met11, p.Met17, p.Met24), and multiple lab cases of p.Met1? without DICER1 phenotype. SDS = splice donor site; SAS = splice acceptor site. Refer to PS3 weight guidelines when a variant meets criterion for application of both PVS1 and PS3. A disease-specific PVS1 decision tree incorporating the above bullets is also included at the end of this document as an additional curation tool.","Disease-specific,General recommendation"
-DICER1 (HGNC:17098),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-DICER1 (HGNC:17098),PS1,Strong,"For same AA change, must confirm there is no difference in splicing using RNA data or in-silico modeling data (concordance of MaxEntScan and SpliceAI). For non-canonical intronic splicing variants at same nucleotide should have equal or worse splicing impact.
-This rule code can only be used to compare variants asserted as pathogenic by the ClinGen DICER1 VCEP. Likely pathogenic changes do not apply.",General recommendation
-DICER1 (HGNC:17098),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-DICER1 (HGNC:17098),PS2,Very Strong,≥4 de novo points,Strength
-DICER1 (HGNC:17098),PS2,Strong,≥2 but less than 4 de novo points,Strength
-DICER1 (HGNC:17098),PS2,Moderate,≥1 but less than 2 de novo points,General recommendation
-DICER1 (HGNC:17098),PS2,Supporting,≥0.5 but less than 1 de novo points,Strength
-DICER1 (HGNC:17098),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-DICER1 (HGNC:17098),PS3,Strong,"RNA assay shows splicing impact that is out-of-frame, in-frame ≥193 residues, or in-frame with RNase IIIb disruption. (PS3_Moderate if PVS1_Strong is applied).",Disease-specific
-DICER1 (HGNC:17098),PS3,Moderate,RNA assay shows in-frame splicing impact with change in protein length <193 residues AND RNase IIIb domain not disrupted.,"Disease-specific,General recommendation"
-DICER1 (HGNC:17098),PS3,Supporting,In vitro cleavage assay shows failure or severely reduced capacity to produce either 5p or 3p microRNAs from a premiRNA (positive and negative controls also performed).,"Disease-specific,Strength"
-DICER1 (HGNC:17098),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-DICER1 (HGNC:17098),PS4,Strong,≥4 phenotype points,General recommendation
-DICER1 (HGNC:17098),PS4,Moderate,2 – 3.5 phenotype points,Strength
-DICER1 (HGNC:17098),PS4,Supporting,1 – 1.5 phenotype points,Strength
-DICER1 (HGNC:17098),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-DICER1 (HGNC:17098),PM1,Moderate,"Putative missense variants at residues affecting metal ion-binding: codons p.S1344, p.E1705, p.D1709, p.D1713, p.G1809, p.D1810, p.E1813",Disease-specific
-DICER1 (HGNC:17098),PM1,Supporting,"Putative missense variants at residues in the RNase IIIb domain (p.Y1682 – p.S1846), besides the metal ion-binding residues (see PM1).",Strength
-DICER1 (HGNC:17098),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-DICER1 (HGNC:17098),PM2,Supporting,Allele frequency <0.000005 across gnomAD (non-cancer) with no more than one allele in any subpopulation and at least 20x coverage.,"Disease-specific,Strength"
-DICER1 (HGNC:17098),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-DICER1 (HGNC:17098),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-DICER1 (HGNC:17098),PM4,Moderate,In-frame indels with a residue within the RNase IIIb domain (p.Y1682 – p.S1846).,Disease-specific
-DICER1 (HGNC:17098),PM4,Supporting,In-frame indels outside of the RNase IIIb domain (p.Y1682 – p.S1846) and repeat regions (p.D606-p.D609; p.E1418-p.E1420; p.E1422-p.E1425).,Strength
-DICER1 (HGNC:17098),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-DICER1 (HGNC:17098),PM5,Moderate,Missense variant under evaluation should have equal or worse Grantham score. Splicing should be ruled out with either RNA data or agreement in splicing predictors (MaxEntScan and SpliceAI) that show no splicing effects. The other variant must be interpreted as pathogenic by the ClinGen DICER1 VCEP. Likely pathogenic changes do not apply. This rule cannot be applied in combination with PM1 or PS1.,General recommendation
-DICER1 (HGNC:17098),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-DICER1 (HGNC:17098),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-DICER1 (HGNC:17098),PP1,Strong,≥7 meioses across ≥2 families,Strength
-DICER1 (HGNC:17098),PP1,Moderate,5 – 6 meioses across ≥1 family,Strength
-DICER1 (HGNC:17098),PP1,Supporting,3 – 4 meioses across ≥1 family,General recommendation
-DICER1 (HGNC:17098),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-DICER1 (HGNC:17098),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-DICER1 (HGNC:17098),PP3,Supporting,"For missense variants, REVEL score ≥ 0.75 OR agreement in splicing predictors predict splicing effects. For splicing variants, concordance of MaxEntScan and SpliceAI.",Disease-specific
-DICER1 (HGNC:17098),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-DICER1 (HGNC:17098),PP4,Supporting,"Somatic tumor testing identifies somatic hotspot second hit and no additional somatic LOF variants. Tumor testing
-6
- of a neoplasm with known DICER1 association in a proband who carries the germline variant under evaluation reveals the following:
-
-
-
-
-A previously reported somatic second hit of DICER1 in an RNase IIIb-disrupting “hotspot” codon (p.S1344, p.E1705, p.D1709, p.D1713, p.G1809, p.D1810, or p.E1813) AND
-
-
-Retention of the germline DICER1 variant under evaluation. PP4 is NOT applicable if:
-
-
-The germline variant is a missense variant in one of the seven RNase IIIb “hotspot” codons (see PM1), OR
-
-
-Somatic sequencing reveals additional DICER1 non-hotspot variants (could be consistent with sporadic tumorigenesis).",Disease-specific
-DICER1 (HGNC:17098),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-DICER1 (HGNC:17098),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-DICER1 (HGNC:17098),BA1,Stand Alone,"Frequency >0.003 (0.3%) in gnomAD (non-cancer) subpopulations. Subpopulations must have >2,000 alleles tested and a minimum of 5 alleles present.",Disease-specific
-DICER1 (HGNC:17098),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-DICER1 (HGNC:17098),BS1,Strong,"Frequency >0.0003 (0.03%) in gnomAD (non-cancer) subpopulations. Subpopulations must have >2,000 alleles tested and a minimum of 5 alleles present.",Disease-specific
-DICER1 (HGNC:17098),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-DICER1 (HGNC:17098),BS2,Strong,"40+ unrelated females from a single source are tumor-free through age 50 (caveat: ratio of BS2-eligible females to PS4-eligible probands must be ≥ 40:1) 
-OR 2+ observations of homozygosity in healthy individuals
-OR 1+ observation(s) of homozygosity in a healthy individual with status confirmed by parental testing.",Disease-specific
-DICER1 (HGNC:17098),BS2,Supporting,"10+ unrelated females from a single source are tumor-free through age 50 (caveat: ratio of BS2-eligible females to PS4-eligible probands must be ≥ 10:1) 
-OR 2+ observations of homozygosity in individuals lacking clinical information",Disease-specific
-DICER1 (HGNC:17098),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-DICER1 (HGNC:17098),BS3,Strong,"For intronic or synonymous variants, no splicing impact observed via RNA assay. (Should be observed more than once.)",Disease-specific
-DICER1 (HGNC:17098),BS3,Supporting,"An in vitro cleavage assay must demonstrate the variant produces both 5p and 3p microRNAs from a pre-miRNA (positive and negative controls also performed). An example of an appropriate assay to which criteria could be applied is Wu et al. 2018
-7
-.",Disease-specific
-DICER1 (HGNC:17098),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-DICER1 (HGNC:17098),BS4,Strong,"Family members should be phenotype-positive (must be high- or moderatespecificity phenotype; see phenotype table), genotype-negative 1st, 2nd, or 3rd degree relatives of the proband.",General recommendation
-DICER1 (HGNC:17098),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-DICER1 (HGNC:17098),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-DICER1 (HGNC:17098),BP2,Supporting,"≥1 observation in trans with P/LP DICER1 variant or ≥3
-observations in cis or phase unknown with 2+ different
-P/LP DICER1 variants.",Disease-specific
-DICER1 (HGNC:17098),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-DICER1 (HGNC:17098),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-DICER1 (HGNC:17098),BP4,Supporting,"For missense variants, REVEL score < 0.50 and agreement in splicing predictors that no splicing effects are predicted. For synonymous/intronic/non-coding variants concordance of MaxEntScan and SpliceAI.",Disease-specific
-DICER1 (HGNC:17098),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-DICER1 (HGNC:17098),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-DICER1 (HGNC:17098),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-DICER1 (HGNC:17098),BP7,Supporting,"Silent variant
-OR Intronic variant at or beyond +7 to -21 positions
-OR Other intronic or non-coding variant if the variant is the reference nucleotide in ≥1 primate and/or ≥4 mammalian species.
-Caveat: Variant must meet BP4 to apply BP7",General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenDICER1andmiRNA-ProcessingGeneExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDICER1Version1.3.0_version=1.3.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenDICER1andmiRNA-ProcessingGeneExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDICER1Version1.3.0_version=1.3.0.csv
deleted file mode 100644
index ac99a0c7ffa5283132d92c73887b00bc4396e213..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenDICER1andmiRNA-ProcessingGeneExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDICER1Version1.3.0_version=1.3.0.csv
+++ /dev/null
@@ -1,139 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-DICER1 (HGNC:17098),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-DICER1 (HGNC:17098),PVS1,Very Strong,"Follow SVI guidance, using DICER1-specific information. Per the PVS1 workflow guidance provided in Tayoun et al. 2018
-1
-, the following will apply:
-
-
-
-
-Nonsense or frameshift variants:
-
-
-PVS1 applies to variants predicted to result in nonsense-mediated decay (NMD); the predicted NMD cutoff for DICER1 occurs at p.Pro1850.
-
-
-PVS1_Moderate applies to variants resulting in protein truncation 3’ of this cutoff
-
-
-Canonical splice variants (+/- 1,2 intronic positions): PVS1 applies with the following exceptions:
-
-
-Exon 10 SDS/SAS: PVS1_Strong (in-frame but exon includes >10% protein)
-
-
-Exons 5, 15, 18, 22 SDS/SAS: PVS1_Moderate (in-frame and each <10% of protein)
-
-
-Exon 27 SAS: PVS1_Moderate (final exon)
-
-
-Exon 1: no criteria (non-coding)
-
-
-Variants that disrupt the translation start site (p.M1?): no criteria applied given p.M1 is not highly conserved, there are three in-frame possible alternate start codons (p.Met11, p.Met17, p.Met24), and multiple lab cases of p.Met1? without DICER1 phenotype. SDS = splice donor site; SAS = splice acceptor site. Refer to PS3 weight guidelines when a variant meets criterion for application of both PVS1 and PS3. A disease-specific PVS1 decision tree incorporating the above bullets is also included at the end of this document as an additional curation tool.","Disease-specific,General recommendation"
-DICER1 (HGNC:17098),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-DICER1 (HGNC:17098),PS1,Strong,"For same AA change, must confirm there is no difference in splicing using RNA data or in-silico modeling data (concordance of MaxEntScan and SpliceAI). For non-canonical intronic splicing variants at same nucleotide should have equal or worse splicing impact.
-This rule code can only be used to compare variants asserted as pathogenic by the ClinGen DICER1 VCEP. Likely pathogenic changes do not apply.",General recommendation
-DICER1 (HGNC:17098),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-DICER1 (HGNC:17098),PS2,Very Strong,≥4 de novo points,Strength
-DICER1 (HGNC:17098),PS2,Strong,≥2 but less than 4 de novo points,Strength
-DICER1 (HGNC:17098),PS2,Moderate,≥1 but less than 2 de novo points,General recommendation
-DICER1 (HGNC:17098),PS2,Supporting,≥0.5 but less than 1 de novo points,Strength
-DICER1 (HGNC:17098),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-DICER1 (HGNC:17098),PS3,Strong,"RNA assay shows splicing impact that is out-of-frame, in-frame ≥193 residues, or in-frame with RNase IIIb disruption. (PS3_Moderate if PVS1_Strong is applied).",Disease-specific
-DICER1 (HGNC:17098),PS3,Moderate,RNA assay shows in-frame splicing impact with change in protein length <193 residues AND RNase IIIb domain not disrupted.,"Disease-specific,General recommendation"
-DICER1 (HGNC:17098),PS3,Supporting,In vitro cleavage assay shows failure or severely reduced capacity to produce either 5p or 3p microRNAs from a premiRNA (positive and negative controls also performed).,"Disease-specific,Strength"
-DICER1 (HGNC:17098),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-DICER1 (HGNC:17098),PS4,Strong,≥4 phenotype points,General recommendation
-DICER1 (HGNC:17098),PS4,Moderate,2 – 3.5 phenotype points,Strength
-DICER1 (HGNC:17098),PS4,Supporting,1 – 1.5 phenotype points,Strength
-DICER1 (HGNC:17098),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-DICER1 (HGNC:17098),PM1,Moderate,"Putative missense variants at residues affecting metal ion-binding: codons p.S1344, p.E1705, p.D1709, p.D1713, p.G1809, p.D1810, p.E1813",Disease-specific
-DICER1 (HGNC:17098),PM1,Supporting,"Putative missense variants at residues in the RNase IIIb domain (p.Y1682 – p.S1846), besides the metal ion-binding residues (see PM1).",Strength
-DICER1 (HGNC:17098),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-DICER1 (HGNC:17098),PM2,Supporting,Allele frequency <0.000005 across gnomAD with no more than one allele in any subpopulation and at least 20x coverage.,"Disease-specific,Strength"
-DICER1 (HGNC:17098),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-DICER1 (HGNC:17098),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-DICER1 (HGNC:17098),PM4,Moderate,In-frame indels with a residue within the RNase IIIb domain (p.Y1682 – p.S1846).,Disease-specific
-DICER1 (HGNC:17098),PM4,Supporting,In-frame indels outside of the RNase IIIb domain (p.Y1682 – p.S1846) and repeat regions (p.D606-p.D609; p.E1418-p.E1420; p.E1422-p.E1425).,Strength
-DICER1 (HGNC:17098),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-DICER1 (HGNC:17098),PM5,Moderate,Missense variant under evaluation should have equal or worse Grantham score. Splicing should be ruled out with either RNA data or agreement in splicing predictors (MaxEntScan and SpliceAI) that show no splicing effects. The other variant must be interpreted as pathogenic by the ClinGen DICER1 VCEP. Likely pathogenic changes do not apply. This rule cannot be applied in combination with PM1 or PS1.,General recommendation
-DICER1 (HGNC:17098),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-DICER1 (HGNC:17098),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-DICER1 (HGNC:17098),PP1,Strong,≥7 meioses across ≥2 families,Strength
-DICER1 (HGNC:17098),PP1,Moderate,5 – 6 meioses across ≥1 family,Strength
-DICER1 (HGNC:17098),PP1,Supporting,3 – 4 meioses across ≥1 family,General recommendation
-DICER1 (HGNC:17098),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-DICER1 (HGNC:17098),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-DICER1 (HGNC:17098),PP3,Supporting,"For missense variants, REVEL score ≥ 0.75 OR agreement in splicing predictors predict splicing effects. For splicing variants, concordance of MaxEntScan and SpliceAI.",Disease-specific
-DICER1 (HGNC:17098),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-DICER1 (HGNC:17098),PP4,Supporting,"Somatic tumor testing identifies somatic hotspot second hit and no additional somatic LOF variants. Tumor testing
-6
- of a neoplasm with known DICER1 association in a proband who carries the germline variant under evaluation reveals the following:
-
-
-
-
-A previously reported somatic second hit of DICER1 in an RNase IIIb-disrupting “hotspot” codon (p.S1344, p.E1705, p.D1709, p.D1713, p.G1809, p.D1810, or p.E1813) AND
-
-
-Retention of the germline DICER1 variant under evaluation. PP4 is NOT applicable if:
-
-
-The germline variant is a missense variant in one of the seven RNase IIIb “hotspot” codons (see PM1), OR
-
-
-Somatic sequencing reveals additional DICER1 non-hotspot variants (could be consistent with sporadic tumorigenesis).",Disease-specific
-DICER1 (HGNC:17098),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-DICER1 (HGNC:17098),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-DICER1 (HGNC:17098),BA1,Stand Alone,"Frequency >0.003 (0.3%) in gnomAD subpopulations. Subpopulations must have >2,000 alleles tested and a minimum of 5 alleles present.",Disease-specific
-DICER1 (HGNC:17098),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-DICER1 (HGNC:17098),BS1,Strong,"Frequency >0.0003 (0.03%) in gnomAD subpopulations. Subpopulations must have >2,000 alleles tested and a minimum of 5 alleles present.",Disease-specific
-DICER1 (HGNC:17098),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-DICER1 (HGNC:17098),BS2,Strong,"40+ unrelated females from a single source are tumor-free through age 50 (caveat: ratio of BS2-eligible females to PS4-eligible probands must be ≥ 40:1) 
-OR 2+ observations of homozygosity in healthy individuals
-OR 1+ observation(s) of homozygosity in a healthy individual with status confirmed by parental testing.",Disease-specific
-DICER1 (HGNC:17098),BS2,Supporting,"10+ unrelated females from a single source are tumor-free through age 50 (caveat: ratio of BS2-eligible females to PS4-eligible probands must be ≥ 10:1) 
-OR 2+ observations of homozygosity in individuals lacking clinical information",Disease-specific
-DICER1 (HGNC:17098),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-DICER1 (HGNC:17098),BS3,Strong,"For intronic or synonymous variants, no splicing impact observed via RNA assay. (Should be observed more than once.)",Disease-specific
-DICER1 (HGNC:17098),BS3,Supporting,"An in vitro cleavage assay must demonstrate the variant produces both 5p and 3p microRNAs from a pre-miRNA (positive and negative controls also performed). An example of an appropriate assay to which criteria could be applied is Wu et al. 2018
-7
-.",Disease-specific
-DICER1 (HGNC:17098),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-DICER1 (HGNC:17098),BS4,Strong,"Family members should be phenotype-positive (must be high- or moderatespecificity phenotype; see phenotype table), genotype-negative 1st, 2nd, or 3rd degree relatives of the proband.",General recommendation
-DICER1 (HGNC:17098),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-DICER1 (HGNC:17098),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-DICER1 (HGNC:17098),BP2,Supporting,"≥1 observation in trans with P/LP DICER1 variant or ≥3
-observations in cis or phase unknown with 2+ different
-P/LP DICER1 variants.",Disease-specific
-DICER1 (HGNC:17098),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-DICER1 (HGNC:17098),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-DICER1 (HGNC:17098),BP4,Supporting,"For missense variants, REVEL score < 0.50 and agreement in splicing predictors that no splicing effects are predicted. For synonymous/intronic/non-coding variants concordance of MaxEntScan and SpliceAI.",Disease-specific
-DICER1 (HGNC:17098),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-DICER1 (HGNC:17098),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-DICER1 (HGNC:17098),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-DICER1 (HGNC:17098),BP7,Supporting,"Silent variant
-OR Intronic variant at or beyond +7 to -21 positions
-OR Other intronic or non-coding variant if the variant is the reference nucleotide in ≥1 primate and/or ≥4 mammalian species.
-Caveat: Variant must meet BP4 to apply BP7",General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenDICER1andmiRNA-ProcessingGeneExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDICER1Version1_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenDICER1andmiRNA-ProcessingGeneExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDICER1Version1_version=1.0.0.csv
deleted file mode 100644
index 9fe846c0ee095698c6f262a589fbef51dc38a93d..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenDICER1andmiRNA-ProcessingGeneExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDICER1Version1_version=1.0.0.csv
+++ /dev/null
@@ -1,212 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-DICER1 (HGNC:17098),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-DICER1 (HGNC:17098),PVS1,Very Strong,"Follow SVI guidance, using DICER1-specific information.
-Per the PVS1 workflow guidance provided in Tayoun et al. 2018 (PMID 30192042), the following will apply:
-
-
-
-
-Nonsense or frameshift variants:
-
-
-PVS1 applies to variants predicted to result in nonsense-mediated decay (NMD); the predicted NMD cutoff for DICER1 occurs at p.Pro1850.
-
-
-PVS1_Moderate applies to variants resulting in protein truncation 3’ of this cutoff
-
-
-Canonical splice variants (+/- 1,2 intronic positions): PVS1 applies with the following exceptions:
-
-
-Exon 10 SDS/SAS: PVS1_Strong (in-frame but exon includes >10% protein)
-
-
-Exons 5, 15, 18, 22 SDS/SAS: PVS1_Moderate (in-frame and each <10% of protein)
-
-
-Exon 27 SAS: PVS1_Moderate (final exon)
-
-
-Exon 1: no criteria (non-coding)
-
-
-Variants that disrupt the translation start site (p.M1?): no criteria applied given p.M1 is not highly conserved, there are three in-frame possible alternate start codons (p.Met11, p.Met17, p.Met24), and multiple lab cases of p.Met1? without
-DICER1 phenotype.
-SDS = splice donor site; SAS = splice acceptor site.
-Refer to PS3 weight guidelines when a variant meets criterion for application of both PVS1 and PS3.
-A disease-specific PVS1 decision tree incorporating the above bullets is also included at the end of this document as an additional curation tool.","Disease-specific,General recommendation"
-DICER1 (HGNC:17098),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-DICER1 (HGNC:17098),PS1,Strong,"For same AA change, must confirm there is no difference in splicing using RNA data or in-silico modeling data (concordance of MaxEntScan and SpliceAI). For non-canonical intronic splicing variants at same nucleotide should have equal or worse splicing impact.
-This rule code can only be used to compare variants asserted as pathogenic by the ClinGen DICER1 VCEP. Likely pathogenic changes do not apply.",General recommendation
-DICER1 (HGNC:17098),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-DICER1 (HGNC:17098),PS2,Very Strong,"≥4 de novo points.
-De novo points should be tallied using the simplified table for tallying
-proband points and used to determine the applied strength of PS2, consistent
-with SVI guidance. To avoid redundancy and increase consistency, the EP has
-opted to drop PM6 and exclusively use PS2 for de novo evidence.",Strength
-DICER1 (HGNC:17098),PS2,Strong,"≥2 but less than 4 de novo points.
-De novo points should be tallied using the simplified table for tallying
-proband points and used to determine the applied strength of PS2, consistent
-with SVI guidance. To avoid redundancy and increase consistency, the EP has
-opted to drop PM6 and exclusively use PS2 for de novo evidence.",Strength
-DICER1 (HGNC:17098),PS2,Moderate,"≥1 but less than 2 de novo points.
-De novo points should be tallied using the simplified table for tallying proband points and used to determine the applied strength of PS2, consistent with SVI guidance. To avoid redundancy and increase consistency, the EP has opted to drop PM6 and exclusively use PS2 for de novo evidence.",General recommendation
-DICER1 (HGNC:17098),PS2,Supporting,"≥0.5 but less than 1 de novo points.
-De novo points should be tallied using the simplified table for tallying
-proband points and used to determine the applied strength of PS2, consistent with SVI guidance. To avoid redundancy and increase consistency, the EP has opted to drop PM6 and exclusively use PS2 for de novo evidence.",Strength
-DICER1 (HGNC:17098),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-DICER1 (HGNC:17098),PS3,Strong,"RNA assay shows splicing impact that is out-of-frame, in-frame ≥193 residues, or in-frame with RNase IIIb disruption.
-(PS3_Moderate if PVS1_Strong is applied).
-This rule should be used and weighted appropriately for variants with functional evidence of a splicing impact and/or reduced DICER1 ability to cleave pre-miRNA. Follow SVI guidance regarding control numbers for functional studies. Do not apply PS3 at any strength if PVS1 is applied at full strength.",Disease-specific
-DICER1 (HGNC:17098),PS3,Moderate,"RNA assay shows in-frame splicing impact with change in protein length <193 residues AND RNase IIIb domain not disrupted.
-This rule should be used and weighted appropriately for variants with functional evidence of a splicing impact and/or reduced DICER1 ability to cleave pre-miRNA. Follow SVI guidance regarding control numbers for functional studies. Do not apply PS3 at any strength if PVS1 is applied at full strength.","Disease-specific,General recommendation"
-DICER1 (HGNC:17098),PS3,Supporting,"In vitro cleavage assay shows failure or severely reduced capacity to produce either 5p or 3p microRNAs from a premiRNA (positive and negative controls also performed). 
-This rule should be used and weighted appropriately for variants with functional evidence of a splicing impact and/or reduced DICER1 ability to cleave pre-miRNA. Follow SVI guidance regarding control numbers for functional studies. Do not apply PS3 at any strength if PVS1 is applied at full strength.","Disease-specific,Strength"
-DICER1 (HGNC:17098),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-DICER1 (HGNC:17098),PS4,Strong,"≥4 phenotype points.
-Unrelated probands may contribute up to 1 point each based on phenotype (see Tables 2 & 3 in ruleset)
-Caveats:
-
-
-
-
-Do not apply PS4 if variant meets BA1/BS1 criteria.
-
-
-Do not apply points for a phenotype in an individual with a likely pathogenic germline variant in a second gene that could have reasonably contributed to the phenotype (e.g. Wilms tumor in an individual with a P/LP WT1 variant).
-
-
-Do not apply points for a proband whose tumor sequencing is consistent with a likely sporadic event (i.e. sequencing reveals a somatic, VCEPcurated, non-hotspot, likely pathogenic DICER1 variant in addition to a somatic hotspot variant and the germline variant under assessment). Of note, DICER1 tumors that consistently or occasionally follow a classical 2- hit hypothesis (i.e. LOF of both alleles) are exempt from this caveat. For example, identification of a somatic pathogenic non-hotspot DICER1 variant in pineoblastoma (PMID: 25022261), pituitary blastoma (PMID: 24839956), and lung cysts or cystic nephroma lacking mesenchymal cells (PMIDs: 25500911, 25978641) should not exclude the proband from PS4.",General recommendation
-DICER1 (HGNC:17098),PS4,Moderate,"2 – 3.5 phenotype points.
-Unrelated probands may contribute up to 1 point each based on phenotype (see Tables 2 & 3 in ruleset)
-Caveats:
-
-
-
-
-Do not apply PS4 if variant meets BA1/BS1 criteria.
-
-
-Do not apply points for a phenotype in an individual with a likely pathogenic germline variant in a second gene that could have reasonably contributed to the phenotype (e.g. Wilms tumor in an individual with a P/LP WT1 variant).
-
-
-Do not apply points for a proband whose tumor sequencing is consistent with a likely sporadic event (i.e. sequencing reveals a somatic, VCEPcurated, non-hotspot, likely pathogenic DICER1 variant in addition to a somatic hotspot variant and the germline variant under assessment). Of note, DICER1 tumors that consistently or occasionally follow a classical 2- hit hypothesis (i.e. LOF of both alleles) are exempt from this caveat. For example, identification of a somatic pathogenic non-hotspot DICER1 variant in pineoblastoma (PMID: 25022261), pituitary blastoma (PMID: 24839956), and lung cysts or cystic nephroma lacking mesenchymal cells (PMIDs: 25500911, 25978641) should not exclude the proband from PS4.",Strength
-DICER1 (HGNC:17098),PS4,Supporting,"1 – 1.5 phenotype points.
-Unrelated probands may contribute up to 1 point each based on phenotype (see Tables 2 & 3 in ruleset)
-Caveats:
-
-
-
-
-Do not apply PS4 if variant meets BA1/BS1 criteria.
-
-
-Do not apply points for a phenotype in an individual with a likely pathogenic germline variant in a second gene that could have reasonably contributed to the phenotype (e.g. Wilms tumor in an individual with a P/LP WT1 variant).
-
-
-Do not apply points for a proband whose tumor sequencing is consistent with a likely sporadic event (i.e. sequencing reveals a somatic, VCEPcurated, non-hotspot, likely pathogenic DICER1 variant in addition to a somatic hotspot variant and the germline variant under assessment). Of note, DICER1 tumors that consistently or occasionally follow a classical 2- hit hypothesis (i.e. LOF of both alleles) are exempt from this caveat. For example, identification of a somatic pathogenic non-hotspot DICER1 variant in pineoblastoma (PMID: 25022261), pituitary blastoma (PMID: 24839956), and lung cysts or cystic nephroma lacking mesenchymal cells (PMIDs: 25500911, 25978641) should not exclude the proband from PS4.",Strength
-DICER1 (HGNC:17098),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-DICER1 (HGNC:17098),PM1,Moderate,"Residues affecting metal ion-binding: codons p.S1344, p.E1705, p.D1709, p.D1713, p.G1809, p.D1810, p.E1813",Disease-specific
-DICER1 (HGNC:17098),PM1,Supporting,"Residues in the RNase IIIb domain (p.Y1682 – p.S1846),
-besides the metal ion-binding residues (see PM1).",Strength
-DICER1 (HGNC:17098),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-DICER1 (HGNC:17098),PM2,Supporting,Allele frequency <0.000005 across gnomAD (non-cancer) with no more than one allele in any subpopulation and at least 20x coverage.,"Disease-specific,Strength"
-DICER1 (HGNC:17098),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-DICER1 (HGNC:17098),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-DICER1 (HGNC:17098),PM4,Moderate,In-frame indels with a residue within the RNase IIIb domain (p.Y1682 – p.S1846).,Disease-specific
-DICER1 (HGNC:17098),PM4,Supporting,In-frame indels outside of the RNase IIIb domain (p.Y1682 – p.S1846) and repeat regions (p.D606-p.D609; p.E1418-p.E1420; p.E1422-p.E1425).,Strength
-DICER1 (HGNC:17098),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-DICER1 (HGNC:17098),PM5,Moderate,"Missense variant under evaluation should have equal or worse Grantham score. Splicing should be
-ruled out with either RNA data or agreement in splicing predictors (MaxEntScan and SpliceAI) that show no splicing effects (either an increase in the canonical
-splice site score or a decrease in the canonical splice site score by no more than 10% AND no putative cryptic splice sites are created).
-The other variant must be interpreted as pathogenic by the ClinGen DICER1 VCEP. Likely pathogenic changes do not apply. This rule cannot be applied in combination with
-PM1 or PS1.",General recommendation
-DICER1 (HGNC:17098),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-DICER1 (HGNC:17098),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-DICER1 (HGNC:17098),PP1,Strong,"≥7 meioses across ≥2 families.
-Phenotype-positive individuals should have high, moderate, or low-specificity phenotypes (see phenotype table). (Caveat: segregation with a single low-specificity phenotype across multiple individuals (e.g. familial Wilms tumor) does not fulfill PP1.)
-Do not apply PP1 if variant meets BA1/BS1 criteria.",Strength
-DICER1 (HGNC:17098),PP1,Moderate,"5 – 6 meioses across ≥1 family.
-Phenotype-positive individuals should have high, moderate, or low-specificity phenotypes (see phenotype table). (Caveat: segregation with a single low-specificity
-phenotype across multiple individuals (e.g. familial Wilms tumor) does not fulfill PP1.)
-Do not apply PP1 if variant meets BA1/BS1 criteria.",Strength
-DICER1 (HGNC:17098),PP1,Supporting,"3 – 4 meioses across ≥1 family.
-Phenotype-positive individuals should have high, moderate, or low-specificity phenotypes (see phenotype table). (Caveat: segregation with a single low-specificity phenotype across multiple individuals (e.g. familial Wilms tumor) does not fulfill PP1.) 
-Do not apply PP1 if variant meets BA1/BS1 criteria.",General recommendation
-DICER1 (HGNC:17098),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-DICER1 (HGNC:17098),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-DICER1 (HGNC:17098),PP3,Supporting,"For missense variants, REVEL score ≥ 0.75 OR agreement in splicing predictors predict splicing effects. For splicing variants, concordance of MaxEntScan and SpliceAI.
-PP3 may be applied for intronic variants located in reference to exons at +3 to +5 for donor splice sites or -3 to -5 for acceptor splice sites (PMID: 27313609) and have a predicted decrease in the score of the canonical splice site by at least 75%, regardless of the predicted creation or presence of a putative cryptic splice site. Must have concordance of both MaxEntScan and SpliceAI.",Disease-specific
-DICER1 (HGNC:17098),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-DICER1 (HGNC:17098),PP4,Supporting,"Somatic tumor testing identifies somatic hotspot second hit and no additional somatic LOF variants.
-Tumor testing (PMID: 30311369) of a neoplasm with known DICER1 association in a proband who carries the germline variant under evaluation reveals the
-following:
-
-
-
-
-A previously reported somatic second hit of DICER1 in an RNase IIIb-disrupting “hotspot” codon (p.S1344, p.E1705, p.D1709, p.D1713, p.G1809, p.D1810, or
-p.E1813) AND 
-
-
-Retention of the germline DICER1 variant under evaluation. 
-PP4 is NOT applicable if:
-
-
-The germline variant is a missense variant in one of the seven RNase IIIb “hotspot” codons (see PM1), OR
-
-
-Somatic sequencing reveals additional DICER1 non-hotspot variants (could be consistent with sporadic tumorigenesis).",Disease-specific
-DICER1 (HGNC:17098),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-DICER1 (HGNC:17098),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-DICER1 (HGNC:17098),BA1,Stand Alone,"Frequency >0.003 (0.3%) in gnomAD (non-cancer) subpopulations. Subpopulations must have >2,000 alleles tested and a minimum of 5 alleles present.",Disease-specific
-DICER1 (HGNC:17098),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-DICER1 (HGNC:17098),BS1,Strong,"Frequency >0.0003 (0.03%) in gnomAD (non-cancer) subpopulations. Subpopulations must have >2,000 alleles tested and a minimum of 5 alleles present.",Disease-specific
-DICER1 (HGNC:17098),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-DICER1 (HGNC:17098),BS2,Strong,"40+ unrelated females from a single source are tumor-free through age 50 (caveat: ratio of BS2-eligible females to PS4-eligible probands must be ≥ 40:1) 
-OR 2+ observations of homozygosity in healthy individuals
-OR 1+ observation(s) of homozygosity in a healthy individual with status confirmed by parental testing.",Disease-specific
-DICER1 (HGNC:17098),BS2,Supporting,"10+ unrelated females from a single source are tumor-free through age 50 (caveat: ratio of BS2-eligible females to PS4-eligible probands must be ≥ 10:1) 
-OR 2+ observations of homozygosity in individuals lacking clinical information",Disease-specific
-DICER1 (HGNC:17098),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-DICER1 (HGNC:17098),BS3,Strong,"This rule should be used and weighted appropriately for variants with functional evidence of no splicing impact and/or no reduced DICER1 ability to cleave pre-miRNA. Follow SVI guidance regarding control numbers for functional studies.
-For intronic or synonymous variants, no splicing impact observed via RNA assay. (Should be observed more than once.)",Disease-specific
-DICER1 (HGNC:17098),BS3,Supporting,"This rule should be used and weighted appropriately for variants with functional evidence of no splicing impact and/or no reduced DICER1 ability to cleave pre-miRNA. Follow SVI guidance regarding control numbers for functional studies.
-An in vitro cleavage assay must demonstrate the variant produces both 5p and 3p microRNAs from a pre-miRNA (positive and negative controls also performed). An example of an appropriate assay to which criteria could be applied is Wu et al. 2018 (PMID: 28862265).",Disease-specific
-DICER1 (HGNC:17098),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-DICER1 (HGNC:17098),BS4,Strong,"Family members should be phenotype-positive (must be high- or moderatespecificity phenotype; see phenotype table), genotype-negative 1st, 2nd, or 3rd degree relatives of the proband.",General recommendation
-DICER1 (HGNC:17098),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-DICER1 (HGNC:17098),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-DICER1 (HGNC:17098),BP2,Supporting,"≥1 observation in trans with P/LP DICER1 variant or ≥3
-observations in cis or phase unknown with 2+ different
-P/LP DICER1 variants.",Disease-specific
-DICER1 (HGNC:17098),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-DICER1 (HGNC:17098),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-DICER1 (HGNC:17098),BP4,Supporting,"For missense variants, REVEL score < 0.50 and agreement in splicing predictors that no splicing effects are predicted. For synonymous/intronic/non-coding variants concordance of MaxEntScan and SpliceAI.
-MaxEntScan and SpliceAI should predict either no change in splicing, an increase in canonical splice site score, or a decrease of the canonical splice site score by no more than 10% AND no putative cryptic splice sites are created.",Disease-specific
-DICER1 (HGNC:17098),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-DICER1 (HGNC:17098),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-DICER1 (HGNC:17098),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-DICER1 (HGNC:17098),BP7,Supporting,"Silent variant
-OR Intronic variant at or beyond +7 to -21 positions
-OR Other intronic or non-coding variant if the variant is the reference nucleotide in ≥1 primate and/or ≥4 mammalian species.
-Caveat: Variant must meet BP4 to apply BP7",
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA1Version1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA1Version1.0.0_version=1.0.0.csv
deleted file mode 100644
index 62228570e4ba91843ff82bf46a8e0952ba8ab633..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA1Version1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,373 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-BRCA1 (HGNC:1100),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-BRCA1 (HGNC:1100),PVS1,Very Strong,"Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.
-
-
-Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of a damaging effect 
-as measured by effect on mRNA transcript profile (mRNA assay only).
- Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",Gene-specific
-BRCA1 (HGNC:1100),PVS1,Strong,"Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.
-
-
-Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of a damaging effect 
-as measured by effect on mRNA transcript profile (mRNA assay only).
- Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",Gene-specific
-BRCA1 (HGNC:1100),PVS1,Moderate,"Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.
-
-
-Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of a damaging effect 
-as measured by effect on mRNA transcript profile (mRNA assay only).
- Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",Gene-specific
-BRCA1 (HGNC:1100),PVS1,Supporting,"Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.
-
-
-Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of a damaging effect 
-as measured by effect on mRNA transcript profile (mRNA assay only).
- Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",Gene-specific
-BRCA1 (HGNC:1100),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-BRCA1 (HGNC:1100),PS1,Strong,"Apply 
-PS1
-, for predicted 
-missense
- substitutions, where a previously classified 
-pathogenic
- variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).
-
-
-Apply 
-PS1
-, for exonic and intronic variants with same predicted impact on 
-splicing
-, as a previously classified 
-pathogenic
- variant. Vary weight depending on relative positions, and confidence in classification of the reference variant. 
-
-
-See Specifications Table 5 and Appendix E, J and K for details.",General recommendation
-BRCA1 (HGNC:1100),PS1,Moderate,"Apply 
-PS1_Moderate
-, for predicted 
-missense
- substitutions, where previously classified 
-likely pathogenic
- variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).
-
-
-Apply 
-PS1_Moderate
-, for exonic and intronic variants with same predicted impact on 
-splicing
-, as a previously classified 
-(likely) pathogenic
- variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.
-
-
-See Specifications Table 5 and Appendix E, J and K for details.",General recommendation
-BRCA1 (HGNC:1100),PS1,Supporting,"Apply 
-PS1_Supporting
-, for exonic and intronic variants with same predicted impact on 
-splicing,
- as a previously classified 
-(likely) pathogenic
- variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.
-
-
-See Specifications Table 5 and Appendix E, J and K for details.",General recommendation
-BRCA1 (HGNC:1100),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",NA
-BRCA1 (HGNC:1100),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-BRCA1 (HGNC:1100),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect. Apply PS3 for assays measuring effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.
-
-
-Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of a damaging effect 
-as measured by effect on mRNA transcript profile (mRNA assay only).
- Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",General recommendation
-BRCA1 (HGNC:1100),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-BRCA1 (HGNC:1100),PS4,Strong,The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Case-control studies; p-value ≤0.05 and OR ≥4 (lower confidence interval excludes 2.0). See Appendix F for details.,"Clarification,Gene-specific"
-BRCA1 (HGNC:1100),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-BRCA1 (HGNC:1100),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-BRCA1 (HGNC:1100),PM2,Supporting,"Absent from controls in an outbred population, from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). Region around the variant must have an average read depth ≥25. See Appendix G for details.",Gene-specific
-BRCA1 (HGNC:1100),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-BRCA1 (HGNC:1100),PM3,Strong,"Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene.Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:
-
-
-(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis 
-≤5yr
-.
-
-
-(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.
-
-
-See 
-Specifications Table 6
- for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.
-
-
-PM3_Strong = ≥4 points",Gene-specific
-BRCA1 (HGNC:1100),PM3,Moderate,"Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene.Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:
-
-
-(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis 
-≤5yr
-.
-
-
-(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.
-
-
-See 
-Specifications Table 6
- for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.
-
-
-PM3 = 2 points",Gene-specific
-BRCA1 (HGNC:1100),PM3,Supporting,"Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene.Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:
-
-
-(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis 
-≤5yr
-.
-
-
-(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.
-
-
-See 
-Specifications Table 6
- for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.
-
-
-PM3_Supporting = 1 point",Gene-specific
-BRCA1 (HGNC:1100),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,NA
-BRCA1 (HGNC:1100),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-BRCA1 (HGNC:1100),PM5,Strong,Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5_PTC code strengths applicable per exon. See Appendix D for additional details.,Other
-BRCA1 (HGNC:1100),PM5,Moderate,Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5_PTC code strengths applicable per exon. See Appendix D for additional details.,Other
-BRCA1 (HGNC:1100),PM5,Supporting,Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5_PTC code strengths applicable per exon. See Appendix D for additional details.,Other
-BRCA1 (HGNC:1100),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-BRCA1 (HGNC:1100),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-BRCA1 (HGNC:1100),PP1,Strong,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.
-
-
-Apply weight as per Bayes Score:
-
-
-PP1_Strong – LR>18.7:1
-
-
-PP1_Very Strong – LR>350:1",Gene-specific
-BRCA1 (HGNC:1100),PP1,Moderate,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.
-
-
-Apply weight as per Bayes Score:
-
-
-PP1_Moderate – LR>4.3:1",Gene-specific
-BRCA1 (HGNC:1100),PP1,Supporting,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.
-
-
-Apply weight as per Bayes Score:
-
-
-PP1 - LR >2.08:1",Gene-specific
-BRCA1 (HGNC:1100),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-BRCA1 (HGNC:1100),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-BRCA1 (HGNC:1100),PP3,Supporting,"Apply PP3 for missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain and predicted impact via protein change (BayesDel no-AF score ≥0.28). As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101; BRCA1 coiled-coil aa 1391-1424; BRCA1 BRCT repeats aa 1650-1857.
-
-
-Apply PP3 for predicted splicing (SpliceAI ≥0.2) for silent, missense/in-frame (irrespective of location in clinically important functional domain) and for intronic variants outside of donor and acceptor 1,2 sites.
-
-
-See Specifications Figure1A and Appendix J for details.",Gene-specific
-BRCA1 (HGNC:1100),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-BRCA1 (HGNC:1100),PP4,Strong,"Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.
-
-
-PP4_Strong – LR>18.7:1
-
-
-PP4_Very Strong – LR>350:1
-
-
-Combined LR 1.00-2.08 is not informative (PP4 not applicable).
-
-
-See Specifications Table7 and Appendix B for details.",Gene-specific
-BRCA1 (HGNC:1100),PP4,Moderate,"Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.
-
-
-PP4_Moderate – LR>4.3:1
-
-
-Combined LR 1.00-2.08 is not informative (PP4 not applicable).
-
-
-See Specifications Table7 and Appendix B for details.",Gene-specific
-BRCA1 (HGNC:1100),PP4,Supporting,"Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.
-
-
-PP4 - LR >2.08:1 
-
-
-Combined LR 1.00-2.08 is not informative (PP4 not applicable).
-
-
-See Specifications Table7 and Appendix B for details.",Gene-specific
-BRCA1 (HGNC:1100),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-BRCA1 (HGNC:1100),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-BRCA1 (HGNC:1100),BA1,Stand Alone,"Filter allele frequency (FAF) is above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.",Gene-specific
-BRCA1 (HGNC:1100),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-BRCA1 (HGNC:1100),BS1,Strong,"Filter allele frequency (FAF) is above 0.01% (FAF > 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.",Gene-specific
-BRCA1 (HGNC:1100),BS1,Supporting,"Filter allele frequency (FAF) is above 0.002% (FAF > 0.00002) and less than or equal to 0.01% (FAF ≤ 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.",Gene-specific
-BRCA1 (HGNC:1100),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-BRCA1 (HGNC:1100),BS2,Strong,"Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See 
-Specifications Table 8
- for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.
-
-
-BS2 = ≥ 4 points",Gene-specific
-BRCA1 (HGNC:1100),BS2,Moderate,"Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See 
-Specifications Table 8
- for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.
-
-
-BS2_Moderate = 2 points",Gene-specific
-BRCA1 (HGNC:1100),BS2,Supporting,"Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See 
-Specifications Table 8
- for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.
-
-
-BS2_Supporting = 1 points",Gene-specific
-BRCA1 (HGNC:1100),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-BRCA1 (HGNC:1100),BS3,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function. Assay measures effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.
-
-
-Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of no damaging effect 
-as measured by effect on mRNA transcript profile (mRNA assay only).
- Apply as BP7 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",Gene-specific
-BRCA1 (HGNC:1100),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-BRCA1 (HGNC:1100),BS4,Strong,"Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.
-
-
-Apply weight as per Bayes Score:
-
-
-BS4 - LR <0.05:1
-
-
-BS4_VeryStrong – LR <0.00285:1",Gene-specific
-BRCA1 (HGNC:1100),BS4,Moderate,"Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.
-
-
-Apply weight as per Bayes Score:
-
-
-BS4_Moderate - LR <0.23:1",Gene-specific
-BRCA1 (HGNC:1100),BS4,Supporting,"Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.
-
-
-Apply weight as per Bayes Score:
-
-
-BS4_Supporting  - LR 0.23-0.48:1",Gene-specific
-BRCA1 (HGNC:1100),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-BRCA1 (HGNC:1100),BP1,Strong,"Apply BP1_Strong
- for silent substitution, missense or in-frame insertion, deletion or delins variants outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1). As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101; BRCA1 coiled-coil aa 1391-1424; BRCA1 BRCT repeats aa 1650-1857. See Specifications Figure1A and Appendix J for details.","Gene-specific,Strength"
-BRCA1 (HGNC:1100),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-BRCA1 (HGNC:1100),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-BRCA1 (HGNC:1100),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-BRCA1 (HGNC:1100),BP4,Supporting,"Missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain, and no predicted impact via protein change or splicing (BayesDel no-AF score ≤ 0.15 AND SpliceAI ≤0.1).
-
-
-Silent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (SpliceAI ≤0.1).
-
-
-Intronic variants outside of the native donor and acceptor splice sites (i.e. not +/- 1,2 positions) AND no predicted impact via splicing (SpliceAI ≤0.1).
-
-
-As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101; BRCA1 coiled-coil aa 1391-1424; BRCA1 BRCT repeats aa 1650-1857. See Specifications Figure1A and Appendix J for details.","Clarification,Gene-specific"
-BRCA1 (HGNC:1100),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-BRCA1 (HGNC:1100),BP5,Strong,"Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.
-
-
-BP5_VeryStrong – LR <0.00285:1
-
-
-BP5_Strong  - LR <0.05:1
-
-
-Not applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype.",Gene-specific
-BRCA1 (HGNC:1100),BP5,Moderate,"Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.
-
-
-BP5_Moderate - LR <0.23:1
-
-
-Not applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype.",Gene-specific
-BRCA1 (HGNC:1100),BP5,Supporting,"Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.
-
-
-BP5 - LR 0.23-0.48:1
-
-
-Not applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype.",Gene-specific
-BRCA1 (HGNC:1100),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-BRCA1 (HGNC:1100),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-BRCA1 (HGNC:1100),BP7,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function 
-as measured by effect on mRNA transcript profile – mRNA assay only.
- Apply as BP7 (RNA) for intronic and silent variants, as well as missense/in-frame variants located outside a (potentially) clinically important functional domain. See Specifications Figure1B and Appendix E for details.
-
-
-As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101; BRCA1 coiled-coil aa 1391-1424; BRCA1 BRCT repeats aa 1650-1857. See Specifications Figure1A and Appendix J for details.","General recommendation,Gene-specific"
-BRCA1 (HGNC:1100),BP7,Supporting,"Silent variant inside a (potentially) clinically important functional domain, IF BP4 met.
-
-
-Intronic variants located outside conserved donor or acceptor motif positions (at or beyond positions +7/-21) IF BP4 met.
-
-
-See Specifications Figure1A and Appendix J for additional details.
-
-
-As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101; BRCA1 coiled-coil aa 1391-1424; BRCA1 BRCT repeats aa 1650-1857. See Specifications Figure1A and Appendix J for details.","Clarification,General recommendation"
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA1Version1.1.0_version=1.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA1Version1.1.0_version=1.1.0.csv
deleted file mode 100644
index 62228570e4ba91843ff82bf46a8e0952ba8ab633..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA1Version1.1.0_version=1.1.0.csv
+++ /dev/null
@@ -1,373 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-BRCA1 (HGNC:1100),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-BRCA1 (HGNC:1100),PVS1,Very Strong,"Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.
-
-
-Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of a damaging effect 
-as measured by effect on mRNA transcript profile (mRNA assay only).
- Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",Gene-specific
-BRCA1 (HGNC:1100),PVS1,Strong,"Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.
-
-
-Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of a damaging effect 
-as measured by effect on mRNA transcript profile (mRNA assay only).
- Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",Gene-specific
-BRCA1 (HGNC:1100),PVS1,Moderate,"Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.
-
-
-Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of a damaging effect 
-as measured by effect on mRNA transcript profile (mRNA assay only).
- Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",Gene-specific
-BRCA1 (HGNC:1100),PVS1,Supporting,"Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.
-
-
-Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of a damaging effect 
-as measured by effect on mRNA transcript profile (mRNA assay only).
- Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",Gene-specific
-BRCA1 (HGNC:1100),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-BRCA1 (HGNC:1100),PS1,Strong,"Apply 
-PS1
-, for predicted 
-missense
- substitutions, where a previously classified 
-pathogenic
- variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).
-
-
-Apply 
-PS1
-, for exonic and intronic variants with same predicted impact on 
-splicing
-, as a previously classified 
-pathogenic
- variant. Vary weight depending on relative positions, and confidence in classification of the reference variant. 
-
-
-See Specifications Table 5 and Appendix E, J and K for details.",General recommendation
-BRCA1 (HGNC:1100),PS1,Moderate,"Apply 
-PS1_Moderate
-, for predicted 
-missense
- substitutions, where previously classified 
-likely pathogenic
- variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).
-
-
-Apply 
-PS1_Moderate
-, for exonic and intronic variants with same predicted impact on 
-splicing
-, as a previously classified 
-(likely) pathogenic
- variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.
-
-
-See Specifications Table 5 and Appendix E, J and K for details.",General recommendation
-BRCA1 (HGNC:1100),PS1,Supporting,"Apply 
-PS1_Supporting
-, for exonic and intronic variants with same predicted impact on 
-splicing,
- as a previously classified 
-(likely) pathogenic
- variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.
-
-
-See Specifications Table 5 and Appendix E, J and K for details.",General recommendation
-BRCA1 (HGNC:1100),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",NA
-BRCA1 (HGNC:1100),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-BRCA1 (HGNC:1100),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect. Apply PS3 for assays measuring effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.
-
-
-Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of a damaging effect 
-as measured by effect on mRNA transcript profile (mRNA assay only).
- Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",General recommendation
-BRCA1 (HGNC:1100),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-BRCA1 (HGNC:1100),PS4,Strong,The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Case-control studies; p-value ≤0.05 and OR ≥4 (lower confidence interval excludes 2.0). See Appendix F for details.,"Clarification,Gene-specific"
-BRCA1 (HGNC:1100),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-BRCA1 (HGNC:1100),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-BRCA1 (HGNC:1100),PM2,Supporting,"Absent from controls in an outbred population, from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). Region around the variant must have an average read depth ≥25. See Appendix G for details.",Gene-specific
-BRCA1 (HGNC:1100),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-BRCA1 (HGNC:1100),PM3,Strong,"Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene.Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:
-
-
-(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis 
-≤5yr
-.
-
-
-(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.
-
-
-See 
-Specifications Table 6
- for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.
-
-
-PM3_Strong = ≥4 points",Gene-specific
-BRCA1 (HGNC:1100),PM3,Moderate,"Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene.Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:
-
-
-(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis 
-≤5yr
-.
-
-
-(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.
-
-
-See 
-Specifications Table 6
- for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.
-
-
-PM3 = 2 points",Gene-specific
-BRCA1 (HGNC:1100),PM3,Supporting,"Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene.Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:
-
-
-(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis 
-≤5yr
-.
-
-
-(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.
-
-
-See 
-Specifications Table 6
- for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.
-
-
-PM3_Supporting = 1 point",Gene-specific
-BRCA1 (HGNC:1100),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,NA
-BRCA1 (HGNC:1100),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-BRCA1 (HGNC:1100),PM5,Strong,Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5_PTC code strengths applicable per exon. See Appendix D for additional details.,Other
-BRCA1 (HGNC:1100),PM5,Moderate,Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5_PTC code strengths applicable per exon. See Appendix D for additional details.,Other
-BRCA1 (HGNC:1100),PM5,Supporting,Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5_PTC code strengths applicable per exon. See Appendix D for additional details.,Other
-BRCA1 (HGNC:1100),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-BRCA1 (HGNC:1100),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-BRCA1 (HGNC:1100),PP1,Strong,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.
-
-
-Apply weight as per Bayes Score:
-
-
-PP1_Strong – LR>18.7:1
-
-
-PP1_Very Strong – LR>350:1",Gene-specific
-BRCA1 (HGNC:1100),PP1,Moderate,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.
-
-
-Apply weight as per Bayes Score:
-
-
-PP1_Moderate – LR>4.3:1",Gene-specific
-BRCA1 (HGNC:1100),PP1,Supporting,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.
-
-
-Apply weight as per Bayes Score:
-
-
-PP1 - LR >2.08:1",Gene-specific
-BRCA1 (HGNC:1100),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-BRCA1 (HGNC:1100),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-BRCA1 (HGNC:1100),PP3,Supporting,"Apply PP3 for missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain and predicted impact via protein change (BayesDel no-AF score ≥0.28). As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101; BRCA1 coiled-coil aa 1391-1424; BRCA1 BRCT repeats aa 1650-1857.
-
-
-Apply PP3 for predicted splicing (SpliceAI ≥0.2) for silent, missense/in-frame (irrespective of location in clinically important functional domain) and for intronic variants outside of donor and acceptor 1,2 sites.
-
-
-See Specifications Figure1A and Appendix J for details.",Gene-specific
-BRCA1 (HGNC:1100),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-BRCA1 (HGNC:1100),PP4,Strong,"Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.
-
-
-PP4_Strong – LR>18.7:1
-
-
-PP4_Very Strong – LR>350:1
-
-
-Combined LR 1.00-2.08 is not informative (PP4 not applicable).
-
-
-See Specifications Table7 and Appendix B for details.",Gene-specific
-BRCA1 (HGNC:1100),PP4,Moderate,"Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.
-
-
-PP4_Moderate – LR>4.3:1
-
-
-Combined LR 1.00-2.08 is not informative (PP4 not applicable).
-
-
-See Specifications Table7 and Appendix B for details.",Gene-specific
-BRCA1 (HGNC:1100),PP4,Supporting,"Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.
-
-
-PP4 - LR >2.08:1 
-
-
-Combined LR 1.00-2.08 is not informative (PP4 not applicable).
-
-
-See Specifications Table7 and Appendix B for details.",Gene-specific
-BRCA1 (HGNC:1100),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-BRCA1 (HGNC:1100),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-BRCA1 (HGNC:1100),BA1,Stand Alone,"Filter allele frequency (FAF) is above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.",Gene-specific
-BRCA1 (HGNC:1100),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-BRCA1 (HGNC:1100),BS1,Strong,"Filter allele frequency (FAF) is above 0.01% (FAF > 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.",Gene-specific
-BRCA1 (HGNC:1100),BS1,Supporting,"Filter allele frequency (FAF) is above 0.002% (FAF > 0.00002) and less than or equal to 0.01% (FAF ≤ 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.",Gene-specific
-BRCA1 (HGNC:1100),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-BRCA1 (HGNC:1100),BS2,Strong,"Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See 
-Specifications Table 8
- for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.
-
-
-BS2 = ≥ 4 points",Gene-specific
-BRCA1 (HGNC:1100),BS2,Moderate,"Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See 
-Specifications Table 8
- for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.
-
-
-BS2_Moderate = 2 points",Gene-specific
-BRCA1 (HGNC:1100),BS2,Supporting,"Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See 
-Specifications Table 8
- for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.
-
-
-BS2_Supporting = 1 points",Gene-specific
-BRCA1 (HGNC:1100),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-BRCA1 (HGNC:1100),BS3,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function. Assay measures effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.
-
-
-Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of no damaging effect 
-as measured by effect on mRNA transcript profile (mRNA assay only).
- Apply as BP7 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",Gene-specific
-BRCA1 (HGNC:1100),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-BRCA1 (HGNC:1100),BS4,Strong,"Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.
-
-
-Apply weight as per Bayes Score:
-
-
-BS4 - LR <0.05:1
-
-
-BS4_VeryStrong – LR <0.00285:1",Gene-specific
-BRCA1 (HGNC:1100),BS4,Moderate,"Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.
-
-
-Apply weight as per Bayes Score:
-
-
-BS4_Moderate - LR <0.23:1",Gene-specific
-BRCA1 (HGNC:1100),BS4,Supporting,"Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.
-
-
-Apply weight as per Bayes Score:
-
-
-BS4_Supporting  - LR 0.23-0.48:1",Gene-specific
-BRCA1 (HGNC:1100),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-BRCA1 (HGNC:1100),BP1,Strong,"Apply BP1_Strong
- for silent substitution, missense or in-frame insertion, deletion or delins variants outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1). As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101; BRCA1 coiled-coil aa 1391-1424; BRCA1 BRCT repeats aa 1650-1857. See Specifications Figure1A and Appendix J for details.","Gene-specific,Strength"
-BRCA1 (HGNC:1100),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-BRCA1 (HGNC:1100),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-BRCA1 (HGNC:1100),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-BRCA1 (HGNC:1100),BP4,Supporting,"Missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain, and no predicted impact via protein change or splicing (BayesDel no-AF score ≤ 0.15 AND SpliceAI ≤0.1).
-
-
-Silent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (SpliceAI ≤0.1).
-
-
-Intronic variants outside of the native donor and acceptor splice sites (i.e. not +/- 1,2 positions) AND no predicted impact via splicing (SpliceAI ≤0.1).
-
-
-As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101; BRCA1 coiled-coil aa 1391-1424; BRCA1 BRCT repeats aa 1650-1857. See Specifications Figure1A and Appendix J for details.","Clarification,Gene-specific"
-BRCA1 (HGNC:1100),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-BRCA1 (HGNC:1100),BP5,Strong,"Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.
-
-
-BP5_VeryStrong – LR <0.00285:1
-
-
-BP5_Strong  - LR <0.05:1
-
-
-Not applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype.",Gene-specific
-BRCA1 (HGNC:1100),BP5,Moderate,"Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.
-
-
-BP5_Moderate - LR <0.23:1
-
-
-Not applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype.",Gene-specific
-BRCA1 (HGNC:1100),BP5,Supporting,"Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.
-
-
-BP5 - LR 0.23-0.48:1
-
-
-Not applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype.",Gene-specific
-BRCA1 (HGNC:1100),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-BRCA1 (HGNC:1100),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-BRCA1 (HGNC:1100),BP7,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function 
-as measured by effect on mRNA transcript profile – mRNA assay only.
- Apply as BP7 (RNA) for intronic and silent variants, as well as missense/in-frame variants located outside a (potentially) clinically important functional domain. See Specifications Figure1B and Appendix E for details.
-
-
-As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101; BRCA1 coiled-coil aa 1391-1424; BRCA1 BRCT repeats aa 1650-1857. See Specifications Figure1A and Appendix J for details.","General recommendation,Gene-specific"
-BRCA1 (HGNC:1100),BP7,Supporting,"Silent variant inside a (potentially) clinically important functional domain, IF BP4 met.
-
-
-Intronic variants located outside conserved donor or acceptor motif positions (at or beyond positions +7/-21) IF BP4 met.
-
-
-See Specifications Figure1A and Appendix J for additional details.
-
-
-As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101; BRCA1 coiled-coil aa 1391-1424; BRCA1 BRCT repeats aa 1650-1857. See Specifications Figure1A and Appendix J for details.","Clarification,General recommendation"
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA1Version1.2.0_version=1.2.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA1Version1.2.0_version=1.2.0.csv
deleted file mode 100644
index 5cd745cd2b731273c7ebb572799d13309bbbd2b7..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA1Version1.2.0_version=1.2.0.csv
+++ /dev/null
@@ -1,364 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-BRCA1 (HGNC:1100),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-BRCA1 (HGNC:1100),PVS1,Very Strong,"Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.
-
-
-Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of a damaging effect 
-as measured by effect on mRNA transcript profile (mRNA assay only).
- Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",Gene-specific
-BRCA1 (HGNC:1100),PVS1,Strong,"Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.
-
-
-Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of a damaging effect 
-as measured by effect on mRNA transcript profile (mRNA assay only).
- Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",Gene-specific
-BRCA1 (HGNC:1100),PVS1,Moderate,"Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.
-
-
-Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of a damaging effect 
-as measured by effect on mRNA transcript profile (mRNA assay only).
- Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",Gene-specific
-BRCA1 (HGNC:1100),PVS1,Supporting,"Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.
-
-
-Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of a damaging effect 
-as measured by effect on mRNA transcript profile (mRNA assay only).
- Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",Gene-specific
-BRCA1 (HGNC:1100),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-BRCA1 (HGNC:1100),PS1,Strong,"Apply 
-PS1
-, for predicted 
-missense
- substitutions, where a previously classified 
-pathogenic
- variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).
-
-
-Apply 
-PS1
-, for exonic and intronic variants with same predicted impact on 
-splicing
-, as a previously classified 
-pathogenic
- variant. Vary weight depending on relative positions, and confidence in classification of the reference variant. 
-
-
-See Specifications Table 5 and Appendix E, J and K for details.",General recommendation
-BRCA1 (HGNC:1100),PS1,Moderate,"Apply 
-PS1_Moderate
-, for predicted 
-missense
- substitutions, where previously classified 
-likely pathogenic
- variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).
-
-
-Apply 
-PS1_Moderate
-, for exonic and intronic variants with same predicted impact on 
-splicing
-, as a previously classified 
-(likely) pathogenic
- variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.
-
-
-See Specifications Table 5 and Appendix E, J and K for details.",General recommendation
-BRCA1 (HGNC:1100),PS1,Supporting,"Apply 
-PS1_Supporting
-, for exonic and intronic variants with same predicted impact on 
-splicing,
- as a previously classified 
-(likely) pathogenic
- variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.
-
-
-See Specifications Table 5 and Appendix E, J and K for details.",General recommendation
-BRCA1 (HGNC:1100),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",NA
-BRCA1 (HGNC:1100),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-BRCA1 (HGNC:1100),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect. Apply PS3 for assays measuring effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.
-
-
-Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of a damaging effect 
-as measured by effect on mRNA transcript profile (mRNA assay only).
- Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",General recommendation
-BRCA1 (HGNC:1100),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-BRCA1 (HGNC:1100),PS4,Strong,The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Case-control studies; p-value ≤0.05 and OR ≥4 (lower confidence interval excludes 2.0). See Appendix F for details.,"Clarification,Gene-specific"
-BRCA1 (HGNC:1100),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-BRCA1 (HGNC:1100),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-BRCA1 (HGNC:1100),PM2,Supporting,"Absent from controls in an outbred population, from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). Region around the variant must have an average read depth ≥25. See Appendix G for details.",Gene-specific
-BRCA1 (HGNC:1100),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-BRCA1 (HGNC:1100),PM3,Strong,"Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene.Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:
-
-
-(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis 
-≤5yr
-.
-
-
-(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.
-
-
-See 
-Specifications Table 6
- for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.
-
-
-PM3_Strong = ≥4 points",Gene-specific
-BRCA1 (HGNC:1100),PM3,Moderate,"Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene.Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:
-
-
-(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis 
-≤5yr
-.
-
-
-(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.
-
-
-See 
-Specifications Table 6
- for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.
-
-
-PM3 = 2 points",Gene-specific
-BRCA1 (HGNC:1100),PM3,Supporting,"Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene.Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:
-
-
-(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis 
-≤5yr
-.
-
-
-(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.
-
-
-See 
-Specifications Table 6
- for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.
-
-
-PM3_Supporting = 1 point",Gene-specific
-BRCA1 (HGNC:1100),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,NA
-BRCA1 (HGNC:1100),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-BRCA1 (HGNC:1100),PM5,Strong,Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5_PTC code strengths applicable per exon. See Appendix D for additional details.,Other
-BRCA1 (HGNC:1100),PM5,Moderate,Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5_PTC code strengths applicable per exon. See Appendix D for additional details.,Other
-BRCA1 (HGNC:1100),PM5,Supporting,Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5_PTC code strengths applicable per exon. See Appendix D for additional details.,Other
-BRCA1 (HGNC:1100),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-BRCA1 (HGNC:1100),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-BRCA1 (HGNC:1100),PP1,Strong,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.
-
-
-Apply weight as per Bayes Score:
-
-
-PP1_Strong – LR ≥18.7:1
-
-
-PP1_Very Strong – LR ≥350:1",Gene-specific
-BRCA1 (HGNC:1100),PP1,Moderate,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.
-
-
-Apply weight as per Bayes Score:
-
-
-PP1_Moderate – LR ≥4.3:1",Gene-specific
-BRCA1 (HGNC:1100),PP1,Supporting,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.
-
-
-Apply weight as per Bayes Score:
-
-
-PP1 - LR ≥2.08:1",Gene-specific
-BRCA1 (HGNC:1100),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-BRCA1 (HGNC:1100),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-BRCA1 (HGNC:1100),PP3,Supporting,"Apply PP3 for missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain and predicted impact via protein change (BayesDel no-AF score ≥0.28). As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101; BRCA1 coiled-coil aa 1391-1424; BRCA1 BRCT repeats aa 1650-1857.
-
-
-Apply PP3 for predicted splicing (SpliceAI ≥0.2) for silent, missense/in-frame (irrespective of location in clinically important functional domain) and for intronic variants outside of donor and acceptor 1,2 sites.
-
-
-See Specifications Figure1A and Appendix J for details.",Gene-specific
-BRCA1 (HGNC:1100),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-BRCA1 (HGNC:1100),PP4,Strong,"Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.
-
-
-PP4_Strong – LR ≥18.7:1
-
-
-PP4_Very Strong – LR ≥350:1
-
-
-See Specifications Table7 and Appendix B for details.",Gene-specific
-BRCA1 (HGNC:1100),PP4,Moderate,"Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.
-
-
-PP4_Moderate – LR ≥4.3:1
-
-
-See Specifications Table7 and Appendix B for details.",Gene-specific
-BRCA1 (HGNC:1100),PP4,Supporting,"Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.
-
-
-PP4 - LR ≥2.08:1 
-
-
-See Specifications Table7 and Appendix B for details.",Gene-specific
-BRCA1 (HGNC:1100),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-BRCA1 (HGNC:1100),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-BRCA1 (HGNC:1100),BA1,Stand Alone,"Filter allele frequency (FAF) is above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.",Gene-specific
-BRCA1 (HGNC:1100),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-BRCA1 (HGNC:1100),BS1,Strong,"Filter allele frequency (FAF) is above 0.01% (FAF > 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.",Gene-specific
-BRCA1 (HGNC:1100),BS1,Supporting,"Filter allele frequency (FAF) is above 0.002% (FAF > 0.00002) and less than or equal to 0.01% (FAF ≤ 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.",Gene-specific
-BRCA1 (HGNC:1100),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-BRCA1 (HGNC:1100),BS2,Strong,"Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See 
-Specifications Table 8
- for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.
-
-
-BS2 = ≥ 4 points",Gene-specific
-BRCA1 (HGNC:1100),BS2,Moderate,"Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See 
-Specifications Table 8
- for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.
-
-
-BS2_Moderate = 2 points",Gene-specific
-BRCA1 (HGNC:1100),BS2,Supporting,"Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See 
-Specifications Table 8
- for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.
-
-
-BS2_Supporting = 1 points",Gene-specific
-BRCA1 (HGNC:1100),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-BRCA1 (HGNC:1100),BS3,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function. Assay measures effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.
-
-
-Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of no damaging effect 
-as measured by effect on mRNA transcript profile (mRNA assay only).
- Apply as BP7 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",Gene-specific
-BRCA1 (HGNC:1100),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-BRCA1 (HGNC:1100),BS4,Strong,"Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.
-
-
-Apply weight as per Bayes Score:
-
-
-BS4 - LR ≤0.05:1
-
-
-BS4_VeryStrong – LR ≤0.00285:1",Gene-specific
-BRCA1 (HGNC:1100),BS4,Moderate,"Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.
-
-
-Apply weight as per Bayes Score:
-
-
-BS4_Moderate - LR ≤0.23:1",Gene-specific
-BRCA1 (HGNC:1100),BS4,Supporting,"Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.
-
-
-Apply weight as per Bayes Score:
-
-
-BS4_Supporting  - LR ≤0.48:1",Gene-specific
-BRCA1 (HGNC:1100),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-BRCA1 (HGNC:1100),BP1,Strong,"Apply BP1_Strong
- for silent substitution, missense or in-frame insertion, deletion or delins variants outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1). As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101; BRCA1 coiled-coil aa 1391-1424; BRCA1 BRCT repeats aa 1650-1857. See Specifications Figure1A and Appendix J for details.","Gene-specific,Strength"
-BRCA1 (HGNC:1100),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-BRCA1 (HGNC:1100),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-BRCA1 (HGNC:1100),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-BRCA1 (HGNC:1100),BP4,Supporting,"Missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain, and no predicted impact via protein change or splicing (BayesDel no-AF score ≤0.15 AND SpliceAI ≤0.1).
-
-
-Silent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (SpliceAI ≤0.1).
-
-
-Intronic variants outside of the native donor and acceptor splice sites (i.e. not +/- 1,2 positions) AND no predicted impact via splicing (SpliceAI ≤0.1).
-
-
-As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101; BRCA1 coiled-coil aa 1391-1424; BRCA1 BRCT repeats aa 1650-1857. See Specifications Figure1A and Appendix J for details.","Clarification,Gene-specific"
-BRCA1 (HGNC:1100),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-BRCA1 (HGNC:1100),BP5,Strong,"Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.
-
-
-BP5_VeryStrong - LR ≤0.00285:1
-
-
-BP5_Strong - LR ≤0.05:1
-
-
-Not applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype.",Gene-specific
-BRCA1 (HGNC:1100),BP5,Moderate,"Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.
-
-
-BP5_Moderate - LR ≤0.23:1
-
-
-Not applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype.",Gene-specific
-BRCA1 (HGNC:1100),BP5,Supporting,"Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.
-
-
-BP5 - LR ≤0.48:1
-
-
-Not applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype.",Gene-specific
-BRCA1 (HGNC:1100),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-BRCA1 (HGNC:1100),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-BRCA1 (HGNC:1100),BP7,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function 
-as measured by effect on mRNA transcript profile – mRNA assay only.
- Apply as BP7_Strong (RNA) for intronic and silent variants, as well as missense/in-frame variants located outside a (potentially) clinically important functional domain. Missense variants located inside a (potentially) clinically important functional domain must meet BS3 to be eligible for BP7_Strong (RNA). See Specifications Figure1B and Appendix E for details.
-
-
-As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101; BRCA1 coiled-coil aa 1391-1424; BRCA1 BRCT repeats aa 1650-1857. See Specifications Figure1A and Appendix J for details.","General recommendation,Gene-specific"
-BRCA1 (HGNC:1100),BP7,Supporting,"Silent variant inside a (potentially) clinically important functional domain, IF BP4 met.
-
-
-Intronic variants located outside conserved donor or acceptor motif positions (at or beyond positions +7/-21) IF BP4 met.
-
-
-See Specifications Figure1A and Appendix J for additional details.
-
-
-As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101; BRCA1 coiled-coil aa 1391-1424; BRCA1 BRCT repeats aa 1650-1857. See Specifications Figure1A and Appendix J for details.","Clarification,General recommendation"
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA2Version1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA2Version1.0.0_version=1.0.0.csv
deleted file mode 100644
index 4b87363f9a12ef7c69382ad16706a100fdf4ce02..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA2Version1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,373 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-BRCA2 (HGNC:1101),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-BRCA2 (HGNC:1101),PVS1,Very Strong,"Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.
-
-
-Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of a damaging effect 
-as measured by effect on mRNA transcript profile (mRNA assay only).
- Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",Gene-specific
-BRCA2 (HGNC:1101),PVS1,Strong,"Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.
-
-
-Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of a damaging effect 
-as measured by effect on mRNA transcript profile (mRNA assay only).
- Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",Gene-specific
-BRCA2 (HGNC:1101),PVS1,Moderate,"Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.
-
-
-Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of a damaging effect 
-as measured by effect on mRNA transcript profile (mRNA assay only).
- Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",Gene-specific
-BRCA2 (HGNC:1101),PVS1,Supporting,"Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.
-
-
-Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of a damaging effect 
-as measured by effect on mRNA transcript profile (mRNA assay only).
- Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",Gene-specific
-BRCA2 (HGNC:1101),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-BRCA2 (HGNC:1101),PS1,Strong,"Apply 
-PS1
-, for predicted 
-missense
- substitutions, where a previously classified 
-pathogenic
- variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).
-
-
-Apply 
-PS1
-, for exonic and intronic variants with same predicted impact on 
-splicing,
- as a previously classified 
-pathogenic
- variant. Vary weight depending on relative positions, and confidence in classification of the reference variant. 
-
-
-See Specifications Table 5 and Appendix E, J and K for details.",General recommendation
-BRCA2 (HGNC:1101),PS1,Moderate,"Apply 
-PS1_Moderate
-, for predicted 
-missense
- substitutions, where a previously classified 
-likely pathogenic
- variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).
-
-
-Apply 
-PS1_Moderate
-, for exonic and intronic variants with same predicted impact on 
-splicing
-, as a previously classified 
-(likely) pathogenic
- variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.
-
-
-See Specifications Table 5 and Appendix E, J and K for details.",General recommendation
-BRCA2 (HGNC:1101),PS1,Supporting,"Apply 
-PS1
-, for exonic and intronic variants with same predicted impact on 
-splicing
-, as a previously classified 
-(likely) pathogenic
- variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.
-
-
-See Specifications Table 5 and Appendix E, J and K for details.",General recommendation
-BRCA2 (HGNC:1101),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",NA
-BRCA2 (HGNC:1101),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-BRCA2 (HGNC:1101),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect. Apply PS3 for assays measuring effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.
-
-
-Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of a damaging effect 
-as measured by effect on mRNA transcript profile (mRNA assay only).
- Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",General recommendation
-BRCA2 (HGNC:1101),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-BRCA2 (HGNC:1101),PS4,Strong,The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Case-control studies; p-value ≤0.05 and OR ≥4 (lower confidence interval excludes 2.0). See Appendix F for details.,"Clarification,Gene-specific"
-BRCA2 (HGNC:1101),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-BRCA2 (HGNC:1101),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-BRCA2 (HGNC:1101),PM2,Supporting,"Absent from controls in an outbred population, from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). Region around the variant must have an average read depth ≥25. See Appendix G for details.",Gene-specific
-BRCA2 (HGNC:1101),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-BRCA2 (HGNC:1101),PM3,Strong,"Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene. Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:
-
-
-(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis 
-≤5yr
-.
-
-
-(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.
-
-
-See 
-Specifications Table 6
- for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.
-
-
-PM3_Strong = ≥4 points",Gene-specific
-BRCA2 (HGNC:1101),PM3,Moderate,"Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene. Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:
-
-
-(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis 
-≤5yr
-.
-
-
-(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.
-
-
-See 
-Specifications Table 6
- for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.
-
-
-PM3 = 2 points",Gene-specific
-BRCA2 (HGNC:1101),PM3,Supporting,"Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene.Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:
-
-
-(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis 
-≤5yr
-.
-
-
-(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.
-
-
-See 
-Specifications Table 6
- for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.
-
-
-PM3_Supporting = 1 point",Gene-specific
-BRCA2 (HGNC:1101),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,NA
-BRCA2 (HGNC:1101),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-BRCA2 (HGNC:1101),PM5,Strong,Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5_PTC code strengths applicable per exon. See Appendix D for additional details.,Other
-BRCA2 (HGNC:1101),PM5,Moderate,Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5_PTC code strengths applicable per exon. See Appendix D for additional details.,Other
-BRCA2 (HGNC:1101),PM5,Supporting,Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5_PTC code strengths applicable per exon. See Appendix D for additional details.,Other
-BRCA2 (HGNC:1101),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-BRCA2 (HGNC:1101),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-BRCA2 (HGNC:1101),PP1,Strong,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.
-
-
-Apply weight as per Bayes Score:
-
-
-PP1_Strong – LR>18.7:1
-
-
-PP1_Very Strong – LR>350:1",Gene-specific
-BRCA2 (HGNC:1101),PP1,Moderate,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.
-
-
-Apply weight as per Bayes Score:
-
-
-PP1_Moderate – LR>4.3:1",Gene-specific
-BRCA2 (HGNC:1101),PP1,Supporting,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.
-
-
-Apply weight as per Bayes Score:
-
-
-PP1 - LR >2.08:1",Gene-specific
-BRCA2 (HGNC:1101),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-BRCA2 (HGNC:1101),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-BRCA2 (HGNC:1101),PP3,Supporting,"Apply PP3 for missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain and predicted impact via protein change (BayesDel no-AF score ≥0.30). As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186.
-
-
-Apply PP3 for predicted splicing (SpliceAI ≥0.2) for silent, missense/in-frame (irrespective of location in clinically important functional domain) and for intronic variants outside of donor and acceptor 1,2 sites.
-
-
-See Specifications Figure1A and Appendix J for details.",Gene-specific
-BRCA2 (HGNC:1101),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-BRCA2 (HGNC:1101),PP4,Strong,"Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.
-
-
-PP4_Strong – LR>18.7:1
-
-
-PP4_Very Strong – LR>350:1
-
-
-Combined LR 1.00-2.08 is not informative (PP4 not applicable).
-
-
-See Specifications Table7 and Appendix B for details.",Gene-specific
-BRCA2 (HGNC:1101),PP4,Moderate,"Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.
-
-
-PP4_Moderate – LR>4.3:1
-
-
-Combined LR 1.00-2.08 is not informative (PP4 not applicable).
-
-
-See Specifications Table7 and Appendix B for details.",Gene-specific
-BRCA2 (HGNC:1101),PP4,Supporting,"Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.
-
-
-PP4 - LR >2.08:1 
-
-
-Combined LR 1.00-2.08 is not informative (PP4 not applicable).
-
-
-See Specifications Table7 and Appendix B for details.",Gene-specific
-BRCA2 (HGNC:1101),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-BRCA2 (HGNC:1101),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-BRCA2 (HGNC:1101),BA1,Stand Alone,"Filter allele frequency (FAF) is above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.",Gene-specific
-BRCA2 (HGNC:1101),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-BRCA2 (HGNC:1101),BS1,Strong,"Filter allele frequency (FAF) is above 0.01% (FAF > 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.",Gene-specific
-BRCA2 (HGNC:1101),BS1,Supporting,"Filter allele frequency (FAF) is above 0.002% (FAF > 0.00002) and less than or equal to 0.01% (FAF ≤ 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.",Gene-specific
-BRCA2 (HGNC:1101),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-BRCA2 (HGNC:1101),BS2,Strong,"Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See 
-Specifications Table 8
- for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.
-
-
-BS2 = ≥ 4 points",Gene-specific
-BRCA2 (HGNC:1101),BS2,Moderate,"Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See 
-Specifications Table 8
- for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.
-
-
-BS2_Moderate = 2 points",Gene-specific
-BRCA2 (HGNC:1101),BS2,Supporting,"Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See 
-Specifications Table 8
- for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.
-
-
-BS2_Supporting = 1 points",Gene-specific
-BRCA2 (HGNC:1101),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-BRCA2 (HGNC:1101),BS3,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function. Assay measures effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.
-
-
-Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of no damaging effect 
-as measured by effect on mRNA transcript profile (mRNA assay only).
- Apply as BP7 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",Gene-specific
-BRCA2 (HGNC:1101),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-BRCA2 (HGNC:1101),BS4,Strong,"Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.
-
-
-Apply weight as per Bayes Score:
-
-
-BS4 - LR <0.05:1
-
-
-BS4_VeryStrong – LR <0.00285:1",Gene-specific
-BRCA2 (HGNC:1101),BS4,Moderate,"Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.
-
-
-Apply weight as per Bayes Score:
-
-
-BS4_Moderate - LR <0.23:1",Gene-specific
-BRCA2 (HGNC:1101),BS4,Supporting,"Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.
-
-
-Apply weight as per Bayes Score:
-
-
-BS4_Supporting  - LR 0.23-0.48:1",Gene-specific
-BRCA2 (HGNC:1101),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-BRCA2 (HGNC:1101),BP1,Strong,"Apply BP1_Strong
- for silent substitution, missense or in-frame insertion, deletion or delins variants outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1). As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186. See Specifications Figure1A and Appendix J for details.","Gene-specific,Strength"
-BRCA2 (HGNC:1101),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-BRCA2 (HGNC:1101),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-BRCA2 (HGNC:1101),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-BRCA2 (HGNC:1101),BP4,Supporting,"Missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain, and no predicted impact via protein change or splicing (BayesDel no-AF score ≤ 0.18 AND SpliceAI ≤0.1).
-
-
-Silent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (SpliceAI ≤0.1).
-
-
-Intronic variants outside of the native donor and acceptor splice sites (i.e. not +/- 1,2 positions) AND no predicted impact via splicing (SpliceAI ≤0.1).
-
-
-As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186. See Specifications Figure1A and Appendix J for details.","Clarification,Gene-specific"
-BRCA2 (HGNC:1101),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-BRCA2 (HGNC:1101),BP5,Strong,"Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.
-
-
-BP5_VeryStrong – LR <0.00285:1
-
-
-BP5_Strong  - LR <0.05:1
-
-
-Not applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype.",Gene-specific
-BRCA2 (HGNC:1101),BP5,Moderate,"Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.
-
-
-BP5_Moderate - LR <0.23:1
-
-
-Not applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype.",Gene-specific
-BRCA2 (HGNC:1101),BP5,Supporting,"Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.
-
-
-BP5 - LR 0.23-0.48:1
-
-
-Not applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype.",Gene-specific
-BRCA2 (HGNC:1101),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-BRCA2 (HGNC:1101),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-BRCA2 (HGNC:1101),BP7,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function 
-as measured by effect on mRNA transcript profile – mRNA assay only.
- Apply as BP7_Strong (RNA) for intronic and silent variants, as well as missense/in-frame variants located outside a (potentially) clinically important functional domain. See Specifications Figure1B and Appendix E for details.
-
-
-As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186. See Specifications Figure1A and Appendix J for details.","General recommendation,Gene-specific"
-BRCA2 (HGNC:1101),BP7,Supporting,"Silent variant inside a (potentially) clinically important functional domain, IF BP4 met.
-
-
-Intronic variants located outside conserved donor or acceptor motif positions (at or beyond positions +7/-21) IF BP4 met.
-
-
-See Specifications Figure1A and Appendix J for additional details.
-
-
-As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186. See Specifications Figure1A and Appendix J for details.","Clarification,General recommendation"
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA2Version1.1.0_version=1.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA2Version1.1.0_version=1.1.0.csv
deleted file mode 100644
index 4b87363f9a12ef7c69382ad16706a100fdf4ce02..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA2Version1.1.0_version=1.1.0.csv
+++ /dev/null
@@ -1,373 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-BRCA2 (HGNC:1101),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-BRCA2 (HGNC:1101),PVS1,Very Strong,"Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.
-
-
-Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of a damaging effect 
-as measured by effect on mRNA transcript profile (mRNA assay only).
- Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",Gene-specific
-BRCA2 (HGNC:1101),PVS1,Strong,"Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.
-
-
-Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of a damaging effect 
-as measured by effect on mRNA transcript profile (mRNA assay only).
- Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",Gene-specific
-BRCA2 (HGNC:1101),PVS1,Moderate,"Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.
-
-
-Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of a damaging effect 
-as measured by effect on mRNA transcript profile (mRNA assay only).
- Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",Gene-specific
-BRCA2 (HGNC:1101),PVS1,Supporting,"Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.
-
-
-Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of a damaging effect 
-as measured by effect on mRNA transcript profile (mRNA assay only).
- Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",Gene-specific
-BRCA2 (HGNC:1101),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-BRCA2 (HGNC:1101),PS1,Strong,"Apply 
-PS1
-, for predicted 
-missense
- substitutions, where a previously classified 
-pathogenic
- variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).
-
-
-Apply 
-PS1
-, for exonic and intronic variants with same predicted impact on 
-splicing,
- as a previously classified 
-pathogenic
- variant. Vary weight depending on relative positions, and confidence in classification of the reference variant. 
-
-
-See Specifications Table 5 and Appendix E, J and K for details.",General recommendation
-BRCA2 (HGNC:1101),PS1,Moderate,"Apply 
-PS1_Moderate
-, for predicted 
-missense
- substitutions, where a previously classified 
-likely pathogenic
- variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).
-
-
-Apply 
-PS1_Moderate
-, for exonic and intronic variants with same predicted impact on 
-splicing
-, as a previously classified 
-(likely) pathogenic
- variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.
-
-
-See Specifications Table 5 and Appendix E, J and K for details.",General recommendation
-BRCA2 (HGNC:1101),PS1,Supporting,"Apply 
-PS1
-, for exonic and intronic variants with same predicted impact on 
-splicing
-, as a previously classified 
-(likely) pathogenic
- variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.
-
-
-See Specifications Table 5 and Appendix E, J and K for details.",General recommendation
-BRCA2 (HGNC:1101),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",NA
-BRCA2 (HGNC:1101),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-BRCA2 (HGNC:1101),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect. Apply PS3 for assays measuring effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.
-
-
-Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of a damaging effect 
-as measured by effect on mRNA transcript profile (mRNA assay only).
- Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",General recommendation
-BRCA2 (HGNC:1101),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-BRCA2 (HGNC:1101),PS4,Strong,The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Case-control studies; p-value ≤0.05 and OR ≥4 (lower confidence interval excludes 2.0). See Appendix F for details.,"Clarification,Gene-specific"
-BRCA2 (HGNC:1101),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-BRCA2 (HGNC:1101),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-BRCA2 (HGNC:1101),PM2,Supporting,"Absent from controls in an outbred population, from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). Region around the variant must have an average read depth ≥25. See Appendix G for details.",Gene-specific
-BRCA2 (HGNC:1101),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-BRCA2 (HGNC:1101),PM3,Strong,"Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene. Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:
-
-
-(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis 
-≤5yr
-.
-
-
-(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.
-
-
-See 
-Specifications Table 6
- for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.
-
-
-PM3_Strong = ≥4 points",Gene-specific
-BRCA2 (HGNC:1101),PM3,Moderate,"Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene. Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:
-
-
-(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis 
-≤5yr
-.
-
-
-(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.
-
-
-See 
-Specifications Table 6
- for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.
-
-
-PM3 = 2 points",Gene-specific
-BRCA2 (HGNC:1101),PM3,Supporting,"Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene.Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:
-
-
-(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis 
-≤5yr
-.
-
-
-(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.
-
-
-See 
-Specifications Table 6
- for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.
-
-
-PM3_Supporting = 1 point",Gene-specific
-BRCA2 (HGNC:1101),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,NA
-BRCA2 (HGNC:1101),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-BRCA2 (HGNC:1101),PM5,Strong,Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5_PTC code strengths applicable per exon. See Appendix D for additional details.,Other
-BRCA2 (HGNC:1101),PM5,Moderate,Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5_PTC code strengths applicable per exon. See Appendix D for additional details.,Other
-BRCA2 (HGNC:1101),PM5,Supporting,Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5_PTC code strengths applicable per exon. See Appendix D for additional details.,Other
-BRCA2 (HGNC:1101),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-BRCA2 (HGNC:1101),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-BRCA2 (HGNC:1101),PP1,Strong,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.
-
-
-Apply weight as per Bayes Score:
-
-
-PP1_Strong – LR>18.7:1
-
-
-PP1_Very Strong – LR>350:1",Gene-specific
-BRCA2 (HGNC:1101),PP1,Moderate,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.
-
-
-Apply weight as per Bayes Score:
-
-
-PP1_Moderate – LR>4.3:1",Gene-specific
-BRCA2 (HGNC:1101),PP1,Supporting,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.
-
-
-Apply weight as per Bayes Score:
-
-
-PP1 - LR >2.08:1",Gene-specific
-BRCA2 (HGNC:1101),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-BRCA2 (HGNC:1101),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-BRCA2 (HGNC:1101),PP3,Supporting,"Apply PP3 for missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain and predicted impact via protein change (BayesDel no-AF score ≥0.30). As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186.
-
-
-Apply PP3 for predicted splicing (SpliceAI ≥0.2) for silent, missense/in-frame (irrespective of location in clinically important functional domain) and for intronic variants outside of donor and acceptor 1,2 sites.
-
-
-See Specifications Figure1A and Appendix J for details.",Gene-specific
-BRCA2 (HGNC:1101),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-BRCA2 (HGNC:1101),PP4,Strong,"Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.
-
-
-PP4_Strong – LR>18.7:1
-
-
-PP4_Very Strong – LR>350:1
-
-
-Combined LR 1.00-2.08 is not informative (PP4 not applicable).
-
-
-See Specifications Table7 and Appendix B for details.",Gene-specific
-BRCA2 (HGNC:1101),PP4,Moderate,"Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.
-
-
-PP4_Moderate – LR>4.3:1
-
-
-Combined LR 1.00-2.08 is not informative (PP4 not applicable).
-
-
-See Specifications Table7 and Appendix B for details.",Gene-specific
-BRCA2 (HGNC:1101),PP4,Supporting,"Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.
-
-
-PP4 - LR >2.08:1 
-
-
-Combined LR 1.00-2.08 is not informative (PP4 not applicable).
-
-
-See Specifications Table7 and Appendix B for details.",Gene-specific
-BRCA2 (HGNC:1101),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-BRCA2 (HGNC:1101),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-BRCA2 (HGNC:1101),BA1,Stand Alone,"Filter allele frequency (FAF) is above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.",Gene-specific
-BRCA2 (HGNC:1101),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-BRCA2 (HGNC:1101),BS1,Strong,"Filter allele frequency (FAF) is above 0.01% (FAF > 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.",Gene-specific
-BRCA2 (HGNC:1101),BS1,Supporting,"Filter allele frequency (FAF) is above 0.002% (FAF > 0.00002) and less than or equal to 0.01% (FAF ≤ 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.",Gene-specific
-BRCA2 (HGNC:1101),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-BRCA2 (HGNC:1101),BS2,Strong,"Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See 
-Specifications Table 8
- for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.
-
-
-BS2 = ≥ 4 points",Gene-specific
-BRCA2 (HGNC:1101),BS2,Moderate,"Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See 
-Specifications Table 8
- for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.
-
-
-BS2_Moderate = 2 points",Gene-specific
-BRCA2 (HGNC:1101),BS2,Supporting,"Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See 
-Specifications Table 8
- for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.
-
-
-BS2_Supporting = 1 points",Gene-specific
-BRCA2 (HGNC:1101),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-BRCA2 (HGNC:1101),BS3,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function. Assay measures effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.
-
-
-Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of no damaging effect 
-as measured by effect on mRNA transcript profile (mRNA assay only).
- Apply as BP7 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",Gene-specific
-BRCA2 (HGNC:1101),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-BRCA2 (HGNC:1101),BS4,Strong,"Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.
-
-
-Apply weight as per Bayes Score:
-
-
-BS4 - LR <0.05:1
-
-
-BS4_VeryStrong – LR <0.00285:1",Gene-specific
-BRCA2 (HGNC:1101),BS4,Moderate,"Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.
-
-
-Apply weight as per Bayes Score:
-
-
-BS4_Moderate - LR <0.23:1",Gene-specific
-BRCA2 (HGNC:1101),BS4,Supporting,"Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.
-
-
-Apply weight as per Bayes Score:
-
-
-BS4_Supporting  - LR 0.23-0.48:1",Gene-specific
-BRCA2 (HGNC:1101),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-BRCA2 (HGNC:1101),BP1,Strong,"Apply BP1_Strong
- for silent substitution, missense or in-frame insertion, deletion or delins variants outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1). As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186. See Specifications Figure1A and Appendix J for details.","Gene-specific,Strength"
-BRCA2 (HGNC:1101),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-BRCA2 (HGNC:1101),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-BRCA2 (HGNC:1101),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-BRCA2 (HGNC:1101),BP4,Supporting,"Missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain, and no predicted impact via protein change or splicing (BayesDel no-AF score ≤ 0.18 AND SpliceAI ≤0.1).
-
-
-Silent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (SpliceAI ≤0.1).
-
-
-Intronic variants outside of the native donor and acceptor splice sites (i.e. not +/- 1,2 positions) AND no predicted impact via splicing (SpliceAI ≤0.1).
-
-
-As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186. See Specifications Figure1A and Appendix J for details.","Clarification,Gene-specific"
-BRCA2 (HGNC:1101),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-BRCA2 (HGNC:1101),BP5,Strong,"Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.
-
-
-BP5_VeryStrong – LR <0.00285:1
-
-
-BP5_Strong  - LR <0.05:1
-
-
-Not applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype.",Gene-specific
-BRCA2 (HGNC:1101),BP5,Moderate,"Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.
-
-
-BP5_Moderate - LR <0.23:1
-
-
-Not applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype.",Gene-specific
-BRCA2 (HGNC:1101),BP5,Supporting,"Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.
-
-
-BP5 - LR 0.23-0.48:1
-
-
-Not applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype.",Gene-specific
-BRCA2 (HGNC:1101),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-BRCA2 (HGNC:1101),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-BRCA2 (HGNC:1101),BP7,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function 
-as measured by effect on mRNA transcript profile – mRNA assay only.
- Apply as BP7_Strong (RNA) for intronic and silent variants, as well as missense/in-frame variants located outside a (potentially) clinically important functional domain. See Specifications Figure1B and Appendix E for details.
-
-
-As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186. See Specifications Figure1A and Appendix J for details.","General recommendation,Gene-specific"
-BRCA2 (HGNC:1101),BP7,Supporting,"Silent variant inside a (potentially) clinically important functional domain, IF BP4 met.
-
-
-Intronic variants located outside conserved donor or acceptor motif positions (at or beyond positions +7/-21) IF BP4 met.
-
-
-See Specifications Figure1A and Appendix J for additional details.
-
-
-As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186. See Specifications Figure1A and Appendix J for details.","Clarification,General recommendation"
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA2Version1.2.0_version=1.2.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA2Version1.2.0_version=1.2.0.csv
deleted file mode 100644
index 4fe9de8ca1eacda55acb3e950fc853b2ebcdaed1..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA2Version1.2.0_version=1.2.0.csv
+++ /dev/null
@@ -1,364 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-BRCA2 (HGNC:1101),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-BRCA2 (HGNC:1101),PVS1,Very Strong,"Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.
-
-
-Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of a damaging effect 
-as measured by effect on mRNA transcript profile (mRNA assay only).
- Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",Gene-specific
-BRCA2 (HGNC:1101),PVS1,Strong,"Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.
-
-
-Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of a damaging effect 
-as measured by effect on mRNA transcript profile (mRNA assay only).
- Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",Gene-specific
-BRCA2 (HGNC:1101),PVS1,Moderate,"Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.
-
-
-Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of a damaging effect 
-as measured by effect on mRNA transcript profile (mRNA assay only).
- Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",Gene-specific
-BRCA2 (HGNC:1101),PVS1,Supporting,"Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details.
-
-
-Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of a damaging effect 
-as measured by effect on mRNA transcript profile (mRNA assay only).
- Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",Gene-specific
-BRCA2 (HGNC:1101),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-BRCA2 (HGNC:1101),PS1,Strong,"Apply 
-PS1
-, for predicted 
-missense
- substitutions, where a previously classified 
-pathogenic
- variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).
-
-
-Apply 
-PS1
-, for exonic and intronic variants with same predicted impact on 
-splicing,
- as a previously classified 
-pathogenic
- variant. Vary weight depending on relative positions, and confidence in classification of the reference variant. 
-
-
-See Specifications Table 5 and Appendix E, J and K for details.",General recommendation
-BRCA2 (HGNC:1101),PS1,Moderate,"Apply 
-PS1_Moderate
-, for predicted 
-missense
- substitutions, where a previously classified 
-likely pathogenic
- variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).
-
-
-Apply 
-PS1_Moderate
-, for exonic and intronic variants with same predicted impact on 
-splicing
-, as a previously classified 
-(likely) pathogenic
- variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.
-
-
-See Specifications Table 5 and Appendix E, J and K for details.",General recommendation
-BRCA2 (HGNC:1101),PS1,Supporting,"Apply 
-PS1
-, for exonic and intronic variants with same predicted impact on 
-splicing
-, as a previously classified 
-(likely) pathogenic
- variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.
-
-
-See Specifications Table 5 and Appendix E, J and K for details.",General recommendation
-BRCA2 (HGNC:1101),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",NA
-BRCA2 (HGNC:1101),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-BRCA2 (HGNC:1101),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect. Apply PS3 for assays measuring effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.
-
-
-Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of a damaging effect 
-as measured by effect on mRNA transcript profile (mRNA assay only).
- Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",General recommendation
-BRCA2 (HGNC:1101),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-BRCA2 (HGNC:1101),PS4,Strong,The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Case-control studies; p-value ≤0.05 and OR ≥4 (lower confidence interval excludes 2.0). See Appendix F for details.,"Clarification,Gene-specific"
-BRCA2 (HGNC:1101),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-BRCA2 (HGNC:1101),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-BRCA2 (HGNC:1101),PM2,Supporting,"Absent from controls in an outbred population, from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). Region around the variant must have an average read depth ≥25. See Appendix G for details.",Gene-specific
-BRCA2 (HGNC:1101),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-BRCA2 (HGNC:1101),PM3,Strong,"Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene. Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:
-
-
-(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis 
-≤5yr
-.
-
-
-(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.
-
-
-See 
-Specifications Table 6
- for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.
-
-
-PM3_Strong = ≥4 points",Gene-specific
-BRCA2 (HGNC:1101),PM3,Moderate,"Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene. Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:
-
-
-(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis 
-≤5yr
-.
-
-
-(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.
-
-
-See 
-Specifications Table 6
- for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.
-
-
-PM3 = 2 points",Gene-specific
-BRCA2 (HGNC:1101),PM3,Supporting,"Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene.Phenotype is considered consistent with BRCA1- or BRCA2-related FA if:
-
-
-(i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis 
-≤5yr
-.
-
-
-(ii) Result unknown for chromosome breakage, and at least two clinical features indicative of BRCA1/2-related FA under at least two of the three categories: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr.
-
-
-See 
-Specifications Table 6
- for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. Also see Appendix H for additional details.
-
-
-PM3_Supporting = 1 point",Gene-specific
-BRCA2 (HGNC:1101),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,NA
-BRCA2 (HGNC:1101),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-BRCA2 (HGNC:1101),PM5,Strong,Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5_PTC code strengths applicable per exon. See Appendix D for additional details.,Other
-BRCA2 (HGNC:1101),PM5,Moderate,Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5_PTC code strengths applicable per exon. See Appendix D for additional details.,Other
-BRCA2 (HGNC:1101),PM5,Supporting,Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5_PTC code strengths applicable per exon. See Appendix D for additional details.,Other
-BRCA2 (HGNC:1101),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-BRCA2 (HGNC:1101),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-BRCA2 (HGNC:1101),PP1,Strong,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.
-
-
-Apply weight as per Bayes Score:
-
-
-PP1_Strong – LR ≥18.7:1
-
-
-PP1_Very Strong – LR ≥350:1",Gene-specific
-BRCA2 (HGNC:1101),PP1,Moderate,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.
-
-
-Apply weight as per Bayes Score:
-
-
-PP1_Moderate – LR ≥4.3:1",Gene-specific
-BRCA2 (HGNC:1101),PP1,Supporting,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details.
-
-
-Apply weight as per Bayes Score:
-
-
-PP1 - LR ≥2.08:1",Gene-specific
-BRCA2 (HGNC:1101),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-BRCA2 (HGNC:1101),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-BRCA2 (HGNC:1101),PP3,Supporting,"Apply PP3 for missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain and predicted impact via protein change (BayesDel no-AF score ≥0.30). As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186.
-
-
-Apply PP3 for predicted splicing (SpliceAI ≥0.2) for silent, missense/in-frame (irrespective of location in clinically important functional domain) and for intronic variants outside of donor and acceptor 1,2 sites.
-
-
-See Specifications Figure1A and Appendix J for details.",Gene-specific
-BRCA2 (HGNC:1101),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-BRCA2 (HGNC:1101),PP4,Strong,"Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.
-
-
-PP4_Strong – LR ≥18.7:1
-
-
-PP4_Very Strong – LR ≥350:1
-
-
-See Specifications Table7 and Appendix B for details.",Gene-specific
-BRCA2 (HGNC:1101),PP4,Moderate,"Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.
-
-
-PP4_Moderate – LR ≥4.3:1
-
-
-See Specifications Table7 and Appendix B for details.",Gene-specific
-BRCA2 (HGNC:1101),PP4,Supporting,"Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data.
-
-
-PP4 - LR ≥2.08:1 
-
-
-See Specifications Table7 and Appendix B for details.",Gene-specific
-BRCA2 (HGNC:1101),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-BRCA2 (HGNC:1101),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-BRCA2 (HGNC:1101),BA1,Stand Alone,"Filter allele frequency (FAF) is above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.",Gene-specific
-BRCA2 (HGNC:1101),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-BRCA2 (HGNC:1101),BS1,Strong,"Filter allele frequency (FAF) is above 0.01% (FAF > 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.",Gene-specific
-BRCA2 (HGNC:1101),BS1,Supporting,"Filter allele frequency (FAF) is above 0.002% (FAF > 0.00002) and less than or equal to 0.01% (FAF ≤ 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.",Gene-specific
-BRCA2 (HGNC:1101),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-BRCA2 (HGNC:1101),BS2,Strong,"Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See 
-Specifications Table 8
- for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.
-
-
-BS2 = ≥ 4 points",Gene-specific
-BRCA2 (HGNC:1101),BS2,Moderate,"Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See 
-Specifications Table 8
- for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.
-
-
-BS2_Moderate = 2 points",Gene-specific
-BRCA2 (HGNC:1101),BS2,Supporting,"Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See 
-Specifications Table 8
- for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.
-
-
-BS2_Supporting = 1 points",Gene-specific
-BRCA2 (HGNC:1101),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-BRCA2 (HGNC:1101),BS3,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function. Assay measures effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.
-
-
-Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of no damaging effect 
-as measured by effect on mRNA transcript profile (mRNA assay only).
- Apply as BP7 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details.",Gene-specific
-BRCA2 (HGNC:1101),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-BRCA2 (HGNC:1101),BS4,Strong,"Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.
-
-
-Apply weight as per Bayes Score:
-
-
-BS4 - LR ≤0.05:1
-
-
-BS4_VeryStrong – LR ≤0.00285:1",Gene-specific
-BRCA2 (HGNC:1101),BS4,Moderate,"Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.
-
-
-Apply weight as per Bayes Score:
-
-
-BS4_Moderate - LR ≤0.23:1",Gene-specific
-BRCA2 (HGNC:1101),BS4,Supporting,"Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details.
-
-
-Apply weight as per Bayes Score:
-
-
-BS4_Supporting  - LR ≤0.48:1",Gene-specific
-BRCA2 (HGNC:1101),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-BRCA2 (HGNC:1101),BP1,Strong,"Apply BP1_Strong
- for silent substitution, missense or in-frame insertion, deletion or delins variants outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1). As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186. See Specifications Figure1A and Appendix J for details.","Gene-specific,Strength"
-BRCA2 (HGNC:1101),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-BRCA2 (HGNC:1101),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-BRCA2 (HGNC:1101),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-BRCA2 (HGNC:1101),BP4,Supporting,"Missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain, and no predicted impact via protein change or splicing (BayesDel no-AF score ≤ 0.18 AND SpliceAI ≤0.1).
-
-
-Silent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (SpliceAI ≤0.1).
-
-
-Intronic variants outside of the native donor and acceptor splice sites (i.e. not +/- 1,2 positions) AND no predicted impact via splicing (SpliceAI ≤0.1).
-
-
-As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186. See Specifications Figure1A and Appendix J for details.","Clarification,Gene-specific"
-BRCA2 (HGNC:1101),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-BRCA2 (HGNC:1101),BP5,Strong,"Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.
-
-
-BP5_VeryStrong – LR ≤0.00285:1
-
-
-BP5_Strong  - LR ≤0.05:1
-
-
-Not applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype.",Gene-specific
-BRCA2 (HGNC:1101),BP5,Moderate,"Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.
-
-
-BP5_Moderate - LR ≤0.23:1
-
-
-Not applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype.",Gene-specific
-BRCA2 (HGNC:1101),BP5,Supporting,"Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data.
-
-
-BP5 - LR ≤0.48:1
-
-
-Not applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype.",Gene-specific
-BRCA2 (HGNC:1101),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-BRCA2 (HGNC:1101),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-BRCA2 (HGNC:1101),BP7,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function 
-as measured by effect on mRNA transcript profile – mRNA assay only.
- Apply as BP7_Strong (RNA) for intronic and silent variants, as well as missense/in-frame variants located outside a (potentially) clinically important functional domain. Missense variants located inside a (potentially) clinically important functional domain must meet BS3 to be eligible for BP7_Strong (RNA). See Specifications Figure1B and Appendix E for details.
-
-
-As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186. See Specifications Figure1A and Appendix J for details.","General recommendation,Gene-specific"
-BRCA2 (HGNC:1101),BP7,Supporting,"Silent variant inside a (potentially) clinically important functional domain, IF BP4 met.
-
-
-Intronic variants located outside conserved donor or acceptor motif positions (at or beyond positions +7/-21) IF BP4 met.
-
-
-See Specifications Figure1A and Appendix J for additional details.
-
-
-As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA2 PALB2 binding domain aa 10-40; BRCA2 DNA binding aa 2481-3186. See Specifications Figure1A and Appendix J for details.","Clarification,General recommendation"
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN1AVersion1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN1AVersion1.0.0_version=1.0.0.csv
deleted file mode 100644
index ae70037b7ed17076746c584f4c0c15f402a781c3..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN1AVersion1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,521 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-SCN1A (HGNC:10585),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-SCN1A (HGNC:10585),PVS1,Very Strong,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN1A-specific information.
-
-
-Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1601. 
-
-
-In-frame exons: 1, 7, 8, 12, 17, 25
-
-
-Out-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26
-
-
-Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.
-
-
-For splice region variants, this criterion should not be applied with PP3.","Disease-specific,General recommendation"
-SCN1A (HGNC:10585),PVS1,Strong,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN1A-specific information.
-
-
-Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1601. 
-
-
-In-frame exons: 1, 7, 8, 12, 17, 25
-
-
-Out-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26
-
-
-Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.
-
-
-For splice region variants, this criterion should not be applied with PP3.","Disease-specific,General recommendation"
-SCN1A (HGNC:10585),PVS1,Moderate,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN1A-specific information.
-
-
-Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1601. 
-
-
-In-frame exons: 1, 7, 8, 12, 17, 25
-
-
-Out-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26
-
-
-Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.
-
-
-For splice region variants, this criterion should not be applied with PP3.","Disease-specific,General recommendation"
-SCN1A (HGNC:10585),PVS1,Supporting,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN1A-specific information.
-
-
-Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1601. 
-
-
-In-frame exons: 1, 7, 8, 12, 17, 25
-
-
-Out-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26
-
-
-Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.
-
-
-For splice region variants, this criterion should not be applied with PP3.","Disease-specific,General recommendation"
-SCN1A (HGNC:10585),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SCN1A (HGNC:10585),PS1,Strong,"Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).
-
-
-
-
-Same amino acid change as a previously established 
-Pathogenic
- variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.
-
-
->1
- Identical amino acid change in paralogous gene previously established as 
-Pathogenic or Likely Pathogenic
-, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions.
-
-
-
-
-Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023). 
-
-
-
-
-PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (""PS1_Variants impacting splicing"").",Gene-specific
-SCN1A (HGNC:10585),PS1,Moderate,"Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).
-
-
-
-
-Same amino acid change as a previously established 
-Likely Pathogenic
- variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.
-
-
-
-
-Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).
-
-
-
-
-PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (""PS1_Variants impacting splicing"").","Gene-specific,Strength"
-SCN1A (HGNC:10585),PS1,Supporting,"Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).
-
-
-
-
-A single identical amino acid change in a paralogous gene previously established as 
-Pathogenic or Likely Pathogenic
-, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions.
-
-
-
-
-Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).
-
-
-
-
-PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (""PS1_Variants impacting splicing"").",Gene-specific
-SCN1A (HGNC:10585),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-SCN1A (HGNC:10585),PS2,Very Strong,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-4 points
- will arrive at 
-Very Strong
-. 
-
-
-Dravet*: 2 points
-
-
-Genetic Epilepsy with Febrile Seizures Plus: 1 point
-
-
-Developmental and Epileptic Encephalopathy: 1 point
-
-
-Hemiplegic migraine: 0.5 points
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN1A (HGNC:10585),PS2,Strong,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-2 points
- will arrive at 
-Strong
-. 
-
-
-Dravet*: 2 points
-
-
-Genetic Epilepsy with Febrile Seizures Plus: 1 point
-
-
-Developmental and Epileptic Encephalopathy: 1 point
-
-
-Hemiplegic migraine: 0.5 points
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN1A (HGNC:10585),PS2,Moderate,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-1 point
- will arrive at 
-Moderate
-. 
-
-
-Dravet*: 2 points
-
-
-Genetic Epilepsy with Febrile Seizures Plus: 1 point
-
-
-Developmental and Epileptic Encephalopathy: 1 point
-
-
-Hemiplegic migraine: 0.5 points
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN1A (HGNC:10585),PS2,Supporting,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-0.5 points
- will arrive at 
-Supporting
-. 
-
-
-Dravet*: 2 points
-
-
-Genetic Epilepsy with Febrile Seizures Plus: 1 point
-
-
-Developmental and Epileptic Encephalopathy: 1 point
-
-
-Hemiplegic migraine: 0.5 points
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN1A (HGNC:10585),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-SCN1A (HGNC:10585),PS3,Strong,"In patch clamping experiments: Peak current as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is less than or equal to 72.7% of wildtype.
-
-
-In patch clamping experiments: Persistent current as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is greater than or equal to 135% of wildtype.
-
-
-In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is shifted by at least 2.2 mV (absolute value).
-
-
-In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is shifted by at least 4.1 mV (absolute value).
-
-
-Mouse knock-in model displays spontaneous seizures.","Disease-specific,Gene-specific"
-SCN1A (HGNC:10585),PS3,Moderate,"In patch clamping experiments: Peak current as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is less than or equal to 80.6% of wildtype.
-
-
-In patch clamping experiments: Persistent current as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is greater than or equal to 125% of wildtype.
-
-
-In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is shifted by at least 2.1 mV (absolute value).
-
-
-In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is shifted by at least 3.0 mV (absolute value).
-
-
-Mouse knock-in model displays induced seizures
-
-
-Zebrafish knock-in model displays spontaneous seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies","Gene-specific,Strength"
-SCN1A (HGNC:10585),PS3,Supporting,"Zebrafish knock-in model displays induced seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies","Gene-specific,Strength"
-SCN1A (HGNC:10585),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-SCN1A (HGNC:10585),PS4,Very Strong,"Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-16+ points
- will arrive at 
-Very Strong
-. 
-
-
-Dravet*: 2 points
-
-
-Genetic Epilepsy with Febrile Seizures Plus: 1 point
-
-
-Developmental and Epileptic Encephalopathy: 1 point
-
-
-Hemiplegic migraine: 0.5 points
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points","Disease-specific,Gene-specific,Strength"
-SCN1A (HGNC:10585),PS4,Strong,"Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-4-15.5 points
- will arrive at 
-Strong
-. 
-
-
-Dravet*: 2 points
-
-
-Genetic Epilepsy with Febrile Seizures Plus: 1 point
-
-
-Developmental and Epileptic Encephalopathy: 1 point
-
-
-Hemiplegic migraine: 0.5 points
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points","Disease-specific,Gene-specific"
-SCN1A (HGNC:10585),PS4,Moderate,"Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-2-3.5 points
- will arrive at 
-Moderate
-. 
-
-
-Dravet*: 2 points
-
-
-Genetic Epilepsy with Febrile Seizures Plus: 1 point
-
-
-Developmental and Epileptic Encephalopathy: 1 point
-
-
-Hemiplegic migraine: 0.5 points
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points","Disease-specific,Gene-specific,Strength"
-SCN1A (HGNC:10585),PS4,Supporting,"Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-1-1.5 points
- will arrive at 
-Supporting
-. 
-
-
-Dravet*: 2 points
-
-
-Genetic Epilepsy with Febrile Seizures Plus: 1 point
-
-
-Developmental and Epileptic Encephalopathy: 1 point
-
-
-Hemiplegic migraine: 0.5 points
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points","Disease-specific,Gene-specific,Strength"
-SCN1A (HGNC:10585),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-SCN1A (HGNC:10585),PM1,Moderate,"Variant is located within a Pathogenic Enriched Region. See specific amino acid residues noted in the attached “PM1 Table"".",Gene-specific
-SCN1A (HGNC:10585),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-SCN1A (HGNC:10585),PM2,Supporting,"One or fewer alleles, if a minimum of 10,000 alleles assessed in population databases, such as the Genome Aggregation Database (gnomAD). Caveat: Population data for indels may be poorly called by next generation sequencing.","General recommendation,Other"
-SCN1A (HGNC:10585),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-SCN1A (HGNC:10585),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-SCN1A (HGNC:10585),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,No change
-SCN1A (HGNC:10585),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SCN1A (HGNC:10585),PM5,Strong,Greater than or equal to 2 known pathogenic variants at same site as novel change (within the same gene).,"Disease-specific,Gene-specific,Strength"
-SCN1A (HGNC:10585),PM5,Moderate,Novel missense change at an amino acid residue in the same gene where a different missense variant was determined to be Pathogenic.,General recommendation
-SCN1A (HGNC:10585),PM5,Supporting,"Novel missense change at an amino acid residue where a different missense change determined to be 
-Likely Pathogenic
- has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. 
-
-
->1 Non-Identical aa change in paralogous gene(s) where a different missense change determined to be 
-Pathogenic
- or 
-Likely Pathogenic
-, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A)
-
-
-
-
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.","Disease-specific,Gene-specific,Strength"
-SCN1A (HGNC:10585),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-SCN1A (HGNC:10585),PM6,Strong,"Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-2 points
- will arrive at 
-Strong
-. Total of 
-4 points
- will arrive at 
-Very Strong
-. 
-
-
-Dravet*: 1 points
-
-
-Genetic Epilepsy with Febrile Seizures Plus: 0.5 points
-
-
-Developmental and Epileptic Encephalopathy: 0.5 points
-
-
-Hemiplegic migraine: 0.25 points
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.25 points","Disease-specific,Strength"
-SCN1A (HGNC:10585),PM6,Moderate,"Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-1 point
- will arrive at 
-Moderate
-. 
-
-
-Dravet*: 1 points
-
-
-Genetic Epilepsy with Febrile Seizures Plus: 0.5 points
-
-
-Developmental and Epileptic Encephalopathy: 0.5 points
-
-
-Hemiplegic migraine: 0.25 points
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.25 points","Disease-specific,Strength"
-SCN1A (HGNC:10585),PM6,Supporting,"Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-0.5 points
- will arrive at 
-Supporting
-. 
-
-
-Dravet*: 1 points
-
-
-Genetic Epilepsy with Febrile Seizures Plus: 0.5 points
-
-
-Developmental and Epileptic Encephalopathy: 0.5 points
-
-
-Hemiplegic migraine: 0.25 points
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.25 points","Disease-specific,Strength"
-SCN1A (HGNC:10585),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-SCN1A (HGNC:10585),PP1,Strong,"Co-segregation with disease in multiple affected family members.
-
-
->=7 independent meioses",Strength
-SCN1A (HGNC:10585),PP1,Moderate,"Co-segregation with disease in multiple affected family members.
-
-
-5-6 independent meioses",Strength
-SCN1A (HGNC:10585),PP1,Supporting,"Co-segregation with disease in multiple affected family members.
-
-
-3-4 independent meioses",Strength
-SCN1A (HGNC:10585),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-SCN1A (HGNC:10585),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-SCN1A (HGNC:10585),PP3,Moderate,"Follow ClinGen’s recommendations (
-PMID: 36413997
-) using REVEL as the computational tool, with the following stipulations:
-
-
-
-
-Strength should be capped at Moderate, and 
-
-
-limit the combination of PP3 and PM1 to reach no higher than strong","General recommendation,Strength"
-SCN1A (HGNC:10585),PP3,Supporting,"Follow ClinGen’s recommendations (
-PMID: 36413997
-) using REVEL as the computational tool, with the following stipulations: with the following stipulations:
-
-
-
-
-Strength should be capped at Moderate, and 
-
-
-limit the combination of PP3 and PM1 to reach no higher than strong","General recommendation,Strength"
-SCN1A (HGNC:10585),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-SCN1A (HGNC:10585),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SCN1A (HGNC:10585),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-SCN1A (HGNC:10585),BA1,Stand Alone,"Allele frequency is above 0.02% in GnomAD or other large population database, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.",Disease-specific
-SCN1A (HGNC:10585),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-SCN1A (HGNC:10585),BS1,Strong,"Allele frequency is above 0.0004% in GnomAD or other large population database, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.",Disease-specific
-SCN1A (HGNC:10585),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-SCN1A (HGNC:10585),BS2,Strong,Observed in a healthy adult individual.,No change
-SCN1A (HGNC:10585),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-SCN1A (HGNC:10585),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",NA
-SCN1A (HGNC:10585),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-SCN1A (HGNC:10585),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-SCN1A (HGNC:10585),BP2,Supporting,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,No change
-SCN1A (HGNC:10585),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-SCN1A (HGNC:10585),BP3,Supporting,In frame-deletions/insertions in a repetitive region without a known function.,No change
-SCN1A (HGNC:10585),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SCN1A (HGNC:10585),BP4,Moderate,"Follow ClinGen’s recommendations (
-PMID: 36413997
-) using REVEL as the computational tool.",General recommendation
-SCN1A (HGNC:10585),BP4,Supporting,"Follow ClinGen’s recommendations (
-PMID: 36413997
-) using REVEL as the computational tool.",General recommendation
-SCN1A (HGNC:10585),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-SCN1A (HGNC:10585),BP5,Supporting,Variant found in a case with an alternate molecular basis for disease.,No change
-SCN1A (HGNC:10585),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SCN1A (HGNC:10585),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-SCN1A (HGNC:10585),BP7,Supporting,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,No change
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN1AVersion2.0.0_version=2.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN1AVersion2.0.0_version=2.0.0.csv
deleted file mode 100644
index fd0dcdc7a446de67974151542e3e7a27028a61c6..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN1AVersion2.0.0_version=2.0.0.csv
+++ /dev/null
@@ -1,461 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-SCN1A (HGNC:10585),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-SCN1A (HGNC:10585),PVS1,Very Strong,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”.","Disease-specific,General recommendation"
-SCN1A (HGNC:10585),PVS1,Strong,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”.","Disease-specific,General recommendation"
-SCN1A (HGNC:10585),PVS1,Moderate,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”.","Disease-specific,General recommendation"
-SCN1A (HGNC:10585),PVS1,Supporting,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”.","Disease-specific,General recommendation"
-SCN1A (HGNC:10585),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SCN1A (HGNC:10585),PS1,Strong,"Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).
-
-
-
-
-Same amino acid change as a previously established 
-Pathogenic
- variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.
-
-
->1
- Identical amino acid change in paralogous gene previously established as 
-Pathogenic or Likely Pathogenic
-, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions.
-
-
-
-
-Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023). 
-
-
-
-
-PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (""PS1_Variants impacting splicing"").",Gene-specific
-SCN1A (HGNC:10585),PS1,Moderate,"Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).
-
-
-
-
-Same amino acid change as a previously established 
-Likely Pathogenic
- variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.
-
-
-
-
-Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).
-
-
-
-
-PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (""PS1_Variants impacting splicing"").","Gene-specific,Strength"
-SCN1A (HGNC:10585),PS1,Supporting,"Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).
-
-
-
-
-A single identical amino acid change in a paralogous gene previously established as 
-Pathogenic or Likely Pathogenic
-, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions.
-
-
-
-
-Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).
-
-
-
-
-PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (""PS1_Variants impacting splicing"").",Gene-specific
-SCN1A (HGNC:10585),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-SCN1A (HGNC:10585),PS2,Very Strong,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-4 points
- will arrive at 
-Very Strong
-. 
-
-
-Dravet*: 2 points
-
-
-Genetic Epilepsy with Febrile Seizures Plus: 1 point
-
-
-Developmental and Epileptic Encephalopathy: 1 point
-
-
-Hemiplegic migraine: 0.5 points
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN1A (HGNC:10585),PS2,Strong,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-2 points
- will arrive at 
-Strong
-. 
-
-
-Dravet*: 2 points
-
-
-Genetic Epilepsy with Febrile Seizures Plus: 1 point
-
-
-Developmental and Epileptic Encephalopathy: 1 point
-
-
-Hemiplegic migraine: 0.5 points
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN1A (HGNC:10585),PS2,Moderate,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-1 point
- will arrive at 
-Moderate
-. 
-
-
-Dravet*: 2 points
-
-
-Genetic Epilepsy with Febrile Seizures Plus: 1 point
-
-
-Developmental and Epileptic Encephalopathy: 1 point
-
-
-Hemiplegic migraine: 0.5 points
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN1A (HGNC:10585),PS2,Supporting,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-0.5 points
- will arrive at 
-Supporting
-. 
-
-
-Dravet*: 2 points
-
-
-Genetic Epilepsy with Febrile Seizures Plus: 1 point
-
-
-Developmental and Epileptic Encephalopathy: 1 point
-
-
-Hemiplegic migraine: 0.5 points
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN1A (HGNC:10585),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-SCN1A (HGNC:10585),PS3,Strong,"In patch clamping experiments: Peak current as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is less than or equal to 72.7% of wildtype.
-
-
-In patch clamping experiments: Persistent current as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is greater than or equal to 135% of wildtype.
-
-
-In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is shifted by at least 2.2 mV (absolute value).
-
-
-In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is shifted by at least 4.1 mV (absolute value).
-
-
-Mouse knock-in model displays spontaneous seizures.","Disease-specific,Gene-specific"
-SCN1A (HGNC:10585),PS3,Moderate,"In patch clamping experiments: Peak current as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is less than or equal to 80.6% of wildtype.
-
-
-In patch clamping experiments: Persistent current as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is greater than or equal to 125% of wildtype.
-
-
-In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is shifted by at least 2.1 mV (absolute value).
-
-
-In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is shifted by at least 3.0 mV (absolute value).
-
-
-Mouse knock-in model displays induced seizures
-
-
-Zebrafish knock-in model displays spontaneous seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies","Gene-specific,Strength"
-SCN1A (HGNC:10585),PS3,Supporting,"Zebrafish knock-in model displays induced seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies","Gene-specific,Strength"
-SCN1A (HGNC:10585),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-SCN1A (HGNC:10585),PS4,Very Strong,"Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-16+ points
- will arrive at 
-Very Strong
-. 
-
-
-Dravet*: 2 points
-
-
-Genetic Epilepsy with Febrile Seizures Plus: 1 point
-
-
-Developmental and Epileptic Encephalopathy: 1 point
-
-
-Hemiplegic migraine: 0.5 points
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points","Disease-specific,Gene-specific,Strength"
-SCN1A (HGNC:10585),PS4,Strong,"Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-4-15.5 points
- will arrive at 
-Strong
-. 
-
-
-Dravet*: 2 points
-
-
-Genetic Epilepsy with Febrile Seizures Plus: 1 point
-
-
-Developmental and Epileptic Encephalopathy: 1 point
-
-
-Hemiplegic migraine: 0.5 points
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points","Disease-specific,Gene-specific"
-SCN1A (HGNC:10585),PS4,Moderate,"Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-2-3.5 points
- will arrive at 
-Moderate
-. 
-
-
-Dravet*: 2 points
-
-
-Genetic Epilepsy with Febrile Seizures Plus: 1 point
-
-
-Developmental and Epileptic Encephalopathy: 1 point
-
-
-Hemiplegic migraine: 0.5 points
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points","Disease-specific,Gene-specific,Strength"
-SCN1A (HGNC:10585),PS4,Supporting,"Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-1-1.5 points
- will arrive at 
-Supporting
-. 
-
-
-Dravet*: 2 points
-
-
-Genetic Epilepsy with Febrile Seizures Plus: 1 point
-
-
-Developmental and Epileptic Encephalopathy: 1 point
-
-
-Hemiplegic migraine: 0.5 points
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points","Disease-specific,Gene-specific,Strength"
-SCN1A (HGNC:10585),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-SCN1A (HGNC:10585),PM1,Moderate,"Variant is located within a Pathogenic Enriched Region. See specific amino acid residues noted in the attached “PM1 Table"".",Gene-specific
-SCN1A (HGNC:10585),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-SCN1A (HGNC:10585),PM2,Supporting,"One or fewer alleles, if a minimum of 10,000 alleles assessed in population databases, such as the Genome Aggregation Database (gnomAD). Caveat: Population data for indels may be poorly called by next generation sequencing.","General recommendation,Other"
-SCN1A (HGNC:10585),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-SCN1A (HGNC:10585),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-SCN1A (HGNC:10585),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,No change
-SCN1A (HGNC:10585),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SCN1A (HGNC:10585),PM5,Strong,Greater than or equal to 2 known pathogenic variants at same site as novel change (within the same gene).,"Disease-specific,Gene-specific,Strength"
-SCN1A (HGNC:10585),PM5,Moderate,Novel missense change at an amino acid residue in the same gene where a different missense variant was determined to be Pathogenic.,General recommendation
-SCN1A (HGNC:10585),PM5,Supporting,"Novel missense change at an amino acid residue where a different missense change determined to be 
-Likely Pathogenic
- has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. 
-
-
->1 Non-Identical aa change in paralogous gene(s) where a different missense change determined to be 
-Pathogenic
- or 
-Likely Pathogenic
-, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A)
-
-
-
-
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.","Disease-specific,Gene-specific,Strength"
-SCN1A (HGNC:10585),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-SCN1A (HGNC:10585),PM6,Strong,"Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-2 points
- will arrive at 
-Strong
-. Total of 
-4 points
- will arrive at 
-Very Strong
-. 
-
-
-Dravet*: 1 points
-
-
-Genetic Epilepsy with Febrile Seizures Plus: 0.5 points
-
-
-Developmental and Epileptic Encephalopathy: 0.5 points
-
-
-Hemiplegic migraine: 0.25 points
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.25 points","Disease-specific,Strength"
-SCN1A (HGNC:10585),PM6,Moderate,"Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-1 point
- will arrive at 
-Moderate
-. 
-
-
-Dravet*: 1 points
-
-
-Genetic Epilepsy with Febrile Seizures Plus: 0.5 points
-
-
-Developmental and Epileptic Encephalopathy: 0.5 points
-
-
-Hemiplegic migraine: 0.25 points
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.25 points","Disease-specific,Strength"
-SCN1A (HGNC:10585),PM6,Supporting,"Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-0.5 points
- will arrive at 
-Supporting
-. 
-
-
-Dravet*: 1 points
-
-
-Genetic Epilepsy with Febrile Seizures Plus: 0.5 points
-
-
-Developmental and Epileptic Encephalopathy: 0.5 points
-
-
-Hemiplegic migraine: 0.25 points
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.25 points","Disease-specific,Strength"
-SCN1A (HGNC:10585),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-SCN1A (HGNC:10585),PP1,Strong,"Co-segregation with disease in multiple affected family members.
-
-
->=7 independent meioses",Strength
-SCN1A (HGNC:10585),PP1,Moderate,"Co-segregation with disease in multiple affected family members.
-
-
-5-6 independent meioses",Strength
-SCN1A (HGNC:10585),PP1,Supporting,"Co-segregation with disease in multiple affected family members.
-
-
-3-4 independent meioses",Strength
-SCN1A (HGNC:10585),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-SCN1A (HGNC:10585),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-SCN1A (HGNC:10585),PP3,Moderate,"Follow ClinGen’s recommendations (
-PMID: 36413997
-) using REVEL as the computational tool, with the following stipulations:
-
-
-
-
-Strength should be capped at Moderate, and 
-
-
-limit the combination of PP3 and PM1 to reach no higher than strong","General recommendation,Strength"
-SCN1A (HGNC:10585),PP3,Supporting,"Follow ClinGen’s recommendations (
-PMID: 36413997
-) using REVEL as the computational tool, with the following stipulations: with the following stipulations:
-
-
-
-
-Strength should be capped at Moderate, and 
-
-
-limit the combination of PP3 and PM1 to reach no higher than strong","General recommendation,Strength"
-SCN1A (HGNC:10585),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-SCN1A (HGNC:10585),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SCN1A (HGNC:10585),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-SCN1A (HGNC:10585),BA1,Stand Alone,"Allele frequency is above 0.02% in GnomAD or other large population database, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.",Disease-specific
-SCN1A (HGNC:10585),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-SCN1A (HGNC:10585),BS1,Strong,"Allele frequency is above 0.0004% in GnomAD or other large population database, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.",Disease-specific
-SCN1A (HGNC:10585),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-SCN1A (HGNC:10585),BS2,Strong,Observed in a healthy adult individual.,No change
-SCN1A (HGNC:10585),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-SCN1A (HGNC:10585),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",NA
-SCN1A (HGNC:10585),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-SCN1A (HGNC:10585),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-SCN1A (HGNC:10585),BP2,Supporting,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,No change
-SCN1A (HGNC:10585),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-SCN1A (HGNC:10585),BP3,Supporting,In frame-deletions/insertions in a repetitive region without a known function.,No change
-SCN1A (HGNC:10585),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SCN1A (HGNC:10585),BP4,Moderate,"Follow ClinGen’s recommendations (
-PMID: 36413997
-) using REVEL as the computational tool.",General recommendation
-SCN1A (HGNC:10585),BP4,Supporting,"Follow ClinGen’s recommendations (
-PMID: 36413997
-) using REVEL as the computational tool.",General recommendation
-SCN1A (HGNC:10585),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-SCN1A (HGNC:10585),BP5,Supporting,Variant found in a case with an alternate molecular basis for disease.,No change
-SCN1A (HGNC:10585),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SCN1A (HGNC:10585),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-SCN1A (HGNC:10585),BP7,Supporting,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,No change
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN1BVersion1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN1BVersion1.0.0_version=1.0.0.csv
deleted file mode 100644
index 539026dee9a30a2ce62f19ef64034c08d85329c9..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN1BVersion1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,506 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-SCN1B (HGNC:10586),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-SCN1B (HGNC:10586),PVS1,Very Strong,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN1B-specific information.
-
-
-Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr204. 
-
-
-In-frame exons: 3-5
-
-
-Out-of-frame exons: 1-2
-
-
-For splice region variants, this criterion should not be applied with PP3.",General recommendation
-SCN1B (HGNC:10586),PVS1,Strong,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN1B-specific information.
-
-
-Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr204. 
-
-
-In-frame exons: 3-5
-
-
-Out-of-frame exons: 1-2
-
-
-For splice region variants, this criterion should not be applied with PP3.",General recommendation
-SCN1B (HGNC:10586),PVS1,Moderate,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN1B-specific information.
-
-
-Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr204. 
-
-
-In-frame exons: 3-5
-
-
-Out-of-frame exons: 1-2
-
-
-For splice region variants, this criterion should not be applied with PP3.",General recommendation
-SCN1B (HGNC:10586),PVS1,Supporting,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN1B-specific information.
-
-
-Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr204. 
-
-
-In-frame exons: 3-5
-
-
-Out-of-frame exons: 1-2
-
-
-For splice region variants, this criterion should not be applied with PP3.",General recommendation
-SCN1B (HGNC:10586),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SCN1B (HGNC:10586),PS1,Strong,"Same amino acid change as a previously established 
-Pathogenic
- variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
-
-
-Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).
-
-
-
-
-PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (""PS1_Variants impacting splicing"").",Gene-specific
-SCN1B (HGNC:10586),PS1,Moderate,"Same amino acid change as a previously established 
-Likely Pathogenic
- variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
-
-
-Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).
-
-
-
-
-PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (""PS1_Variants impacting splicing"").","Gene-specific,Strength"
-SCN1B (HGNC:10586),PS1,Supporting,"Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).
-
-
-
-
-PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (""PS1_Variants impacting splicing"").","Gene-specific,Strength"
-SCN1B (HGNC:10586),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-SCN1B (HGNC:10586),PS2,Very Strong,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-4 points
- will arrive at 
-Very Strong
-. 
-
-
-Genetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN1B (HGNC:10586),PS2,Strong,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-2 points
- will arrive at 
-Strong
-. 
-
-
-Genetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN1B (HGNC:10586),PS2,Moderate,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-1 point
- will arrive at 
-Moderate
-. 
-
-
-Genetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN1B (HGNC:10586),PS2,Supporting,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-0.5 points
- will arrive at 
-Supporting
-. 
-
-
-Genetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN1B (HGNC:10586),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-SCN1B (HGNC:10586),PS3,Strong,Mouse knock-in model displays spontaneous seizures.,"Disease-specific,Gene-specific"
-SCN1B (HGNC:10586),PS3,Moderate,"Heterologous expression with voltage clamping shows statistically significant difference over wildtype in at least one parameter (
-https://bioportal.bioontology.org/ontologies/FENICS
-)
-
-
-Mouse knock-in model displays induced seizures
-
-
-Zebrafish knock-in model displays spontaneous seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies","Gene-specific,Strength"
-SCN1B (HGNC:10586),PS3,Supporting,"Zebrafish knock-in model displays induced seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies","Gene-specific,Strength"
-SCN1B (HGNC:10586),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-SCN1B (HGNC:10586),PS4,Very Strong,"Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-16+ points
- will arrive at 
-Very Strong
-. 
-
-
-Genetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points","Disease-specific,Gene-specific,Strength"
-SCN1B (HGNC:10586),PS4,Strong,"Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-4-15.5 points
- will arrive at 
-Strong
-. 
-
-
-Genetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points","Disease-specific,Gene-specific"
-SCN1B (HGNC:10586),PS4,Moderate,"Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-2-3.5 points
- will arrive at 
-Moderate
-. 
-
-
-Genetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points","Disease-specific,Gene-specific,Strength"
-SCN1B (HGNC:10586),PS4,Supporting,"Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-1-1.5 points
- will arrive at 
-Supporting
-. 
-
-
-Genetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points","Disease-specific,Gene-specific,Strength"
-SCN1B (HGNC:10586),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-SCN1B (HGNC:10586),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-SCN1B (HGNC:10586),PM2,Supporting,"One or fewer alleles, if a minimum of 10,000 alleles assessed in population databases, such as the Genome Aggregation Database (gnomAD). Caveat: Population data for indels may be poorly called by next generation sequencing.","General recommendation,Other"
-SCN1B (HGNC:10586),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-SCN1B (HGNC:10586),PM3,Very Strong,"For recessive disorders, points-based system based on confirmation of phase and classification of other variant. Total of 
-4.0 points
- will arrive at 
-Very Strong
-. 
-
-
-
-
-Classification of other variant is Pathogenic/Likely Pathogenic
-
-
-Confirmed in trans: 1 point
-
-
-Phase unknown: 0.5 (P) or 0.25 (LP) points
-
-
-
-
-
-
-Homozygous occurrence (max point 1.0)
-
-
-Confirmed in trans: 0.5 points
-
-
-
-
-
-
-Classification of other variant is Uncertain Significance 
-
-
-Confirmed in trans: 0.25 points
-
-
-Phase unknown: 0 points",General recommendation
-SCN1B (HGNC:10586),PM3,Strong,"For recessive disorders, points-based system based on confirmation of phase and classification of other variant. Total of 
-2.0 points
- will arrive at 
-Strong
-. 
-
-
-
-
-Classification of other variant is Pathogenic/Likely Pathogenic
-
-
-Confirmed in trans: 1 point
-
-
-Phase unknown: 0.5 (P) or 0.25 (LP) points
-
-
-
-
-
-
-Homozygous occurrence (max point 1.0)
-
-
-Confirmed in trans: 0.5 points
-
-
-
-
-
-
-Classification of other variant is Uncertain Significance 
-
-
-Confirmed in trans: 0.25 points
-
-
-Phase unknown: 0 points",General recommendation
-SCN1B (HGNC:10586),PM3,Moderate,"For recessive disorders, points-based system based on confirmation of phase and classification of other variant. Total of 
-1.0 point
- will arrive at 
-Moderate
-. 
-
-
-
-
-Classification of other variant is Pathogenic/Likely Pathogenic
-
-
-Confirmed in trans: 1 point
-
-
-Phase unknown: 0.5 (P) or 0.25 (LP) points
-
-
-
-
-
-
-Homozygous occurrence (max point 1.0)
-
-
-Confirmed in trans: 0.5 points
-
-
-
-
-
-
-Classification of other variant is Uncertain Significance 
-
-
-Confirmed in trans: 0.25 points
-
-
-Phase unknown: 0 points",General recommendation
-SCN1B (HGNC:10586),PM3,Supporting,"For recessive disorders, points-based system based on confirmation of phase and classification of other variant. Total of 
-0.5 points
- will arrive at 
-Supporting
-. 
-
-
-
-
-Classification of other variant is Pathogenic/Likely Pathogenic
-
-
-Confirmed in trans: 1 point
-
-
-Phase unknown: 0.5 (P) or 0.25 (LP) points
-
-
-
-
-
-
-Homozygous occurrence (max point 1.0)
-
-
-Confirmed in trans: 0.5 points
-
-
-
-
-
-
-Classification of other variant is Uncertain Significance 
-
-
-Confirmed in trans: 0.25 points
-
-
-Phase unknown: 0 points",General recommendation
-SCN1B (HGNC:10586),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-SCN1B (HGNC:10586),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,No change
-SCN1B (HGNC:10586),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SCN1B (HGNC:10586),PM5,Strong,This should say greater than or equal to 2 known pathogenic variants at same site as novel change.,"Disease-specific,Gene-specific,Strength"
-SCN1B (HGNC:10586),PM5,Moderate,"Novel missense change at an amino acid residue where a different missense change determined to be 
-Pathogenic
- has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys.
-
-
-
-
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.","Disease-specific,Gene-specific"
-SCN1B (HGNC:10586),PM5,Supporting,"Novel missense change at an amino acid residue where a different missense change determined to be 
-Likely Pathogenic
- has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys.","Disease-specific,Gene-specific,Strength"
-SCN1B (HGNC:10586),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-SCN1B (HGNC:10586),PM6,Strong,"Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-2 points
- will arrive at 
-Strong
-. Total of 
-4 points
- will arrive at 
-Very Strong
-. 
-
-
-Genetic Epilepsy with Febrile Seizures Plus (GEFS+): 0.5 points
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.25 points","Disease-specific,Strength"
-SCN1B (HGNC:10586),PM6,Moderate,"Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-1 point
- will arrive at 
-Moderate
-. 
-
-
-Genetic Epilepsy with Febrile Seizures Plus (GEFS+): 0.5 points
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.25 points","Disease-specific,Strength"
-SCN1B (HGNC:10586),PM6,Supporting,"Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-0.5 points
- will arrive at 
-Supporting
-. 
-
-
-Genetic Epilepsy with Febrile Seizures Plus (GEFS+): 0.5 points
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.25 points","Disease-specific,Strength"
-SCN1B (HGNC:10586),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-SCN1B (HGNC:10586),PP1,Strong,"Co-segregation with disease in multiple affected family members
-
-
-AD: ≥7 independent meioses
-
-
-AR: ≥3 affected segregations",Strength
-SCN1B (HGNC:10586),PP1,Moderate,"Co-segregation with disease in multiple affected family members
-
-
-AD: 5-6 independent meioses
-
-
-AR: 2 affected segregations",Strength
-SCN1B (HGNC:10586),PP1,Supporting,"Co-segregation with disease in multiple affected family members
-
-
-AD: 3-4 independent meioses
-
-
-AR: 1 affected segregation",Strength
-SCN1B (HGNC:10586),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-SCN1B (HGNC:10586),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-SCN1B (HGNC:10586),PP3,Moderate,"Follow ClinGen’s recommendations (
-PMID: 36413997
-), using REVEL as the computational tool, with the following stipulations:
-
-
-
-
-Strength should be capped at Moderate, and 
-
-
-limit the combination of PP3 and PM1 to reach no higher than strong","General recommendation,Strength"
-SCN1B (HGNC:10586),PP3,Supporting,"Follow ClinGen’s recommendations (
-PMID: 36413997
-), using REVEL as the computational tool, with the following stipulations:
-
-
-
-
-Strength should be capped at Moderate, and 
-
-
-limit the combination of PP3 and PM1 to reach no higher than strong","General recommendation,Strength"
-SCN1B (HGNC:10586),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-SCN1B (HGNC:10586),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SCN1B (HGNC:10586),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-SCN1B (HGNC:10586),BA1,Stand Alone,"Allele frequency is above 
-0.3%
- in GnomAD or other large population database, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.",Disease-specific
-SCN1B (HGNC:10586),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-SCN1B (HGNC:10586),BS1,Strong,"Allele frequency is above 
-0.01%
- in GnomAD or other large population database, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.",Disease-specific
-SCN1B (HGNC:10586),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-SCN1B (HGNC:10586),BS2,Strong,Observed in a healthy adult individual.,No change
-SCN1B (HGNC:10586),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-SCN1B (HGNC:10586),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",NA
-SCN1B (HGNC:10586),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-SCN1B (HGNC:10586),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-SCN1B (HGNC:10586),BP2,Supporting,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,No change
-SCN1B (HGNC:10586),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-SCN1B (HGNC:10586),BP3,Supporting,In frame-deletions/insertions in a repetitive region without a known function.,No change
-SCN1B (HGNC:10586),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SCN1B (HGNC:10586),BP4,Moderate,"Follow ClinGen’s recommendations (
-PMID: 36413997
-), using REVEL as the computational tool.",General recommendation
-SCN1B (HGNC:10586),BP4,Supporting,"Follow ClinGen’s recommendations (
-PMID: 36413997
-), using REVEL as the computational tool.",General recommendation
-SCN1B (HGNC:10586),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-SCN1B (HGNC:10586),BP5,Supporting,Variant found in a case with an alternate molecular basis for disease.,No change
-SCN1B (HGNC:10586),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SCN1B (HGNC:10586),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-SCN1B (HGNC:10586),BP7,Supporting,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,No change
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN1BVersion2.0.0_version=2.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN1BVersion2.0.0_version=2.0.0.csv
deleted file mode 100644
index 25e24e88eb027940dbe2e4772766478d3ffa6d13..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN1BVersion2.0.0_version=2.0.0.csv
+++ /dev/null
@@ -1,458 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-SCN1B (HGNC:10586),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-SCN1B (HGNC:10586),PVS1,Very Strong,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”.",General recommendation
-SCN1B (HGNC:10586),PVS1,Strong,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”.",General recommendation
-SCN1B (HGNC:10586),PVS1,Moderate,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”.",General recommendation
-SCN1B (HGNC:10586),PVS1,Supporting,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”.",General recommendation
-SCN1B (HGNC:10586),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SCN1B (HGNC:10586),PS1,Strong,"Same amino acid change as a previously established 
-Pathogenic
- variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
-
-
-Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).
-
-
-
-
-PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (""PS1_Variants impacting splicing"").",Gene-specific
-SCN1B (HGNC:10586),PS1,Moderate,"Same amino acid change as a previously established 
-Likely Pathogenic
- variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
-
-
-Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).
-
-
-
-
-PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (""PS1_Variants impacting splicing"").","Gene-specific,Strength"
-SCN1B (HGNC:10586),PS1,Supporting,"Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).
-
-
-
-
-PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (""PS1_Variants impacting splicing"").","Gene-specific,Strength"
-SCN1B (HGNC:10586),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-SCN1B (HGNC:10586),PS2,Very Strong,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-4 points
- will arrive at 
-Very Strong
-. 
-
-
-Genetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN1B (HGNC:10586),PS2,Strong,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-2 points
- will arrive at 
-Strong
-. 
-
-
-Genetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN1B (HGNC:10586),PS2,Moderate,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-1 point
- will arrive at 
-Moderate
-. 
-
-
-Genetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN1B (HGNC:10586),PS2,Supporting,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-0.5 points
- will arrive at 
-Supporting
-. 
-
-
-Genetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN1B (HGNC:10586),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-SCN1B (HGNC:10586),PS3,Strong,Mouse knock-in model displays spontaneous seizures.,"Disease-specific,Gene-specific"
-SCN1B (HGNC:10586),PS3,Moderate,"Heterologous expression with voltage clamping shows statistically significant difference over wildtype in at least one parameter (
-https://bioportal.bioontology.org/ontologies/FENICS
-)
-
-
-Mouse knock-in model displays induced seizures
-
-
-Zebrafish knock-in model displays spontaneous seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies","Gene-specific,Strength"
-SCN1B (HGNC:10586),PS3,Supporting,"Zebrafish knock-in model displays induced seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies","Gene-specific,Strength"
-SCN1B (HGNC:10586),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-SCN1B (HGNC:10586),PS4,Very Strong,"Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-16+ points
- will arrive at 
-Very Strong
-. 
-
-
-Genetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points","Disease-specific,Gene-specific,Strength"
-SCN1B (HGNC:10586),PS4,Strong,"Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-4-15.5 points
- will arrive at 
-Strong
-. 
-
-
-Genetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points","Disease-specific,Gene-specific"
-SCN1B (HGNC:10586),PS4,Moderate,"Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-2-3.5 points
- will arrive at 
-Moderate
-. 
-
-
-Genetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points","Disease-specific,Gene-specific,Strength"
-SCN1B (HGNC:10586),PS4,Supporting,"Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-1-1.5 points
- will arrive at 
-Supporting
-. 
-
-
-Genetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points","Disease-specific,Gene-specific,Strength"
-SCN1B (HGNC:10586),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-SCN1B (HGNC:10586),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-SCN1B (HGNC:10586),PM2,Supporting,"One or fewer alleles, if a minimum of 10,000 alleles assessed in population databases, such as the Genome Aggregation Database (gnomAD). Caveat: Population data for indels may be poorly called by next generation sequencing.","General recommendation,Other"
-SCN1B (HGNC:10586),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-SCN1B (HGNC:10586),PM3,Very Strong,"For recessive disorders, points-based system based on confirmation of phase and classification of other variant. Total of 
-4.0 points
- will arrive at 
-Very Strong
-. 
-
-
-
-
-Classification of other variant is Pathogenic/Likely Pathogenic
-
-
-Confirmed in trans: 1 point
-
-
-Phase unknown: 0.5 (P) or 0.25 (LP) points
-
-
-
-
-
-
-Homozygous occurrence (max point 1.0)
-
-
-Confirmed in trans: 0.5 points
-
-
-
-
-
-
-Classification of other variant is Uncertain Significance 
-
-
-Confirmed in trans: 0.25 points
-
-
-Phase unknown: 0 points",General recommendation
-SCN1B (HGNC:10586),PM3,Strong,"For recessive disorders, points-based system based on confirmation of phase and classification of other variant. Total of 
-2.0 points
- will arrive at 
-Strong
-. 
-
-
-
-
-Classification of other variant is Pathogenic/Likely Pathogenic
-
-
-Confirmed in trans: 1 point
-
-
-Phase unknown: 0.5 (P) or 0.25 (LP) points
-
-
-
-
-
-
-Homozygous occurrence (max point 1.0)
-
-
-Confirmed in trans: 0.5 points
-
-
-
-
-
-
-Classification of other variant is Uncertain Significance 
-
-
-Confirmed in trans: 0.25 points
-
-
-Phase unknown: 0 points",General recommendation
-SCN1B (HGNC:10586),PM3,Moderate,"For recessive disorders, points-based system based on confirmation of phase and classification of other variant. Total of 
-1.0 point
- will arrive at 
-Moderate
-. 
-
-
-
-
-Classification of other variant is Pathogenic/Likely Pathogenic
-
-
-Confirmed in trans: 1 point
-
-
-Phase unknown: 0.5 (P) or 0.25 (LP) points
-
-
-
-
-
-
-Homozygous occurrence (max point 1.0)
-
-
-Confirmed in trans: 0.5 points
-
-
-
-
-
-
-Classification of other variant is Uncertain Significance 
-
-
-Confirmed in trans: 0.25 points
-
-
-Phase unknown: 0 points",General recommendation
-SCN1B (HGNC:10586),PM3,Supporting,"For recessive disorders, points-based system based on confirmation of phase and classification of other variant. Total of 
-0.5 points
- will arrive at 
-Supporting
-. 
-
-
-
-
-Classification of other variant is Pathogenic/Likely Pathogenic
-
-
-Confirmed in trans: 1 point
-
-
-Phase unknown: 0.5 (P) or 0.25 (LP) points
-
-
-
-
-
-
-Homozygous occurrence (max point 1.0)
-
-
-Confirmed in trans: 0.5 points
-
-
-
-
-
-
-Classification of other variant is Uncertain Significance 
-
-
-Confirmed in trans: 0.25 points
-
-
-Phase unknown: 0 points",General recommendation
-SCN1B (HGNC:10586),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-SCN1B (HGNC:10586),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,No change
-SCN1B (HGNC:10586),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SCN1B (HGNC:10586),PM5,Strong,This should say greater than or equal to 2 known pathogenic variants at same site as novel change.,"Disease-specific,Gene-specific,Strength"
-SCN1B (HGNC:10586),PM5,Moderate,"Novel missense change at an amino acid residue where a different missense change determined to be 
-Pathogenic
- has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys.
-
-
-
-
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.","Disease-specific,Gene-specific"
-SCN1B (HGNC:10586),PM5,Supporting,"Novel missense change at an amino acid residue where a different missense change determined to be 
-Likely Pathogenic
- has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys.","Disease-specific,Gene-specific,Strength"
-SCN1B (HGNC:10586),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-SCN1B (HGNC:10586),PM6,Strong,"Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-2 points
- will arrive at 
-Strong
-. Total of 
-4 points
- will arrive at 
-Very Strong
-. 
-
-
-Genetic Epilepsy with Febrile Seizures Plus (GEFS+): 0.5 points
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.25 points","Disease-specific,Strength"
-SCN1B (HGNC:10586),PM6,Moderate,"Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-1 point
- will arrive at 
-Moderate
-. 
-
-
-Genetic Epilepsy with Febrile Seizures Plus (GEFS+): 0.5 points
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.25 points","Disease-specific,Strength"
-SCN1B (HGNC:10586),PM6,Supporting,"Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-0.5 points
- will arrive at 
-Supporting
-. 
-
-
-Genetic Epilepsy with Febrile Seizures Plus (GEFS+): 0.5 points
-
-
-Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.25 points","Disease-specific,Strength"
-SCN1B (HGNC:10586),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-SCN1B (HGNC:10586),PP1,Strong,"Co-segregation with disease in multiple affected family members
-
-
-AD: ≥7 independent meioses
-
-
-AR: ≥3 affected segregations",Strength
-SCN1B (HGNC:10586),PP1,Moderate,"Co-segregation with disease in multiple affected family members
-
-
-AD: 5-6 independent meioses
-
-
-AR: 2 affected segregations",Strength
-SCN1B (HGNC:10586),PP1,Supporting,"Co-segregation with disease in multiple affected family members
-
-
-AD: 3-4 independent meioses
-
-
-AR: 1 affected segregation",Strength
-SCN1B (HGNC:10586),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-SCN1B (HGNC:10586),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-SCN1B (HGNC:10586),PP3,Moderate,"Follow ClinGen’s recommendations (
-PMID: 36413997
-), using REVEL as the computational tool, with the following stipulations:
-
-
-
-
-Strength should be capped at Moderate, and 
-
-
-limit the combination of PP3 and PM1 to reach no higher than strong","General recommendation,Strength"
-SCN1B (HGNC:10586),PP3,Supporting,"Follow ClinGen’s recommendations (
-PMID: 36413997
-), using REVEL as the computational tool, with the following stipulations:
-
-
-
-
-Strength should be capped at Moderate, and 
-
-
-limit the combination of PP3 and PM1 to reach no higher than strong","General recommendation,Strength"
-SCN1B (HGNC:10586),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-SCN1B (HGNC:10586),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SCN1B (HGNC:10586),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-SCN1B (HGNC:10586),BA1,Stand Alone,"Allele frequency is above 
-0.3%
- in GnomAD or other large population database, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.",Disease-specific
-SCN1B (HGNC:10586),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-SCN1B (HGNC:10586),BS1,Strong,"Allele frequency is above 
-0.01%
- in GnomAD or other large population database, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.",Disease-specific
-SCN1B (HGNC:10586),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-SCN1B (HGNC:10586),BS2,Strong,Observed in a healthy adult individual.,No change
-SCN1B (HGNC:10586),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-SCN1B (HGNC:10586),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",NA
-SCN1B (HGNC:10586),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-SCN1B (HGNC:10586),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-SCN1B (HGNC:10586),BP2,Supporting,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,No change
-SCN1B (HGNC:10586),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-SCN1B (HGNC:10586),BP3,Supporting,In frame-deletions/insertions in a repetitive region without a known function.,No change
-SCN1B (HGNC:10586),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SCN1B (HGNC:10586),BP4,Moderate,"Follow ClinGen’s recommendations (
-PMID: 36413997
-), using REVEL as the computational tool.",General recommendation
-SCN1B (HGNC:10586),BP4,Supporting,"Follow ClinGen’s recommendations (
-PMID: 36413997
-), using REVEL as the computational tool.",General recommendation
-SCN1B (HGNC:10586),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-SCN1B (HGNC:10586),BP5,Supporting,Variant found in a case with an alternate molecular basis for disease.,No change
-SCN1B (HGNC:10586),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SCN1B (HGNC:10586),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-SCN1B (HGNC:10586),BP7,Supporting,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,No change
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN2AVersion1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN2AVersion1.0.0_version=1.0.0.csv
deleted file mode 100644
index ba6694b39ced97ceab43342240dce026713ce8f5..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN2AVersion1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,450 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-SCN2A (HGNC:10588),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-SCN2A (HGNC:10588),PVS1,Very Strong,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN2A-specific information.
-
-
-Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1591. 
-
-
-In-frame exons: 1, 7, 8, 12, 17, 25
-
-
-Out-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26
-
-
-Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.
-
-
-For splice region variants, this criterion should not be applied with PP3.",No change
-SCN2A (HGNC:10588),PVS1,Strong,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN2A-specific information.
-
-
-Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1591.
-
-
-In-frame exons: 1, 7, 8, 12, 17, 25
-
-
-Out-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26
-
-
-Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.
-
-
-For splice region variants, this criterion should not be applied with PP3.",No change
-SCN2A (HGNC:10588),PVS1,Moderate,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN2A-specific information.
-
-
-Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1591. 
-
-
-In-frame exons: 1, 7, 8, 12, 17, 25
-
-
-Out-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26
-
-
-Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.
-
-
-For splice region variants, this criterion should not be applied with PP3.",No change
-SCN2A (HGNC:10588),PVS1,Supporting,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN2A-specific information.
-
-
-Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1591. 
-
-
-In-frame exons: 1, 7, 8, 12, 17, 25
-
-
-Out-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26
-
-
-Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.
-
-
-For splice region variants, this criterion should not be applied with PP3.",No change
-SCN2A (HGNC:10588),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SCN2A (HGNC:10588),PS1,Strong,"Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).
-
-
-
-
-Same amino acid change as a previously established 
-Pathogenic
- variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.
-
-
->1
- Identical amino acid change in paralogous gene previously established as 
-Pathogenic or Likely Pathogenic
-, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions.
-
-
-
-
-Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023). 
-
-
-
-
-PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (""PS1_Variants impacting splicing"").",Gene-specific
-SCN2A (HGNC:10588),PS1,Moderate,"Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).
-
-
-
-
-Same amino acid change as a previously established 
-Likely Pathogenic
- variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.
-
-
-
-
-Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).
-
-
-
-
-PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (""PS1_Variants impacting splicing"").","Gene-specific,Strength"
-SCN2A (HGNC:10588),PS1,Supporting,"Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).
-
-
-
-
-A single identical amino acid change in a paralogous gene previously established as 
-Pathogenic or Likely Pathogenic
-, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions.
-
-
-
-
-Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).
-
-
-
-
-PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (""PS1_Variants impacting splicing"").","Disease-specific,Strength"
-SCN2A (HGNC:10588),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-SCN2A (HGNC:10588),PS2,Very Strong,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-4 points
- will arrive at 
-Very Strong
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 1 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points
-
-
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN2A (HGNC:10588),PS2,Strong,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-2 points
- will arrive at 
-Strong
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 1 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points
-
-
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN2A (HGNC:10588),PS2,Moderate,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-1 point
- will arrive at 
-Moderate
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 1 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points
-
-
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN2A (HGNC:10588),PS2,Supporting,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-0.5 points
- will arrive at 
-Supporting
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 1 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points
-
-
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN2A (HGNC:10588),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-SCN2A (HGNC:10588),PS3,Strong,"In patch clamping experiments: Peak current as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is less than or equal to 72.7% of wildtype.
-
-
-In patch clamping experiments: Persistent current as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is greater than or equal to 135% of wildtype.
-
-
-In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is shifted by at least 2.2 mV (absolute value).
-
-
-In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is shifted by at least 4.1 mV (absolute value).
-
-
-Mouse knock-in model displays spontaneous seizures.","Disease-specific,Gene-specific"
-SCN2A (HGNC:10588),PS3,Moderate,"In patch clamping experiments: Peak current as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is less than or equal to 80.6% of wildtype.
-
-
-In patch clamping experiments: Persistent current as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is greater than or equal to 125% of wildtype.
-
-
-In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is shifted by at least 2.1 mV (absolute value).
-
-
-In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is shifted by at least 3.0 mV (absolute value).
-
-
-Zebrafish knock-in model displays spontaneous seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies","Gene-specific,Strength"
-SCN2A (HGNC:10588),PS3,Supporting,"Zebrafish knock-in model displays induced seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies","Gene-specific,Strength"
-SCN2A (HGNC:10588),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-SCN2A (HGNC:10588),PS4,Very Strong,"Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-16+ points
- will arrive at 
-Very Strong
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 1 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Gene-specific,Strength"
-SCN2A (HGNC:10588),PS4,Strong,"Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-4 - 15.5 points
- will arrive at 
-Strong
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 1 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Gene-specific"
-SCN2A (HGNC:10588),PS4,Moderate,"Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-2 - 3.5 points
- will arrive at 
-Moderate
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 1 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Gene-specific,Strength"
-SCN2A (HGNC:10588),PS4,Supporting,"Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-1 - 1.5 points
- will arrive at 
-Supporting
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 1 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Gene-specific,Strength"
-SCN2A (HGNC:10588),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-SCN2A (HGNC:10588),PM1,Moderate,"Variant is located within a Pathogenic Enriched Region. See specific amino acid residues noted in the attached “PM1 Table"".",Gene-specific
-SCN2A (HGNC:10588),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-SCN2A (HGNC:10588),PM2,Supporting,"One or fewer alleles, if a minimum of 10,000 alleles assessed in population databases, such as the Genome Aggregation Database (gnomAD). Caveat: Population data for indels may be poorly called by next generation sequencing.",Other
-SCN2A (HGNC:10588),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-SCN2A (HGNC:10588),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-SCN2A (HGNC:10588),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,No change
-SCN2A (HGNC:10588),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SCN2A (HGNC:10588),PM5,Strong,"Greater than or equal to 2 known pathogenic variants at same site as novel change (within the same gene).
-
-
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.","Disease-specific,Gene-specific,Strength"
-SCN2A (HGNC:10588),PM5,Moderate,"Novel missense change at an amino acid residue where a different missense change determined to be Pathogenic has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys.
-
-
-
-
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.","Disease-specific,Gene-specific"
-SCN2A (HGNC:10588),PM5,Supporting,"Novel missense change at an amino acid residue where a different missense change determined to be 
-Likely Pathogenic
- has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. 
-
-
->1 Non-Identical aa change in paralogous gene(s) where a different missense change determined to be 
-Pathogenic
-or 
-Likely Pathogenic
-, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A)
-
-
-
-
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.","Disease-specific,Gene-specific,Strength"
-SCN2A (HGNC:10588),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-SCN2A (HGNC:10588),PM6,Strong,"Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-2 points
- will arrive at 
-Strong
-. Total of 
-4 points
- will arrive at 
-Very Strong
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 0.5 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Gene-specific,Strength"
-SCN2A (HGNC:10588),PM6,Moderate,"Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-1 point
- will arrive at 
-Moderate
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 0.5 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Gene-specific,Strength"
-SCN2A (HGNC:10588),PM6,Supporting,"Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-0.5 points
- will arrive at 
-Supporting
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 0.5 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Gene-specific,Strength"
-SCN2A (HGNC:10588),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-SCN2A (HGNC:10588),PP1,Strong,>=7 independent meioses,Strength
-SCN2A (HGNC:10588),PP1,Moderate,5-6 independent meioses,Strength
-SCN2A (HGNC:10588),PP1,Supporting,3-4 independent meioses,Strength
-SCN2A (HGNC:10588),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-SCN2A (HGNC:10588),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-SCN2A (HGNC:10588),PP3,Moderate,"Follow ClinGen’s recommendations (
-PMID: 36413997
-), using REVEL as the computational tool, with the following stipulations:
-
-
-
-
-Strength should be capped at Moderate, and 
-
-
-limit the combination of PP3 and PM1 to reach no higher than strong","General recommendation,Strength"
-SCN2A (HGNC:10588),PP3,Supporting,"Follow ClinGen’s recommendations (
-PMID: 36413997
-), using REVEL as the computational tool, with the following stipulations:
-
-
-
-
-Strength should be capped at Moderate, and 
-
-
-limit the combination of PP3 and PM1 to reach no higher than strong","General recommendation,Strength"
-SCN2A (HGNC:10588),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-SCN2A (HGNC:10588),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SCN2A (HGNC:10588),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-SCN2A (HGNC:10588),BA1,Stand Alone,"Allele frequency is above 
-0.01%
- is gnomAD or other large population databases, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.",Disease-specific
-SCN2A (HGNC:10588),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-SCN2A (HGNC:10588),BS1,Strong,"Allele frequency is above 0.0002% in GnomAD or other large population database, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.","Disease-specific,Gene-specific"
-SCN2A (HGNC:10588),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-SCN2A (HGNC:10588),BS2,Strong,Observed in a healthy adult individual with full penetrance expected at an early age.,No change
-SCN2A (HGNC:10588),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-SCN2A (HGNC:10588),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",NA
-SCN2A (HGNC:10588),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-SCN2A (HGNC:10588),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-SCN2A (HGNC:10588),BP2,Supporting,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,No change
-SCN2A (HGNC:10588),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-SCN2A (HGNC:10588),BP3,Supporting,In frame-deletions/insertions in a repetitive region without a known function.,No change
-SCN2A (HGNC:10588),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SCN2A (HGNC:10588),BP4,Moderate,"Follow ClinGen’s recommendations (
-PMID: 36413997
-) using REVEL as the computational tool.",General recommendation
-SCN2A (HGNC:10588),BP4,Supporting,"Follow ClinGen’s recommendations (
-PMID: 36413997
-) using REVEL as the computational tool.",General recommendation
-SCN2A (HGNC:10588),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-SCN2A (HGNC:10588),BP5,Supporting,Variant found in a case with an alternate molecular basis for disease.,No change
-SCN2A (HGNC:10588),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SCN2A (HGNC:10588),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-SCN2A (HGNC:10588),BP7,Supporting,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,No change
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN2AVersion2.0.0_version=2.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN2AVersion2.0.0_version=2.0.0.csv
deleted file mode 100644
index f5df539410261246aa209c5746f3368cce0a8ee8..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN2AVersion2.0.0_version=2.0.0.csv
+++ /dev/null
@@ -1,390 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-SCN2A (HGNC:10588),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-SCN2A (HGNC:10588),PVS1,Very Strong,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”.",No change
-SCN2A (HGNC:10588),PVS1,Strong,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”.",No change
-SCN2A (HGNC:10588),PVS1,Moderate,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”.",No change
-SCN2A (HGNC:10588),PVS1,Supporting,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”.",No change
-SCN2A (HGNC:10588),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SCN2A (HGNC:10588),PS1,Strong,"Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).
-
-
-
-
-Same amino acid change as a previously established 
-Pathogenic
- variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.
-
-
->1
- Identical amino acid change in paralogous gene previously established as 
-Pathogenic or Likely Pathogenic
-, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions.
-
-
-
-
-Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023). 
-
-
-
-
-PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (""PS1_Variants impacting splicing"").",Gene-specific
-SCN2A (HGNC:10588),PS1,Moderate,"Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).
-
-
-
-
-Same amino acid change as a previously established 
-Likely Pathogenic
- variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.
-
-
-
-
-Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).
-
-
-
-
-PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (""PS1_Variants impacting splicing"").","Gene-specific,Strength"
-SCN2A (HGNC:10588),PS1,Supporting,"Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).
-
-
-
-
-A single identical amino acid change in a paralogous gene previously established as 
-Pathogenic or Likely Pathogenic
-, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions.
-
-
-
-
-Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).
-
-
-
-
-PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (""PS1_Variants impacting splicing"").","Disease-specific,Strength"
-SCN2A (HGNC:10588),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-SCN2A (HGNC:10588),PS2,Very Strong,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-4 points
- will arrive at 
-Very Strong
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 1 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points
-
-
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN2A (HGNC:10588),PS2,Strong,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-2 points
- will arrive at 
-Strong
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 1 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points
-
-
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN2A (HGNC:10588),PS2,Moderate,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-1 point
- will arrive at 
-Moderate
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 1 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points
-
-
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN2A (HGNC:10588),PS2,Supporting,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-0.5 points
- will arrive at 
-Supporting
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 1 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points
-
-
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN2A (HGNC:10588),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-SCN2A (HGNC:10588),PS3,Strong,"In patch clamping experiments: Peak current as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is less than or equal to 72.7% of wildtype.
-
-
-In patch clamping experiments: Persistent current as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is greater than or equal to 135% of wildtype.
-
-
-In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is shifted by at least 2.2 mV (absolute value).
-
-
-In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is shifted by at least 4.1 mV (absolute value).
-
-
-Mouse knock-in model displays spontaneous seizures.","Disease-specific,Gene-specific"
-SCN2A (HGNC:10588),PS3,Moderate,"In patch clamping experiments: Peak current as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is less than or equal to 80.6% of wildtype.
-
-
-In patch clamping experiments: Persistent current as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is greater than or equal to 125% of wildtype.
-
-
-In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is shifted by at least 2.1 mV (absolute value).
-
-
-In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is shifted by at least 3.0 mV (absolute value).
-
-
-Zebrafish knock-in model displays spontaneous seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies","Gene-specific,Strength"
-SCN2A (HGNC:10588),PS3,Supporting,"Zebrafish knock-in model displays induced seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies","Gene-specific,Strength"
-SCN2A (HGNC:10588),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-SCN2A (HGNC:10588),PS4,Very Strong,"Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-16+ points
- will arrive at 
-Very Strong
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 1 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Gene-specific,Strength"
-SCN2A (HGNC:10588),PS4,Strong,"Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-4 - 15.5 points
- will arrive at 
-Strong
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 1 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Gene-specific"
-SCN2A (HGNC:10588),PS4,Moderate,"Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-2 - 3.5 points
- will arrive at 
-Moderate
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 1 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Gene-specific,Strength"
-SCN2A (HGNC:10588),PS4,Supporting,"Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-1 - 1.5 points
- will arrive at 
-Supporting
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 1 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Gene-specific,Strength"
-SCN2A (HGNC:10588),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-SCN2A (HGNC:10588),PM1,Moderate,"Variant is located within a Pathogenic Enriched Region. See specific amino acid residues noted in the attached “PM1 Table"".",Gene-specific
-SCN2A (HGNC:10588),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-SCN2A (HGNC:10588),PM2,Supporting,"One or fewer alleles, if a minimum of 10,000 alleles assessed in population databases, such as the Genome Aggregation Database (gnomAD). Caveat: Population data for indels may be poorly called by next generation sequencing.",Other
-SCN2A (HGNC:10588),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-SCN2A (HGNC:10588),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-SCN2A (HGNC:10588),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,No change
-SCN2A (HGNC:10588),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SCN2A (HGNC:10588),PM5,Strong,"Greater than or equal to 2 known pathogenic variants at same site as novel change (within the same gene).
-
-
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.","Disease-specific,Gene-specific,Strength"
-SCN2A (HGNC:10588),PM5,Moderate,"Novel missense change at an amino acid residue where a different missense change determined to be Pathogenic has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys.
-
-
-
-
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.","Disease-specific,Gene-specific"
-SCN2A (HGNC:10588),PM5,Supporting,"Novel missense change at an amino acid residue where a different missense change determined to be 
-Likely Pathogenic
- has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. 
-
-
->1 Non-Identical aa change in paralogous gene(s) where a different missense change determined to be 
-Pathogenic
-or 
-Likely Pathogenic
-, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A)
-
-
-
-
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.","Disease-specific,Gene-specific,Strength"
-SCN2A (HGNC:10588),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-SCN2A (HGNC:10588),PM6,Strong,"Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-2 points
- will arrive at 
-Strong
-. Total of 
-4 points
- will arrive at 
-Very Strong
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 0.5 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Gene-specific,Strength"
-SCN2A (HGNC:10588),PM6,Moderate,"Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-1 point
- will arrive at 
-Moderate
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 0.5 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Gene-specific,Strength"
-SCN2A (HGNC:10588),PM6,Supporting,"Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-0.5 points
- will arrive at 
-Supporting
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 0.5 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Gene-specific,Strength"
-SCN2A (HGNC:10588),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-SCN2A (HGNC:10588),PP1,Strong,>=7 independent meioses,Strength
-SCN2A (HGNC:10588),PP1,Moderate,5-6 independent meioses,Strength
-SCN2A (HGNC:10588),PP1,Supporting,3-4 independent meioses,Strength
-SCN2A (HGNC:10588),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-SCN2A (HGNC:10588),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-SCN2A (HGNC:10588),PP3,Moderate,"Follow ClinGen’s recommendations (
-PMID: 36413997
-), using REVEL as the computational tool, with the following stipulations:
-
-
-
-
-Strength should be capped at Moderate, and 
-
-
-limit the combination of PP3 and PM1 to reach no higher than strong","General recommendation,Strength"
-SCN2A (HGNC:10588),PP3,Supporting,"Follow ClinGen’s recommendations (
-PMID: 36413997
-), using REVEL as the computational tool, with the following stipulations:
-
-
-
-
-Strength should be capped at Moderate, and 
-
-
-limit the combination of PP3 and PM1 to reach no higher than strong","General recommendation,Strength"
-SCN2A (HGNC:10588),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-SCN2A (HGNC:10588),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SCN2A (HGNC:10588),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-SCN2A (HGNC:10588),BA1,Stand Alone,"Allele frequency is above 
-0.01%
- is gnomAD or other large population databases, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.",Disease-specific
-SCN2A (HGNC:10588),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-SCN2A (HGNC:10588),BS1,Strong,"Allele frequency is above 0.0002% in GnomAD or other large population database, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.","Disease-specific,Gene-specific"
-SCN2A (HGNC:10588),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-SCN2A (HGNC:10588),BS2,Strong,Observed in a healthy adult individual with full penetrance expected at an early age.,No change
-SCN2A (HGNC:10588),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-SCN2A (HGNC:10588),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",NA
-SCN2A (HGNC:10588),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-SCN2A (HGNC:10588),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-SCN2A (HGNC:10588),BP2,Supporting,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,No change
-SCN2A (HGNC:10588),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-SCN2A (HGNC:10588),BP3,Supporting,In frame-deletions/insertions in a repetitive region without a known function.,No change
-SCN2A (HGNC:10588),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SCN2A (HGNC:10588),BP4,Moderate,"Follow ClinGen’s recommendations (
-PMID: 36413997
-) using REVEL as the computational tool.",General recommendation
-SCN2A (HGNC:10588),BP4,Supporting,"Follow ClinGen’s recommendations (
-PMID: 36413997
-) using REVEL as the computational tool.",General recommendation
-SCN2A (HGNC:10588),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-SCN2A (HGNC:10588),BP5,Supporting,Variant found in a case with an alternate molecular basis for disease.,No change
-SCN2A (HGNC:10588),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SCN2A (HGNC:10588),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-SCN2A (HGNC:10588),BP7,Supporting,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,No change
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN3AVersion1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN3AVersion1.0.0_version=1.0.0.csv
deleted file mode 100644
index 9ceaefdd4548f31b92120bc7e20c885aa5a5a25c..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN3AVersion1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,423 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-SCN3A (HGNC:10590),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-SCN3A (HGNC:10590),PVS1,Very Strong,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN3A-specific information.
-
-
-Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1586. 
-
-
-In-frame exons: 1, 7, 8, 12, 17, 25
-
-
-Out-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26
-
-
-Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.
-
-
-For splice region variants, this criterion should not be applied with PP3.",General recommendation
-SCN3A (HGNC:10590),PVS1,Strong,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN3A-specific information.
-
-
-Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1586. 
-
-
-In-frame exons: 1, 7, 8, 12, 17, 25
-
-
-Out-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26
-
-
-Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.
-
-
-For splice region variants, this criterion should not be applied with PP3.",General recommendation
-SCN3A (HGNC:10590),PVS1,Moderate,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN3A-specific information.
-
-
-Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1586. 
-
-
-In-frame exons: 1, 7, 8, 12, 17, 25
-
-
-Out-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26
-
-
-Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.
-
-
-For splice region variants, this criterion should not be applied with PP3.",General recommendation
-SCN3A (HGNC:10590),PVS1,Supporting,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN3A-specific information.
-
-
-Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1586. 
-
-
-In-frame exons: 1, 7, 8, 12, 17, 25
-
-
-Out-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26
-
-
-Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.
-
-
-For splice region variants, this criterion should not be applied with PP3.",General recommendation
-SCN3A (HGNC:10590),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SCN3A (HGNC:10590),PS1,Strong,"Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).
-
-
-
-
-Same amino acid change as a previously established 
-Pathogenic
- variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.
-
-
->1
- Identical amino acid change in paralogous gene previously established as 
-Pathogenic or Likely Pathogenic
-, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions.
-
-
-
-
-Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).
-
-
-
-
-PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (""PS1_Variants impacting splicing"").",Gene-specific
-SCN3A (HGNC:10590),PS1,Moderate,"Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).
-
-
-
-
-Same amino acid change as a previously established 
-Likely Pathogenic
- variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.
-
-
-
-
-Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).
-
-
-
-
-PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (""PS1_Variants impacting splicing"").","Gene-specific,Strength"
-SCN3A (HGNC:10590),PS1,Supporting,"Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).
-
-
-
-
-A single identical amino acid change in a paralogous gene previously established as 
-Pathogenic or Likely Pathogenic
-, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A).
-
-
-
-
-Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).
-
-
-
-
-PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (""PS1_Variants impacting splicing"").",Gene-specific
-SCN3A (HGNC:10590),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-SCN3A (HGNC:10590),PS2,Very Strong,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-4 points
- will arrive at 
-Very Strong
-. 
-
-
-Developmental and Epileptic Encephalopathy: 1 point
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN3A (HGNC:10590),PS2,Strong,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-2 points
- will arrive at 
-Strong
-. 
-
-
-Developmental and Epileptic Encephalopathy: 1 point
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN3A (HGNC:10590),PS2,Moderate,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-1 point
- will arrive at 
-Moderate
-. 
-
-
-Developmental and Epileptic Encephalopathy: 1 point
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN3A (HGNC:10590),PS2,Supporting,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-0.5 points
- will arrive at 
-Supporting
-. 
-
-
-Developmental and Epileptic Encephalopathy: 1 point
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN3A (HGNC:10590),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-SCN3A (HGNC:10590),PS3,Strong,"In patch clamping experiments: Peak current as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is less than or equal to 72.7% of wildtype.
-
-
-In patch clamping experiments: Persistent current as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is greater than or equal to 135% of wildtype.
-
-
-In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is shifted by at least 2.2 mV (absolute value).
-
-
-In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is shifted by at least 4.1 mV (absolute value).
-
-
-Mouse knock-in model displays spontaneous seizures.","Disease-specific,Gene-specific"
-SCN3A (HGNC:10590),PS3,Moderate,"In patch clamping experiments: Peak current as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is less than or equal to 80.6% of wildtype.
-
-
-In patch clamping experiments: Persistent current as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is greater than or equal to 125% of wildtype.
-
-
-In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is shifted by at least 2.1 mV (absolute value).
-
-
-In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is shifted by at least 3.0 mV (absolute value).
-
-
-Mouse knock-in model displays induced seizures
-
-
-Zebrafish knock-in model displays spontaneous seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies","Gene-specific,Strength"
-SCN3A (HGNC:10590),PS3,Supporting,"Zebrafish knock-in model displays induced seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies","Gene-specific,Strength"
-SCN3A (HGNC:10590),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-SCN3A (HGNC:10590),PS4,Very Strong,"Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-16+ points
- will arrive at 
-Very Strong
-. 
-
-
-Developmental and Epileptic Encephalopathy: 1 point
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Gene-specific,Strength"
-SCN3A (HGNC:10590),PS4,Strong,"Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-4-15.5 points
- will arrive at 
-Strong
-. 
-
-
-Developmental and Epileptic Encephalopathy: 1 point
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Gene-specific,Strength"
-SCN3A (HGNC:10590),PS4,Moderate,"Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-2-3.5 points
- will arrive at 
-Moderate
-. 
-
-
-Developmental and Epileptic Encephalopathy: 1 point
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Gene-specific,Strength"
-SCN3A (HGNC:10590),PS4,Supporting,"Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-1-1.5 points
- will arrive at 
-Supporting
-. 
-
-
-Developmental and Epileptic Encephalopathy: 1 point
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Gene-specific,Strength"
-SCN3A (HGNC:10590),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-SCN3A (HGNC:10590),PM1,Moderate,"Variant is located within a Pathogenic Enriched Region. See specific amino acid residues noted in the attached “PM1 Table"".",Gene-specific
-SCN3A (HGNC:10590),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-SCN3A (HGNC:10590),PM2,Supporting,"One or fewer alleles, if a minimum of 10,000 alleles assessed in population databases, such as the Genome Aggregation Database (gnomAD). Caveat: Population data for indels may be poorly called by next generation sequencing.","General recommendation,Other"
-SCN3A (HGNC:10590),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-SCN3A (HGNC:10590),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-SCN3A (HGNC:10590),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,No change
-SCN3A (HGNC:10590),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SCN3A (HGNC:10590),PM5,Strong,"Greater than or equal to 2 known pathogenic variants at same site as novel change (within the same gene).
-
-
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.","Disease-specific,Gene-specific,Strength"
-SCN3A (HGNC:10590),PM5,Moderate,"Novel missense change at an amino acid residue where a different missense change determined to be Pathogenic has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys.
-
-
-
-
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.","Disease-specific,Gene-specific"
-SCN3A (HGNC:10590),PM5,Supporting,"Novel missense change at an amino acid residue where a different missense change determined to be 
-Likely Pathogenic
- has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. 
-
-
->1 Non-Identical aa change in paralogous gene(s) where a different missense change determined to be 
-Pathogenic
-or 
-Likely Pathogenic
-, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A)
-
-
-
-
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.","Disease-specific,Gene-specific,Strength"
-SCN3A (HGNC:10590),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-SCN3A (HGNC:10590),PM6,Strong,"Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-2 points
- will arrive at 
-Strong
-. Total of 
-4 points
- will arrive at 
-Very Strong
-. 
-
-
-Developmental and Epileptic Encephalopathy: 0.5 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Strength"
-SCN3A (HGNC:10590),PM6,Moderate,"Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-1 point
- will arrive at 
-Moderate
-. 
-
-
-Developmental and Epileptic Encephalopathy: 0.5 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Strength"
-SCN3A (HGNC:10590),PM6,Supporting,"Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-0.5 points
- will arrive at 
-Supporting
-. 
-
-
-Developmental and Epileptic Encephalopathy: 0.5 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Strength"
-SCN3A (HGNC:10590),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-SCN3A (HGNC:10590),PP1,Strong,>=7 independent meioses,Strength
-SCN3A (HGNC:10590),PP1,Moderate,5-6 independent meioses,Strength
-SCN3A (HGNC:10590),PP1,Supporting,3-4 independent meioses,Strength
-SCN3A (HGNC:10590),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-SCN3A (HGNC:10590),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-SCN3A (HGNC:10590),PP3,Moderate,"Follow ClinGen’s recommendations (
-PMID: 36413997
-), using REVEL as the computational tool, with the following stipulations:
-
-
-
-
-Strength should be capped at Moderate, and 
-
-
-limit the combination of PP3 and PM1 to reach no higher than strong","General recommendation,Strength"
-SCN3A (HGNC:10590),PP3,Supporting,"Follow ClinGen’s recommendations (
-PMID: 36413997
-), using REVEL as the computational tool, with the following stipulations:
-
-
-
-
-Strength should be capped at Moderate, and 
-
-
-limit the combination of PP3 and PM1 to reach no higher than strong","General recommendation,Strength"
-SCN3A (HGNC:10590),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-SCN3A (HGNC:10590),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SCN3A (HGNC:10590),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-SCN3A (HGNC:10590),BA1,Stand Alone,"Allele frequency is above 
-0.01%
- is gnomAD or other large population databases, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.",Disease-specific
-SCN3A (HGNC:10590),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-SCN3A (HGNC:10590),BS1,Strong,"Allele frequency is above 0.0002% in GnomAD or other large population database, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.",Disease-specific
-SCN3A (HGNC:10590),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-SCN3A (HGNC:10590),BS2,Strong,Observed in a healthy adult individual.,No change
-SCN3A (HGNC:10590),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-SCN3A (HGNC:10590),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",NA
-SCN3A (HGNC:10590),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-SCN3A (HGNC:10590),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-SCN3A (HGNC:10590),BP2,Supporting,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,No change
-SCN3A (HGNC:10590),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-SCN3A (HGNC:10590),BP3,Supporting,In frame-deletions/insertions in a repetitive region without a known function.,No change
-SCN3A (HGNC:10590),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SCN3A (HGNC:10590),BP4,Moderate,"Follow ClinGen’s recommendations (
-PMID: 36413997
-), using REVEL as the computational tool.",General recommendation
-SCN3A (HGNC:10590),BP4,Supporting,"Follow ClinGen’s recommendations (
-PMID: 36413997
-), using REVEL as the computational tool.",General recommendation
-SCN3A (HGNC:10590),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-SCN3A (HGNC:10590),BP5,Supporting,Variant found in a case with an alternate molecular basis for disease.,No change
-SCN3A (HGNC:10590),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SCN3A (HGNC:10590),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-SCN3A (HGNC:10590),BP7,Supporting,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,No change
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN3AVersion2.0.0_version=2.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN3AVersion2.0.0_version=2.0.0.csv
deleted file mode 100644
index dca299048ed544c775b2bac8e5188cb455bb9884..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN3AVersion2.0.0_version=2.0.0.csv
+++ /dev/null
@@ -1,363 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-SCN3A (HGNC:10590),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-SCN3A (HGNC:10590),PVS1,Very Strong,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”.",General recommendation
-SCN3A (HGNC:10590),PVS1,Strong,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”.",General recommendation
-SCN3A (HGNC:10590),PVS1,Moderate,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”.",General recommendation
-SCN3A (HGNC:10590),PVS1,Supporting,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”.",General recommendation
-SCN3A (HGNC:10590),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SCN3A (HGNC:10590),PS1,Strong,"Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).
-
-
-
-
-Same amino acid change as a previously established 
-Pathogenic
- variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.
-
-
->1
- Identical amino acid change in paralogous gene previously established as 
-Pathogenic or Likely Pathogenic
-, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions.
-
-
-
-
-Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).
-
-
-
-
-PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (""PS1_Variants impacting splicing"").",Gene-specific
-SCN3A (HGNC:10590),PS1,Moderate,"Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).
-
-
-
-
-Same amino acid change as a previously established 
-Likely Pathogenic
- variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.
-
-
-
-
-Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).
-
-
-
-
-PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (""PS1_Variants impacting splicing"").","Gene-specific,Strength"
-SCN3A (HGNC:10590),PS1,Supporting,"Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).
-
-
-
-
-A single identical amino acid change in a paralogous gene previously established as 
-Pathogenic or Likely Pathogenic
-, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A).
-
-
-
-
-Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).
-
-
-
-
-PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (""PS1_Variants impacting splicing"").",Gene-specific
-SCN3A (HGNC:10590),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-SCN3A (HGNC:10590),PS2,Very Strong,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-4 points
- will arrive at 
-Very Strong
-. 
-
-
-Developmental and Epileptic Encephalopathy: 1 point
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN3A (HGNC:10590),PS2,Strong,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-2 points
- will arrive at 
-Strong
-. 
-
-
-Developmental and Epileptic Encephalopathy: 1 point
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN3A (HGNC:10590),PS2,Moderate,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-1 point
- will arrive at 
-Moderate
-. 
-
-
-Developmental and Epileptic Encephalopathy: 1 point
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN3A (HGNC:10590),PS2,Supporting,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-0.5 points
- will arrive at 
-Supporting
-. 
-
-
-Developmental and Epileptic Encephalopathy: 1 point
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN3A (HGNC:10590),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-SCN3A (HGNC:10590),PS3,Strong,"In patch clamping experiments: Peak current as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is less than or equal to 72.7% of wildtype.
-
-
-In patch clamping experiments: Persistent current as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is greater than or equal to 135% of wildtype.
-
-
-In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is shifted by at least 2.2 mV (absolute value).
-
-
-In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is shifted by at least 4.1 mV (absolute value).
-
-
-Mouse knock-in model displays spontaneous seizures.","Disease-specific,Gene-specific"
-SCN3A (HGNC:10590),PS3,Moderate,"In patch clamping experiments: Peak current as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is less than or equal to 80.6% of wildtype.
-
-
-In patch clamping experiments: Persistent current as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is greater than or equal to 125% of wildtype.
-
-
-In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is shifted by at least 2.1 mV (absolute value).
-
-
-In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is shifted by at least 3.0 mV (absolute value).
-
-
-Mouse knock-in model displays induced seizures
-
-
-Zebrafish knock-in model displays spontaneous seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies","Gene-specific,Strength"
-SCN3A (HGNC:10590),PS3,Supporting,"Zebrafish knock-in model displays induced seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies","Gene-specific,Strength"
-SCN3A (HGNC:10590),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-SCN3A (HGNC:10590),PS4,Very Strong,"Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-16+ points
- will arrive at 
-Very Strong
-. 
-
-
-Developmental and Epileptic Encephalopathy: 1 point
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Gene-specific,Strength"
-SCN3A (HGNC:10590),PS4,Strong,"Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-4-15.5 points
- will arrive at 
-Strong
-. 
-
-
-Developmental and Epileptic Encephalopathy: 1 point
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Gene-specific,Strength"
-SCN3A (HGNC:10590),PS4,Moderate,"Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-2-3.5 points
- will arrive at 
-Moderate
-. 
-
-
-Developmental and Epileptic Encephalopathy: 1 point
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Gene-specific,Strength"
-SCN3A (HGNC:10590),PS4,Supporting,"Present in in multiple unrelated patients with consistent phenotype. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-1-1.5 points
- will arrive at 
-Supporting
-. 
-
-
-Developmental and Epileptic Encephalopathy: 1 point
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Gene-specific,Strength"
-SCN3A (HGNC:10590),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-SCN3A (HGNC:10590),PM1,Moderate,"Variant is located within a Pathogenic Enriched Region. See specific amino acid residues noted in the attached “PM1 Table"".",Gene-specific
-SCN3A (HGNC:10590),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-SCN3A (HGNC:10590),PM2,Supporting,"One or fewer alleles, if a minimum of 10,000 alleles assessed in population databases, such as the Genome Aggregation Database (gnomAD). Caveat: Population data for indels may be poorly called by next generation sequencing.","General recommendation,Other"
-SCN3A (HGNC:10590),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-SCN3A (HGNC:10590),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-SCN3A (HGNC:10590),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,No change
-SCN3A (HGNC:10590),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SCN3A (HGNC:10590),PM5,Strong,"Greater than or equal to 2 known pathogenic variants at same site as novel change (within the same gene).
-
-
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.","Disease-specific,Gene-specific,Strength"
-SCN3A (HGNC:10590),PM5,Moderate,"Novel missense change at an amino acid residue where a different missense change determined to be Pathogenic has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys.
-
-
-
-
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.","Disease-specific,Gene-specific"
-SCN3A (HGNC:10590),PM5,Supporting,"Novel missense change at an amino acid residue where a different missense change determined to be 
-Likely Pathogenic
- has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. 
-
-
->1 Non-Identical aa change in paralogous gene(s) where a different missense change determined to be 
-Pathogenic
-or 
-Likely Pathogenic
-, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A)
-
-
-
-
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.","Disease-specific,Gene-specific,Strength"
-SCN3A (HGNC:10590),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-SCN3A (HGNC:10590),PM6,Strong,"Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-2 points
- will arrive at 
-Strong
-. Total of 
-4 points
- will arrive at 
-Very Strong
-. 
-
-
-Developmental and Epileptic Encephalopathy: 0.5 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Strength"
-SCN3A (HGNC:10590),PM6,Moderate,"Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-1 point
- will arrive at 
-Moderate
-. 
-
-
-Developmental and Epileptic Encephalopathy: 0.5 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Strength"
-SCN3A (HGNC:10590),PM6,Supporting,"Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-0.5 points
- will arrive at 
-Supporting
-. 
-
-
-Developmental and Epileptic Encephalopathy: 0.5 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Strength"
-SCN3A (HGNC:10590),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-SCN3A (HGNC:10590),PP1,Strong,>=7 independent meioses,Strength
-SCN3A (HGNC:10590),PP1,Moderate,5-6 independent meioses,Strength
-SCN3A (HGNC:10590),PP1,Supporting,3-4 independent meioses,Strength
-SCN3A (HGNC:10590),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-SCN3A (HGNC:10590),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-SCN3A (HGNC:10590),PP3,Moderate,"Follow ClinGen’s recommendations (
-PMID: 36413997
-), using REVEL as the computational tool, with the following stipulations:
-
-
-
-
-Strength should be capped at Moderate, and 
-
-
-limit the combination of PP3 and PM1 to reach no higher than strong","General recommendation,Strength"
-SCN3A (HGNC:10590),PP3,Supporting,"Follow ClinGen’s recommendations (
-PMID: 36413997
-), using REVEL as the computational tool, with the following stipulations:
-
-
-
-
-Strength should be capped at Moderate, and 
-
-
-limit the combination of PP3 and PM1 to reach no higher than strong","General recommendation,Strength"
-SCN3A (HGNC:10590),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-SCN3A (HGNC:10590),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SCN3A (HGNC:10590),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-SCN3A (HGNC:10590),BA1,Stand Alone,"Allele frequency is above 
-0.01%
- is gnomAD or other large population databases, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.",Disease-specific
-SCN3A (HGNC:10590),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-SCN3A (HGNC:10590),BS1,Strong,"Allele frequency is above 0.0002% in GnomAD or other large population database, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.",Disease-specific
-SCN3A (HGNC:10590),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-SCN3A (HGNC:10590),BS2,Strong,Observed in a healthy adult individual.,No change
-SCN3A (HGNC:10590),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-SCN3A (HGNC:10590),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",NA
-SCN3A (HGNC:10590),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-SCN3A (HGNC:10590),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-SCN3A (HGNC:10590),BP2,Supporting,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,No change
-SCN3A (HGNC:10590),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-SCN3A (HGNC:10590),BP3,Supporting,In frame-deletions/insertions in a repetitive region without a known function.,No change
-SCN3A (HGNC:10590),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SCN3A (HGNC:10590),BP4,Moderate,"Follow ClinGen’s recommendations (
-PMID: 36413997
-), using REVEL as the computational tool.",General recommendation
-SCN3A (HGNC:10590),BP4,Supporting,"Follow ClinGen’s recommendations (
-PMID: 36413997
-), using REVEL as the computational tool.",General recommendation
-SCN3A (HGNC:10590),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-SCN3A (HGNC:10590),BP5,Supporting,Variant found in a case with an alternate molecular basis for disease.,No change
-SCN3A (HGNC:10590),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SCN3A (HGNC:10590),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-SCN3A (HGNC:10590),BP7,Supporting,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,No change
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN8AVersion1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN8AVersion1.0.0_version=1.0.0.csv
deleted file mode 100644
index 9dafcc8b786fcc78b4b3b531e841d40fc8d1817a..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN8AVersion1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,453 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-SCN8A (HGNC:10596),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-SCN8A (HGNC:10596),PVS1,Very Strong,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN8A-specific information.
-
-
-Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1582. 
-
-
-In-frame exons: 1, 7, 8, 12, 17, 19, 25
-
-
-Out-of-frame exons: 2-6, 9-11, 13-16, 18, 20-24, 26
-
-
-Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.
-
-
-For splice region variants, this criterion should not be applied with PP3.",General recommendation
-SCN8A (HGNC:10596),PVS1,Strong,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN8A-specific information.
-
-
-Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1582. 
-
-
-In-frame exons: 1, 7, 8, 12, 17, 19, 25
-
-
-Out-of-frame exons: 2-6, 9-11, 13-16, 18, 20-24, 26
-
-
-Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.
-
-
-For splice region variants, this criterion should not be applied with PP3.",General recommendation
-SCN8A (HGNC:10596),PVS1,Moderate,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN8A-specific information.
-
-
-Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1582. 
-
-
-In-frame exons: 1, 7, 8, 12, 17, 19, 25
-
-
-Out-of-frame exons: 2-6, 9-11, 13-16, 18, 20-24, 26
-
-
-Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.
-
-
-For splice region variants, this criterion should not be applied with PP3.",General recommendation
-SCN8A (HGNC:10596),PVS1,Supporting,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN8A-specific information.
-
-
-Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1582. 
-
-
-In-frame exons: 1, 7, 8, 12, 17, 19, 25
-
-
-Out-of-frame exons: 2-6, 9-11, 13-16, 18, 20-24, 26
-
-
-Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”.
-
-
-For splice region variants, this criterion should not be applied with PP3.",General recommendation
-SCN8A (HGNC:10596),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SCN8A (HGNC:10596),PS1,Strong,"Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).
-
-
-
-
-Same amino acid change as a previously established 
-Pathogenic
- variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.
-
-
->1
- Identical amino acid change in paralogous gene previously established as 
-Pathogenic or Likely Pathogenic
-, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions.
-
-
-
-
-Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).
-
-
-
-
-PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (""PS1_Variants impacting splicing"").",Gene-specific
-SCN8A (HGNC:10596),PS1,Moderate,"Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).
-
-
-
-
-Same amino acid change as a previously established 
-Likely Pathogenic
- variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.
-
-
-
-
-Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).
-
-
-
-
-PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (""PS1_Variants impacting splicing"").","Gene-specific,Strength"
-SCN8A (HGNC:10596),PS1,Supporting,"Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).
-
-
-
-
-A single identical amino acid change in a paralogous gene previously established as 
-Pathogenic or Likely Pathogenic
-, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A).
-
-
-
-
-Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).
-
-
-
-
-PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (""PS1_Variants impacting splicing"").",Gene-specific
-SCN8A (HGNC:10596),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-SCN8A (HGNC:10596),PS2,Very Strong,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-4 points
- will arrive at 
-Very Strong
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 1 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points
-
-
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN8A (HGNC:10596),PS2,Strong,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-2 points
- will arrive at 
-Strong
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 1 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points
-
-
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN8A (HGNC:10596),PS2,Moderate,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-1 point
- will arrive at 
-Moderate
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 1 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points
-
-
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN8A (HGNC:10596),PS2,Supporting,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-0.5 points
- will arrive at 
-Supporting
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 1 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points
-
-
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN8A (HGNC:10596),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-SCN8A (HGNC:10596),PS3,Strong,"In patch clamping experiments: Peak current as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is less than or equal to 72.7% of wildtype.
-
-
-In patch clamping experiments: Persistent current as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is greater than or equal to 135% of wildtype.
-
-
-In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is shifted by at least 2.2 mV (absolute value).
-
-
-In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is shifted by at least 4.1 mV (absolute value).
-
-
-Mouse knock-in model displays spontaneous seizures.","Disease-specific,Gene-specific"
-SCN8A (HGNC:10596),PS3,Moderate,"In patch clamping experiments: Peak current as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is less than or equal to 80.6% of wildtype.
-
-
-In patch clamping experiments: Persistent current as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is greater than or equal to 125% of wildtype.
-
-
-In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is shifted by at least 2.1 mV (absolute value).
-
-
-In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is shifted by at least 3.0 mV (absolute value).
-
-
-Mouse knock-in model displays induced seizures
-
-
-Zebrafish knock-in model displays spontaneous seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies","Gene-specific,Strength"
-SCN8A (HGNC:10596),PS3,Supporting,"Zebrafish knock-in model displays induced seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies","Gene-specific,Strength"
-SCN8A (HGNC:10596),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-SCN8A (HGNC:10596),PS4,Very Strong,"Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-16+ points
- will arrive at 
-Very Strong
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 1 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Gene-specific,Strength"
-SCN8A (HGNC:10596),PS4,Strong,"Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-4 - 15.5 points
- will arrive at 
-Strong
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 1 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Gene-specific,Strength"
-SCN8A (HGNC:10596),PS4,Moderate,"Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-2 - 3.5 points
- will arrive at 
-Moderate
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 1 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Gene-specific,Strength"
-SCN8A (HGNC:10596),PS4,Supporting,"Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-1 - 1.5 points
- will arrive at 
-Supporting
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 1 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Gene-specific,Strength"
-SCN8A (HGNC:10596),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-SCN8A (HGNC:10596),PM1,Moderate,"Variant is located within a Pathogenic Enriched Region. See specific amino acid residues noted in the attached “PM1 Table"".",Gene-specific
-SCN8A (HGNC:10596),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-SCN8A (HGNC:10596),PM2,Supporting,"One or fewer alleles, if a minimum of 10,000 alleles assessed in population databases, such as the Genome Aggregation Database (gnomAD). Caveat: Population data for indels may be poorly called by next generation sequencing.",Other
-SCN8A (HGNC:10596),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-SCN8A (HGNC:10596),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-SCN8A (HGNC:10596),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,No change
-SCN8A (HGNC:10596),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SCN8A (HGNC:10596),PM5,Strong,"Greater than or equal to 2 known pathogenic variants at same site as novel change (within the same gene).
-
-
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.","Disease-specific,Gene-specific,Strength"
-SCN8A (HGNC:10596),PM5,Moderate,"Novel missense change at an amino acid residue where a different missense change determined to be Pathogenic has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys.
-
-
-
-
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.","Disease-specific,Gene-specific"
-SCN8A (HGNC:10596),PM5,Supporting,"Novel missense change at an amino acid residue where a different missense change determined to be 
-Likely Pathogenic
- has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. 
-
-
->1 Non-Identical aa change in paralogous gene(s) where a different missense change determined to be 
-Pathogenic
-or 
-Likely Pathogenic
-, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A)
-
-
-
-
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.","Disease-specific,Gene-specific,Strength"
-SCN8A (HGNC:10596),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-SCN8A (HGNC:10596),PM6,Strong,"Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-2 points
- will arrive at 
-Strong
-. Total of 
-4 points
- will arrive at 
-Very Strong
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 0.5 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Gene-specific,Strength"
-SCN8A (HGNC:10596),PM6,Moderate,"Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-1 point
- will arrive at 
-Moderate
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 0.5 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Gene-specific,Strength"
-SCN8A (HGNC:10596),PM6,Supporting,"Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-0.5 points
- will arrive at 
-Supporting
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 0.5 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Gene-specific,Strength"
-SCN8A (HGNC:10596),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-SCN8A (HGNC:10596),PP1,Strong,>=7 independent meioses,Strength
-SCN8A (HGNC:10596),PP1,Moderate,5-6 independent meioses,Strength
-SCN8A (HGNC:10596),PP1,Supporting,3-4 independent meioses,Strength
-SCN8A (HGNC:10596),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-SCN8A (HGNC:10596),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-SCN8A (HGNC:10596),PP3,Moderate,"Follow ClinGen’s recommendations (
-PMID: 36413997
-), using REVEL as the computational tool, with the following stipulations:
-
-
-
-
-Strength should be capped at Moderate, and 
-
-
-limit the combination of PP3 and PM1 to reach no higher than strong","General recommendation,Strength"
-SCN8A (HGNC:10596),PP3,Supporting,"Follow ClinGen’s recommendations (
-PMID: 36413997
-), using REVEL as the computational tool, with the following stipulations:
-
-
-
-
-Strength should be capped at Moderate, and 
-
-
-limit the combination of PP3 and PM1 to reach no higher than strong","General recommendation,Strength"
-SCN8A (HGNC:10596),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-SCN8A (HGNC:10596),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SCN8A (HGNC:10596),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-SCN8A (HGNC:10596),BA1,Stand Alone,"Allele frequency is above 
-0.01%
- is gnomAD or other large population databases, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.",Disease-specific
-SCN8A (HGNC:10596),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-SCN8A (HGNC:10596),BS1,Strong,"Allele frequency is above 0.0002% in GnomAD or other large population database, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.","Disease-specific,Gene-specific"
-SCN8A (HGNC:10596),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-SCN8A (HGNC:10596),BS2,Strong,Observed in a healthy adult individual with full penetrance expected at an early age.,No change
-SCN8A (HGNC:10596),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-SCN8A (HGNC:10596),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",NA
-SCN8A (HGNC:10596),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-SCN8A (HGNC:10596),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-SCN8A (HGNC:10596),BP2,Supporting,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,No change
-SCN8A (HGNC:10596),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-SCN8A (HGNC:10596),BP3,Supporting,In frame-deletions/insertions in a repetitive region without a known function.,No change
-SCN8A (HGNC:10596),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SCN8A (HGNC:10596),BP4,Moderate,"Follow ClinGen’s recommendations (
-PMID: 36413997
-), using REVEL as the computational tool.",General recommendation
-SCN8A (HGNC:10596),BP4,Supporting,"Follow ClinGen’s recommendations (
-PMID: 36413997
-), using REVEL as the computational tool.",General recommendation
-SCN8A (HGNC:10596),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-SCN8A (HGNC:10596),BP5,Supporting,Variant found in a case with an alternate molecular basis for disease.,No change
-SCN8A (HGNC:10596),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SCN8A (HGNC:10596),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-SCN8A (HGNC:10596),BP7,Supporting,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,No change
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN8AVersion2.0.0_version=2.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN8AVersion2.0.0_version=2.0.0.csv
deleted file mode 100644
index 274421394ce77e0a596f76b14a02b50849475dd4..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN8AVersion2.0.0_version=2.0.0.csv
+++ /dev/null
@@ -1,393 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-SCN8A (HGNC:10596),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-SCN8A (HGNC:10596),PVS1,Very Strong,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”.",General recommendation
-SCN8A (HGNC:10596),PVS1,Strong,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”.",General recommendation
-SCN8A (HGNC:10596),PVS1,Moderate,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”.",General recommendation
-SCN8A (HGNC:10596),PVS1,Supporting,"Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”.",General recommendation
-SCN8A (HGNC:10596),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SCN8A (HGNC:10596),PS1,Strong,"Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).
-
-
-
-
-Same amino acid change as a previously established 
-Pathogenic
- variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.
-
-
->1
- Identical amino acid change in paralogous gene previously established as 
-Pathogenic or Likely Pathogenic
-, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions.
-
-
-
-
-Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).
-
-
-
-
-PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (""PS1_Variants impacting splicing"").",Gene-specific
-SCN8A (HGNC:10596),PS1,Moderate,"Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).
-
-
-
-
-Same amino acid change as a previously established 
-Likely Pathogenic
- variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon.
-
-
-
-
-Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).
-
-
-
-
-PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (""PS1_Variants impacting splicing"").","Gene-specific,Strength"
-SCN8A (HGNC:10596),PS1,Supporting,"Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level).
-
-
-
-
-A single identical amino acid change in a paralogous gene previously established as 
-Pathogenic or Likely Pathogenic
-, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A).
-
-
-
-
-Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023).
-
-
-
-
-PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement (""PS1_Variants impacting splicing"").",Gene-specific
-SCN8A (HGNC:10596),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-SCN8A (HGNC:10596),PS2,Very Strong,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-4 points
- will arrive at 
-Very Strong
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 1 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points
-
-
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN8A (HGNC:10596),PS2,Strong,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-2 points
- will arrive at 
-Strong
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 1 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points
-
-
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN8A (HGNC:10596),PS2,Moderate,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-1 point
- will arrive at 
-Moderate
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 1 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points
-
-
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN8A (HGNC:10596),PS2,Supporting,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-0.5 points
- will arrive at 
-Supporting
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 1 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points
-
-
-
-
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Disease-specific,Strength"
-SCN8A (HGNC:10596),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-SCN8A (HGNC:10596),PS3,Strong,"In patch clamping experiments: Peak current as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is less than or equal to 72.7% of wildtype.
-
-
-In patch clamping experiments: Persistent current as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is greater than or equal to 135% of wildtype.
-
-
-In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is shifted by at least 2.2 mV (absolute value).
-
-
-In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is shifted by at least 4.1 mV (absolute value).
-
-
-Mouse knock-in model displays spontaneous seizures.","Disease-specific,Gene-specific"
-SCN8A (HGNC:10596),PS3,Moderate,"In patch clamping experiments: Peak current as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is less than or equal to 80.6% of wildtype.
-
-
-In patch clamping experiments: Persistent current as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is greater than or equal to 125% of wildtype.
-
-
-In patch clamping experiments: Voltage dependence of activation as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is shifted by at least 2.1 mV (absolute value).
-
-
-In patch clamping experiments: Voltage dependence of inactivation as defined by FENICS ontology (
-https://bioportal.bioontology.org/ontologies/FENICS
-) is shifted by at least 3.0 mV (absolute value).
-
-
-Mouse knock-in model displays induced seizures
-
-
-Zebrafish knock-in model displays spontaneous seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies","Gene-specific,Strength"
-SCN8A (HGNC:10596),PS3,Supporting,"Zebrafish knock-in model displays induced seizures, evidenced by hyperexcitability through electrophysiology or calcium imaging-based studies","Gene-specific,Strength"
-SCN8A (HGNC:10596),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-SCN8A (HGNC:10596),PS4,Very Strong,"Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-16+ points
- will arrive at 
-Very Strong
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 1 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Gene-specific,Strength"
-SCN8A (HGNC:10596),PS4,Strong,"Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-4 - 15.5 points
- will arrive at 
-Strong
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 1 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Gene-specific,Strength"
-SCN8A (HGNC:10596),PS4,Moderate,"Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-2 - 3.5 points
- will arrive at 
-Moderate
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 1 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Gene-specific,Strength"
-SCN8A (HGNC:10596),PS4,Supporting,"Present in multiple unrelated patients with consistent phenotypes and absent in controls. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-1 - 1.5 points
- will arrive at 
-Supporting
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 1 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Gene-specific,Strength"
-SCN8A (HGNC:10596),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-SCN8A (HGNC:10596),PM1,Moderate,"Variant is located within a Pathogenic Enriched Region. See specific amino acid residues noted in the attached “PM1 Table"".",Gene-specific
-SCN8A (HGNC:10596),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-SCN8A (HGNC:10596),PM2,Supporting,"One or fewer alleles, if a minimum of 10,000 alleles assessed in population databases, such as the Genome Aggregation Database (gnomAD). Caveat: Population data for indels may be poorly called by next generation sequencing.",Other
-SCN8A (HGNC:10596),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-SCN8A (HGNC:10596),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-SCN8A (HGNC:10596),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,No change
-SCN8A (HGNC:10596),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SCN8A (HGNC:10596),PM5,Strong,"Greater than or equal to 2 known pathogenic variants at same site as novel change (within the same gene).
-
-
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.","Disease-specific,Gene-specific,Strength"
-SCN8A (HGNC:10596),PM5,Moderate,"Novel missense change at an amino acid residue where a different missense change determined to be Pathogenic has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys.
-
-
-
-
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.","Disease-specific,Gene-specific"
-SCN8A (HGNC:10596),PM5,Supporting,"Novel missense change at an amino acid residue where a different missense change determined to be 
-Likely Pathogenic
- has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. 
-
-
->1 Non-Identical aa change in paralogous gene(s) where a different missense change determined to be 
-Pathogenic
-or 
-Likely Pathogenic
-, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A)
-
-
-
-
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.","Disease-specific,Gene-specific,Strength"
-SCN8A (HGNC:10596),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-SCN8A (HGNC:10596),PM6,Strong,"Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-2 points
- will arrive at 
-Strong
-. Total of 
-4 points
- will arrive at 
-Very Strong
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 0.5 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Gene-specific,Strength"
-SCN8A (HGNC:10596),PM6,Moderate,"Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-1 point
- will arrive at 
-Moderate
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 0.5 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Gene-specific,Strength"
-SCN8A (HGNC:10596),PM6,Supporting,"Assumed de novo, but without confirmation of paternity and maternity. Points based system for each unrelated proband determined by phenotypic specificity. Total of 
-0.5 points
- will arrive at 
-Supporting
-. 
-
-
-
-
-Complex Neurodevelopmental Disorder: 0.5 points
-
-
-Other phenotypes not consistent w/neurodevelopmental disorder: 0 points","Disease-specific,Gene-specific,Strength"
-SCN8A (HGNC:10596),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-SCN8A (HGNC:10596),PP1,Strong,>=7 independent meioses,Strength
-SCN8A (HGNC:10596),PP1,Moderate,5-6 independent meioses,Strength
-SCN8A (HGNC:10596),PP1,Supporting,3-4 independent meioses,Strength
-SCN8A (HGNC:10596),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-SCN8A (HGNC:10596),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-SCN8A (HGNC:10596),PP3,Moderate,"Follow ClinGen’s recommendations (
-PMID: 36413997
-), using REVEL as the computational tool, with the following stipulations:
-
-
-
-
-Strength should be capped at Moderate, and 
-
-
-limit the combination of PP3 and PM1 to reach no higher than strong","General recommendation,Strength"
-SCN8A (HGNC:10596),PP3,Supporting,"Follow ClinGen’s recommendations (
-PMID: 36413997
-), using REVEL as the computational tool, with the following stipulations:
-
-
-
-
-Strength should be capped at Moderate, and 
-
-
-limit the combination of PP3 and PM1 to reach no higher than strong","General recommendation,Strength"
-SCN8A (HGNC:10596),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-SCN8A (HGNC:10596),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SCN8A (HGNC:10596),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-SCN8A (HGNC:10596),BA1,Stand Alone,"Allele frequency is above 
-0.01%
- is gnomAD or other large population databases, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.",Disease-specific
-SCN8A (HGNC:10596),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-SCN8A (HGNC:10596),BS1,Strong,"Allele frequency is above 0.0002% in GnomAD or other large population database, must be greater than or equal to 5 alleles if a minimum of 10,000 alleles was assessed.","Disease-specific,Gene-specific"
-SCN8A (HGNC:10596),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-SCN8A (HGNC:10596),BS2,Strong,Observed in a healthy adult individual with full penetrance expected at an early age.,No change
-SCN8A (HGNC:10596),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-SCN8A (HGNC:10596),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",NA
-SCN8A (HGNC:10596),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-SCN8A (HGNC:10596),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-SCN8A (HGNC:10596),BP2,Supporting,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,No change
-SCN8A (HGNC:10596),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-SCN8A (HGNC:10596),BP3,Supporting,In frame-deletions/insertions in a repetitive region without a known function.,No change
-SCN8A (HGNC:10596),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SCN8A (HGNC:10596),BP4,Moderate,"Follow ClinGen’s recommendations (
-PMID: 36413997
-), using REVEL as the computational tool.",General recommendation
-SCN8A (HGNC:10596),BP4,Supporting,"Follow ClinGen’s recommendations (
-PMID: 36413997
-), using REVEL as the computational tool.",General recommendation
-SCN8A (HGNC:10596),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-SCN8A (HGNC:10596),BP5,Supporting,Variant found in a case with an alternate molecular basis for disease.,No change
-SCN8A (HGNC:10596),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SCN8A (HGNC:10596),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-SCN8A (HGNC:10596),BP7,Supporting,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,No change
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenFBN1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenFBN1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
deleted file mode 100644
index 1213778716874a0dfd4248708633cc553d85a04f..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenFBN1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
+++ /dev/null
@@ -1,190 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-FBN1 (HGNC:3603),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-FBN1 (HGNC:3603),PVS1,Very Strong,"Nonsense/frameshift variants predicted to undergo NMD (not affecting last exon or 55 last nt of penultimate exon).
-
-
-1,2 splice site variants leading to exon skipping or use of a cryptic splice site disrupting the reading frame and predicted to undergo NMD.
-
-
-Full gene deletion.
-
-
-Single to multi-exon deletion disrupting the reading frame and predicted to undergo NMD.
-
-
-Duplication (>=1 exon in size and completely contained within gene) proven in tandem and disrupting the reading frame and predicted to undergo NMD.",Disease-specific
-FBN1 (HGNC:3603),PVS1,Strong,"Nonsense/frameshift variants predicted to escape NMD (affecting last exon, last 55nt of the penultimate exon).
-
-
-1,2 splice site variants leading to exon skipping or use of a cryptic splice site disrupting the reading frame and predicted to escape NMD.
-
-
-1,2 splice site variants leading to exon skipping or use of a cryptic splice site but preserving the reading frame.
-
-
-Single to multi-exon deletion disrupting the reading frame and predicted to escape NMD.
-
-
-Single to multi-exon deletion preserving the reading frame.
-
-
-Duplication (>=1 exon in size and completely contained within gene) presumed in tandem and presumably disrupting the reading frame and predicted to escape NMD.",Strength
-FBN1 (HGNC:3603),PVS1,Moderate,Initiation codon variant with 1 or more pathogenic variant(s) upstream of closest potential in-frame start codon.,Strength
-FBN1 (HGNC:3603),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-FBN1 (HGNC:3603),PS1,Strong,"Beware of changes that impact splicing rather than the amino acid. Splicing predictions should remain the same for WT and mutant alleles.
-
-
-Original variant should be pathogenic according to the (modified) ACMG guidelines for variant classification.",None
-FBN1 (HGNC:3603),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-FBN1 (HGNC:3603),PS2,Very Strong,Four points,Strength
-FBN1 (HGNC:3603),PS2,Strong,Two-three points,Disease-specific
-FBN1 (HGNC:3603),PS2,Moderate,One point,Strength
-FBN1 (HGNC:3603),PS2,Supporting,0.5 points,Strength
-FBN1 (HGNC:3603),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-FBN1 (HGNC:3603),PS3,Strong,Follow the ‘Funtional Assay SVI Documentation’,Disease-specific
-FBN1 (HGNC:3603),PS3,Moderate,Follow the ‘Funtional Assay SVI Documentation’,Strength
-FBN1 (HGNC:3603),PS3,Supporting,Use the ‘Funtional Assay SVI Documentation’.,Strength
-FBN1 (HGNC:3603),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-FBN1 (HGNC:3603),PS4,Strong,If ≥ 4 points.,Disease-specific
-FBN1 (HGNC:3603),PS4,Moderate,If 2-3.5 points.,Strength
-FBN1 (HGNC:3603),PS4,Supporting,If 1-1.5 points.,Strength
-FBN1 (HGNC:3603),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-FBN1 (HGNC:3603),PM1,Strong,"Cys residues in cbEGF-like domains
-
-
-Add caveat: PM5/PS1 should not be used when this argument applies.",Strength
-FBN1 (HGNC:3603),PM1,Moderate,"Cys in EGF-like domain, Cys in TB domain, Cys in hybrid domain, (D/N)-X-(D/N)-(E/Q)-Xm-(D/N)-Xn-(Y/F) substitution in cbEGF-like domain, invariant calcium-binding or hydroxylation residue in cbEGF-like domain, critical Gly between Cys2-Cys3 in cbEGF-like domain, Gly between Cys3-Cys4 if there is an upstream cbEGF domain, Cys-creating variants.
-
-
-Add caveat: N to S substitution in the second N of de consensus sequence and G to A might be tolerated, PM1 should not be used in these cases.",Disease-specific
-FBN1 (HGNC:3603),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-FBN1 (HGNC:3603),PM2,Supporting,"Threshold: <5.0E-6 (<0.0005%).
-
-
-Use the highest ethnic population allele frequency.
-
-
-Caveat: PVS1 + PM2_Supportive may reach Likely Pathogenic.
-
-
-Caveat: Do not use Finnish, Ashkenazi Jewish, or “Other” populations in gnomAD.
-
-
-Minimum amount of studied alleles should be 2000.",Strength
-FBN1 (HGNC:3603),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-FBN1 (HGNC:3603),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-FBN1 (HGNC:3603),PM4,Moderate,Add caveat: cannot be applied simultaneously with PVS1 (at any strength level),None
-FBN1 (HGNC:3603),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-FBN1 (HGNC:3603),PM5,Moderate,"Add caveat: Use argument with caution when the original missense variant created a cysteine especially in a cbEGFlike domain (cfr PM1_strong) as this may increase the
-pathogenicity level of this variant improperly.
-
-
-Add caveat: original variant should be pathogenic according to the (modified) ACMG guidelines for variant classification.",None
-FBN1 (HGNC:3603),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-FBN1 (HGNC:3603),PM6,Very Strong,4 points,Strength
-FBN1 (HGNC:3603),PM6,Strong,2-3 points.,Disease-specific
-FBN1 (HGNC:3603),PM6,Moderate,1 point.,Disease-specific
-FBN1 (HGNC:3603),PM6,Supporting,0.5 points.,Strength
-FBN1 (HGNC:3603),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-FBN1 (HGNC:3603),PP1,Strong,≥5 affected individuals.,Strength
-FBN1 (HGNC:3603),PP1,Moderate,4 affected individuals.,Strength
-FBN1 (HGNC:3603),PP1,Supporting,2-3 affected individuals.,Disease-specific
-FBN1 (HGNC:3603),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,
-FBN1 (HGNC:3603),PP2,Supporting,"Add caveat: if this argument is used pro-pathogenicity, there must be other arguments supporting pathogenicity, and no arguments supporting a benign assertion.",None
-FBN1 (HGNC:3603),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-FBN1 (HGNC:3603),PP3,Supporting,"Recommended prediction program for missense variants: REVEL. Use 0.75 as a discriminatory cut-off value.
-
-
-Recommended prediction programs for splice variants: GeneSplicer, MaxEntscan, and NNSPLICE. The outcome of all 3 prediction programs need to be in concordance.",Disease-specific
-FBN1 (HGNC:3603),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-FBN1 (HGNC:3603),PP4,Supporting,"Use if patient fulfils revised Ghent criteria.
-
-
-Can be used if any of the family members have a highly specific phenotype.",Disease-specific
-FBN1 (HGNC:3603),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-FBN1 (HGNC:3603),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-FBN1 (HGNC:3603),BA1,Stand Alone,"Allele frequency above 0.1% in ExAc and gnomAD
-
-
-
-
-Use the ethnic population with the highest allele frequency.
-
-
-Caveat: Do not use Finnish, Ashkenazi Jewish, or “Other” populations in gnomAD.
-
-
-Minimum amount of studied alleles should be 2000.",Disease-specific
-FBN1 (HGNC:3603),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-FBN1 (HGNC:3603),BS1,Strong,"Allele frequency greater than expected for disease (>0.005%).
-
-
-
-
-Use the ethnic population with the highest allele frequency.
-
-
-Caveat: Do not use Finnish, Ashkenazi Jewish, or “Other” populations in gnomAD.
-
-
-Minimum amount of studied alleles should be 2000.",Disease-specific
-FBN1 (HGNC:3603),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",NA
-FBN1 (HGNC:3603),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-FBN1 (HGNC:3603),BS3,Strong,"Use the ‘Funtional Assay SVI Documentation’ (
-https://clinicalgenome.org/workinggroups/sequence-variant-interpretation/
-).
-For step 2 assessment.
-
-
-
-
-Functional studies deemed appropriate:
-
-
-cDNA analyses showing altered FBN1 sequence.
-
-
-Functional studies showing altered FBN1 protein or RNA expression, proteolysis, folding, assembly, trafficking, secretion, Ca2+ binding, matrix deposition (cfr Dave Hollister assay), microfibril fragmentation/catabolism in an in vitro engineered system.
-
-
-Functional studies NOT deemed appropriate: non-specific altered TGF-beta signaling or histological hallmarks of medial degeneration, which are associated with many other types of variants in genes that are associated with MFS or HTAAD in general.
-For step 3 assessment: Studies should be performed in the presence of NMD inhibitor.",None
-FBN1 (HGNC:3603),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-FBN1 (HGNC:3603),BS4,Strong,Caution is warranted when the phenotype is not highly specific. Lack of segregation should then be clear in >1 affected family member.,None
-FBN1 (HGNC:3603),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-FBN1 (HGNC:3603),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-FBN1 (HGNC:3603),BP2,Supporting,"Observed in trans in multiple cases (+2) with co-occuring pathogenic variants and phenotype is not more severe than when seen in isolation.
-
-
-Observed in cis with a pathogenic variant, if the pathogenic variant has been seen in isolation in a patient with the disease phenotype.",Disease-specific
-FBN1 (HGNC:3603),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-FBN1 (HGNC:3603),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-FBN1 (HGNC:3603),BP4,Supporting,"Recommended prediction program for missense variants: REVEL. Use 0.326 as a discriminatory cut-off value.
-
-
-Recommended prediction programs for splice variants: GeneSplicer, MaxEntscan, and NNSPLICE. The outcome of all 3 prediction programs need to be in concordance.",Disease-specific
-FBN1 (HGNC:3603),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-FBN1 (HGNC:3603),BP5,Supporting,Variant found in a case with an alternate molecular basis for disease.,None
-FBN1 (HGNC:3603),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-FBN1 (HGNC:3603),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-FBN1 (HGNC:3603),BP7,Supporting,"A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
-BP7 applicable as described.",None
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenFamilialHypercholesterolemiaExpertPanelSpecificationstotheACMGAMPVariantClassificationGuidelinesVersion1.2_version=1.2.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenFamilialHypercholesterolemiaExpertPanelSpecificationstotheACMGAMPVariantClassificationGuidelinesVersion1.2_version=1.2.0.csv
deleted file mode 100644
index c96d6aff1693d31f0ec0ff953476f220f1fe1baf..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenFamilialHypercholesterolemiaExpertPanelSpecificationstotheACMGAMPVariantClassificationGuidelinesVersion1.2_version=1.2.0.csv
+++ /dev/null
@@ -1,105 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-LDLR (HGNC:6547),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-LDLR (HGNC:6547),PVS1,Very Strong,See PVS1 flow diagram (Figure 1).,"Disease-specific,Strength"
-LDLR (HGNC:6547),PVS1,Strong,See PVS1 flow diagram (Figure 1).,"Disease-specific,Strength"
-LDLR (HGNC:6547),PVS1,Moderate,See PVS1 flow diagram (Figure 1).,"Disease-specific,Strength"
-LDLR (HGNC:6547),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-LDLR (HGNC:6547),PS1,Strong,"Missense variant at the same codon as a variant classified pathogenic (by these guidelines), and predicts the same amino acid change.
-Caveat: there is no in silico predicted splicing impact for either variant.",Clarification
-LDLR (HGNC:6547),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-LDLR (HGNC:6547),PS2,Strong,"Variant is de novo in a patient with the disease and no family history. Follow SVI guidance for de novo occurrences: 
-https://clinicalgenome.org/working-groups/sequence-variant-interpretation/",Clarification
-LDLR (HGNC:6547),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-LDLR (HGNC:6547),PS3,Strong,"Variant meets Level 1 pathogenic functional study criteria. See Table 3.
-(1) Study of the whole LDLR cycle (LDLR expression/biosynthesis, LDL binding, and LDL internalization) performed in heterologous cells (with noendogenous LDLR) transfected with mutant plasmid. Assay result of <70% ofwild-type activity in either expression/biosynthesis, binding OR internalization.","Disease-specific,Strength"
-LDLR (HGNC:6547),PS3,Moderate,"Variant meets Level 2 pathogenic functional study criteria. See Table 3.
-(1) Study of a) only part of the LDLR cycle following Level 1 methodology, or b) whole or part of the LDLR cycle in true homozygous patient cells. A variant with assay results of <70% of wild type activity in either LDLR expression/biosynthesis, LDL binding OR internalization.
-(2) RNA studies, using RNA extracted from heterozygous or true homozygous patient cells, where aberrant transcript is confirmed by sequencing and is quantified as >25% of total transcript from heterozygous cells or 50% of total transcript from homozygous cells.
-(3) Variants with two or more Level 3 functional studies (must be different assays); or any Level 3 functional study #1-4 performed by two or more independent labs with concordant results.","Disease-specific,Strength"
-LDLR (HGNC:6547),PS3,Supporting,"Variant meets Level 3 pathogenic functional study criteria. See Table 3.
- (1) Study of LDLR cycle (whole or part) in heterozygous patient cells, with assay results of <85% of wild-type activity in either LDLR expression/biosynthesis, LDL binding OR internalization.
- (2) Luciferase studies with transcription levels of <50% compared to wild-type (applicable to 5’UTR/promoter variants).
- (3) Minigene splicing assays with <10% wild-type transcript present where anaberrant transcript from the candidate variant is confirmed by sequencing.
- (4) High-throughput assays, which include alternative microscopy assays (e.g.,Thormaehlen et al., 2015), Multiplex Assays of Variant Effect (MAVE) (e.g.,Weile & Roth, 2018) and deep mutational scanning assays, can be considered here, only if assay has been validated with a minimum of four pathogenic and four benign variant controls in LDLR. Note: % activity thresholds will be defined by the FH VCEP as more data becomes available.
- (5) RNA studies, using RNA extracted from heterozygous or homozygous patient cells, with aberrant transcript confirmed by sequencing (but without transcript quantification).","Disease-specific,Strength"
-LDLR (HGNC:6547),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-LDLR (HGNC:6547),PS4,Strong,"Variant is found in ≥10 unrelated FH cases (FH diagnosis met by validated clinical criteria).
-Caveat: variant must also meet PM2","Disease-specific,Strength"
-LDLR (HGNC:6547),PS4,Moderate,"Variant is found in 6-9 unrelated FH cases (FH diagnosis made by validated clinical criteria).
-Caveat: variant must also meet PM2.","Disease-specific,Strength"
-LDLR (HGNC:6547),PS4,Supporting,"Variant is found in 2-5 unrelated FH cases (FH diagnosis made by validated clinical criteria).
-Caveat: variant must also meet PM2.","Disease-specific,Strength"
-LDLR (HGNC:6547),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-LDLR (HGNC:6547),PM1,Moderate,"Missense variant located in exon 4, or a missense change in one of 60 highly conserved cysteine residues (listed in Supp. Table 4). Caveat: variant must also meet PM2.",Disease-specific
-LDLR (HGNC:6547),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-LDLR (HGNC:6547),PM2,Moderate,Variant has a PopMax MAF ≤0.0002 (0.02%) in gnomAD. Consider exceptions for known founder variants.,Disease-specific
-LDLR (HGNC:6547),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-LDLR (HGNC:6547),PM3,Moderate,"This criterion can be used for a candidate LDLR variant observed in an individual with a homozygous FH phenotype when there is only one other pathogenic or likely pathogenic variant in LDLR (in trans), APOB or PCSK9. Caveat: variant must also meet PM2.",Disease-specific
-LDLR (HGNC:6547),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-LDLR (HGNC:6547),PM4,Moderate,"In-frame deletion/insertions smaller than one whole exon, or in-frame whole-exon duplications not considered in any PVS1 criteria.
-Caveat: variant must also meet PM2.",Disease-specific
-LDLR (HGNC:6547),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-LDLR (HGNC:6547),PM5,Strong,"Missense variant at a codon with ≥2 missense variants classified pathogenic (by these guidelines), and predicts a different amino acid change.",Strength
-LDLR (HGNC:6547),PM5,Moderate,"Missense variant at the same codon as a variant classified pathogenic (by these guidelines), and predicts a different amino acid change.",
-LDLR (HGNC:6547),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-LDLR (HGNC:6547),PM6,Moderate,See PS2 above.,Clarification
-LDLR (HGNC:6547),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-LDLR (HGNC:6547),PP1,Strong,Variant segregates with phenotype in ≥6 informative meioses in ≥1 family. Must include ≥2 affected relatives (LDL-C >75th centile) with the variant.,"Disease-specific,Strength"
-LDLR (HGNC:6547),PP1,Moderate,Variant segregates with phenotype in 4-5 informative meioses in ≥1 family. Must include ≥2 affected relatives (LDL-C >75th centile) with the variant.,"Disease-specific,Strength"
-LDLR (HGNC:6547),PP1,Supporting,Variant segregates with phenotype in 2-3 informative meioses in ≥1 family. Must include ≥1 affected relative (LDL-C >75th centile) with the variant.,"Disease-specific,Strength"
-LDLR (HGNC:6547),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-LDLR (HGNC:6547),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-LDLR (HGNC:6547),PP3,Supporting,"REVEL score ≥0.75 (missense variants), or predicted impact to splicing using MaxEntScan (see Fig. 2 for suggested thresholds).",Disease-specific
-LDLR (HGNC:6547),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-LDLR (HGNC:6547),PP4,Supporting,"Any LDLR variant identified in an FH patient [diagnosis based on validated clinical criteria, e.g. Dutch Lipid Clinic Network (≥6), Simon Broome possible/definite), MEDPED], after alternative causes of high cholesterol are excluded.
-Caveat: variant must also meet PM2.",Disease-specific
-LDLR (HGNC:6547),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-LDLR (HGNC:6547),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-LDLR (HGNC:6547),BA1,Stand Alone,Variant has a PopMax FAF ≥0.005 (0.5%) in gnomAD.,Disease-specific
-LDLR (HGNC:6547),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-LDLR (HGNC:6547),BS1,Strong,Variant has a PopMax FAF ≥0.002 (0.2%) in gnomAD.,Disease-specific
-LDLR (HGNC:6547),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-LDLR (HGNC:6547),BS2,Strong,"Variant is identified in ≥3 heterozygous or ≥1 homozygous well-phenotyped, untreated, normolipidemic adults (unrelated).",Disease-specific
-LDLR (HGNC:6547),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-LDLR (HGNC:6547),BS3,Strong,"Variant meets Level 1 benign functional study criteria. See Table 3.
-(1) Study of the whole LDLR cycle (LDLR expression/biosynthesis, LDL binding, and LDL internalization) performed in heterologous cells (with no endogenous LDLR) transfected with mutant plasmid. Assay result of >90% of wild-type activity in expression/biosynthesis, binding AND internalization.
-Note: studies of only part of the LDLR cycle are not eligible for BS3 or BS3_Supporting.","Disease-specific,Strength"
-LDLR (HGNC:6547),BS3,Supporting,"Variant meets Level 3 benign functional study criteria. See Table 3.
-(1) Study of whole LDLR cycle in a) true homozygous patient cells, with assay result of >90% of wild-type activity in biosynthesis, binding AND internalization; or in b) heterozygous patient cells with assay result of >95% of wild-type activity in biosynthesis, binding AND internalization.
-(2) Luciferase studies with transcription levels of >90% when compared to wild-type (applicable to 5’UTR/promoter variants).
-(3) RNA studies, using RNA extracted from heterozygous or homozygous patientcells, with a) aberrant transcripts quantification, where aberrant transcript is<10% of total transcript OR b) without transcript quantification where noaberrant transcript is confirmed by sequencing.
-(4) Minigene splicing assay where only wild-type transcript is present and confirmed by sequencing.
-(5) High-throughput assays as defined above; only applicable when assay canindicate the whole LDLR cycle (LDLR expression/biosynthesis, LDL binding AND internalization) is unaffected.","Disease-specific,Strength"
-LDLR (HGNC:6547),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-LDLR (HGNC:6547),BS4,Strong,"Lack of segregation in ≥2 index case families (unrelated), when data is available for ≥2 informative meioses in each family.
-Caveat: must be ≥1 unaffected relative (LDL-C <50th centile) who is positive for the variant.",Disease-specific
-LDLR (HGNC:6547),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-LDLR (HGNC:6547),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-LDLR (HGNC:6547),BP2,Supporting,"If a FH patient with a heterozygous phenotype has a pathogenic or likely pathogenic variant in LDLR (in trans), APOB or PCSK9, BP2 is applicable to any additional LDLR variants.",Disease-specific
-LDLR (HGNC:6547),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-LDLR (HGNC:6547),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-LDLR (HGNC:6547),BP4,Supporting,"REVEL score ≤0.5 (missense variants), or no predicted impact to splicing using MaxEntScan (see Fig. 2 for suggested thresholds).",Disease-specific
-LDLR (HGNC:6547),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-LDLR (HGNC:6547),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-LDLR (HGNC:6547),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-LDLR (HGNC:6547),BP7,Supporting,"Variant is synonymous.
-Caveat: variant must also meet BP4 (i.e. no predicted impact on splicing).",Disease-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenGlaucomaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1_version=1.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenGlaucomaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1_version=1.1.0.csv
deleted file mode 100644
index 9bce1234dba670449693e3f33f4064ddf2f1f12c..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenGlaucomaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1_version=1.1.0.csv
+++ /dev/null
@@ -1,307 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-MYOC (HGNC:7610),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-MYOC (HGNC:7610),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MYOC (HGNC:7610),PS1,Strong,The novel change must not affect splicing (SpliceAI ≤ 0.2).,
-MYOC (HGNC:7610),PS1,Moderate,"Same amino acid change as a previously established likely pathogenic variant
-
-
-
-
-The novel change must not affect splicing (SpliceAI ≤ 0.2).",
-MYOC (HGNC:7610),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-MYOC (HGNC:7610),PS2,Strong,"≥2 confirmed de novo in JOAG.
-Use the proposed SVI point recommendations for “phenotype consistent with gene but not highly specific” for JOAG.
-
-
-
-
-Both maternity and paternity need to be proven for confirmed de novo variants.
-
-
-Parents need to be clinically assessed and not have a diagnosis of glaucoma.",
-MYOC (HGNC:7610),PS2,Moderate,"≥2 confirmed de novo in POAG or 1 confirmed de novo in JOAG
-Use proposed SVI point recommendations for “phenotype consistent with the gene but not highly specific and with high genetic heterogeneity” for POAG and “phenotype consistent with gene but not highly specific” for JOAG.
-
-
-
-
-Both maternity and paternity need to be proven for confirmed de novo variants.
-
-
-Parents need to be clinically assessed and not have a diagnosis of glaucoma.",
-MYOC (HGNC:7610),PS2,Supporting,"1 confirmed de novo in POAG.
-Use proposed SVI point recommendations for “phenotype consistent with the gene but not highly specific and with high genetic heterogeneity” for POAG. 
-
-
-
-
-Both maternity and paternity need to be proven for confirmed de novo variants. 
-
-
-Parents need to be clinically assessed and not have a diagnosis of glaucoma.",
-MYOC (HGNC:7610),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-MYOC (HGNC:7610),PS3,Strong,"Assays with OddsPath >18.7 as per the SVI recommendations.
-
-
-
-
-Applies to the following functional studies: Solubility or secretion assays OR animal models that replicate the glaucoma phenotype.
-
-
-PS3 should only be applied if the assay includes both negative and positive controls and includes technical and/or biological replicates.
-
-
-If multiple results from functional assays are available for a single variant, then the evidence from the assay that is best validated should apply.
-
-
-Controls from the same general class of assay can be combined to calculate the odds of pathogenicity (OddsPath) as per the published SVI recommendations.
-
-
-If results from different assays are conflicting for a single variant, then the level of validation of each assay should be considered to decide whether the results from one assay can override the results from another.",
-MYOC (HGNC:7610),PS3,Moderate,"Assays with OddsPath >4.3 as per the SVI recommendations
-
-
-
-
-Applies to the following functional studies: Solubility or secretion assays OR animal models that replicate the glaucoma phenotype.
-
-
-PS3 should only be applied if the assay includes both negative and positive controls and includes technical and/or biological replicates.
-
-
-If multiple results from functional assays are available for a single variant, then the evidence from the assay that is best validated should apply.
-
-
-Controls from the same general class of assay can be combined to calculate the odds of pathogenicity (OddsPath) as per the published SVI recommendations.
-
-
-If results from different assays are conflicting for a single variant, then the level of validation of each assay should be considered to decide whether the results from one assay can override the results from another.",
-MYOC (HGNC:7610),PS3,Supporting,"Assays with OddsPath >2.1 as per the SVI recommendations.
-
-
-
-
-Applies to the following functional studies: Solubility or secretion assays OR animal models that replicate the glaucoma phenotype.
-
-
-PS3 should only be applied if the assay includes both negative and positive controls and includes technical and/or biological replicates.
-
-
-If multiple results from functional assays are available for a single variant, then the evidence from the assay that is best validated should apply.
-
-
-Controls from the same general class of assay can be combined to calculate the odds of pathogenicity (OddsPath) as per the published SVI recommendations.
-
-
-If results from different assays are conflicting for a single variant, then the level of validation of each assay should be considered to decide whether the results from one assay can override the results from another.",
-MYOC (HGNC:7610),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-MYOC (HGNC:7610),PS4,Strong,"≥ 15 probands from multiple independent studies.
-
-
-
-
-Probands counted should be clinically assessed and have a diagnosis of JOAG or POAG.
-
-
-PM2_Supporting must be met.",
-MYOC (HGNC:7610),PS4,Moderate,"≥ 6 probands from multiple independent studies.
-
-
-
-
-Probands counted should be clinically assessed and have a diagnosis of JOAG or POAG.
-
-
-PM2_Supporting must be met.",
-MYOC (HGNC:7610),PS4,Supporting,"≥ 2 probands from multiple independent studies.
-
-
-
-
-Probands counted should be clinically assessed and have a diagnosis of JOAG or POAG.
-
-
-PM2_Supporting must be met.",
-MYOC (HGNC:7610),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-MYOC (HGNC:7610),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-MYOC (HGNC:7610),PM2,Supporting,"Allele frequency ≤ 0.0001 in population databases.
-
-
-
-
-The highest allele frequency in population databases should be used. 
-
-
-Only applies to populations of ≥ 10,000 alleles.",
-MYOC (HGNC:7610),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-MYOC (HGNC:7610),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-MYOC (HGNC:7610),PM4,Moderate,In-frame del/ins and truncating variants involving >10% of the protein and located within the conserved olfactomedin domain (AA 246-502).,
-MYOC (HGNC:7610),PM4,Supporting,In-frame del/ins and truncating variants involving ≤10% of the protein and located within the conserved olfactomedin domain (AA 246-502).,
-MYOC (HGNC:7610),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MYOC (HGNC:7610),PM5,Moderate,"Same residue as a previously established pathogenic variant (assessed independently of PM5) or 2 previously established likely pathogenic variants (both assessed independently of PM5)
-
-
-
-
-The novel change must not affect splicing (SpliceAI ≤ 0.2), must meet PP3 and have a Grantham score equal or greater than the previously established P/LP variants.",
-MYOC (HGNC:7610),PM5,Supporting,"Same residue as a previously established likely pathogenic variant (assessed independently of PM5).
-
-
-
-
-The novel change must not affect splicing (SpliceAI ≤ 0.2), must meet PP3 and have a Grantham score equal or greater than the previously established P/LP variants.",
-MYOC (HGNC:7610),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-MYOC (HGNC:7610),PM6,Moderate,"≥2 assumed de novo in JOAG.
-Use proposed SVI point recommendations for “phenotype consistent with gene but not highly specific” for JOAG.
-
-
-
-
-Both maternity and paternity need to be proven for confirmed de novo variants.
-
-
-Parents need to be clinically assessed and not have a diagnosis of glaucoma.",
-MYOC (HGNC:7610),PM6,Supporting,"≥2 assumed de novo in POAG or 1 assumed de novo in JOAG
-Use proposed SVI point recommendations for “phenotype consistent with the gene but not highly specific and with high genetic heterogeneity” for POAG and “phenotype consistent with gene but not highly specific” for JOAG.
-
-
-
-
-Both maternity and paternity need to be proven for confirmed de novo variants.
-
-
-Parents need to be clinically assessed and not have a diagnosis of glaucoma.",
-MYOC (HGNC:7610),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-MYOC (HGNC:7610),PP1,Strong,"≥7 meioses in >1 family.
-
-
-
-
-BA1 and BS1 must not be met.
-
-
-Only genotype positive/phenotype positive and obligate carriers/phenotype positive individuals should be counted as segregations.
-
-
-Phenotype positive need to be clinically assessed and either have a diagnosis of glaucoma or suspicious signs of glaucoma.",
-MYOC (HGNC:7610),PP1,Moderate,"≥ 5 meioses.
-
-
-
-
-BA1 and BS1 must not be met.
-
-
-Only genotype positive/phenotype positive and obligate carriers/phenotype positive individuals should be counted as segregations.
-
-
-Phenotype positive need to be clinically assessed and either have a diagnosis of glaucoma or suspicious signs of glaucoma.",
-MYOC (HGNC:7610),PP1,Supporting,"≥ 3 meioses.
-
-
-
-
-BA1 and BS1 must not be met.
-
-
-Only genotype positive/phenotype positive and obligate carriers/phenotype positive individuals should be counted as segregations.
-
-
-Phenotype positive need to be clinically assessed and either have a diagnosis of glaucoma or suspicious signs of glaucoma.",
-MYOC (HGNC:7610),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-MYOC (HGNC:7610),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-MYOC (HGNC:7610),PP3,Supporting,Applies to missense variants with a REVEL score of ≥ 0.7.,
-MYOC (HGNC:7610),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-MYOC (HGNC:7610),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MYOC (HGNC:7610),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-MYOC (HGNC:7610),BA1,Stand Alone,"Allele frequency ≥ 0.01 in population databases.
-
-
-
-
-The highest allele frequency in population databases should be used.
-
-
-Variant must be present in ≥ 5 alleles in any validated general continental population dataset of at least 2,000 observed alleles.",
-MYOC (HGNC:7610),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-MYOC (HGNC:7610),BS1,Strong,"Allele frequency ≥ 0.001 in population databases.
-
-
-
-
-The highest allele frequency in population databases should be used. 
-
-
-Variant must be present in ≥ 5 alleles in any validated general continental population dataset of at least 2,000 observed alleles. 
-
-
-Does not apply to p.Gln368Ter.",
-MYOC (HGNC:7610),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",NA
-MYOC (HGNC:7610),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-MYOC (HGNC:7610),BS3,Moderate,"Applies to variants showing solubility or secretion in functional assays for studies with OddsPath <0.23 as per the SVI recommendations.
-
-
-
-
-Only apply if the assay includes both negative and positive controls and includes technical and/or biological replicates.
-
-
-If multiple results from functional assays are available for a single variant, then the evidence from the assay that is best validated should apply.
-
-
-Controls from the same general class of assay can be combined to calculate the odds of pathogenicity (OddsPath) as per the published SVI recommendations.
-
-
-If results from different assays are conflicting for a single variant, then the level of validation of each assay should be considered to decide whether the results from one assay can override the results from another.",
-MYOC (HGNC:7610),BS3,Supporting,"Applies to variants showing solubility or secretion in functional assays for studies with OddsPath <0.48 as per the SVI recommendations.
-
-
-
-
-Only apply if the assay includes both negative and positive controls and includes technical and/or biological replicates.
-
-
-If multiple results from functional assays are available for a single variant, then the evidence from the assay that is best validated should apply.
-
-
-Controls from the same general class of assay can be combined to calculate the odds of pathogenicity (OddsPath) as per the published SVI recommendations.
-
-
-If results from different assays are conflicting for a single variant, then the level of validation of each assay should be considered to decide whether the results from one assay can override the results from another.",
-MYOC (HGNC:7610),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",NA
-MYOC (HGNC:7610),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-MYOC (HGNC:7610),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-MYOC (HGNC:7610),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-MYOC (HGNC:7610),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-MYOC (HGNC:7610),BP4,Supporting,"Applies to:
-
-
-
-
-Missense variants with a REVEL score of ≤ 0.15.
-
-
-Synonymous variants or noncoding variants with a CADD score of ≤ 10 AND SpliceAI ≤ 0.2",
-MYOC (HGNC:7610),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-MYOC (HGNC:7610),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MYOC (HGNC:7610),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-MYOC (HGNC:7610),BP7,Supporting,Applies to synonymous variants or noncoding variants with no impact on splicing (SpliceAI ≤ 0.2) and GERP <0 for conservation.,
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenGlaucomaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenGlaucomaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
deleted file mode 100644
index 215adcd99aeb4e243f01b19694d400c35348d814..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenGlaucomaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
+++ /dev/null
@@ -1,307 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-MYOC (HGNC:7610),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-MYOC (HGNC:7610),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MYOC (HGNC:7610),PS1,Strong,The novel change must not affect splicing (SpliceAI ≤ 0.2).,
-MYOC (HGNC:7610),PS1,Moderate,"Same amino acid change as a previously established likely pathogenic variant
-
-
-
-
-The novel change must not affect splicing (SpliceAI ≤ 0.2).",
-MYOC (HGNC:7610),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-MYOC (HGNC:7610),PS2,Strong,"≥2 confirmed de novo in JOAG
-Use the proposed SVI point recommendations for “phenotype consistent with gene but not highly specific” for JOAG
-
-
-
-
-Both maternity and paternity need to be proven for confirmed de novo variants.
-
-
-Parents need to be clinically assessed and not have a diagnosis of glaucoma.",
-MYOC (HGNC:7610),PS2,Moderate,"≥2 confirmed de novo in POAG or 1 confirmed de novo in JOAG
-Use proposed SVI point recommendations for “phenotype consistent with the gene but not highly specific and with high genetic heterogeneity” for POAG and “phenotype consistent with gene but not highly specific” for JOAG.
-
-
-
-
-Both maternity and paternity need to be proven for confirmed de novo variants.
-
-
-Parents need to be clinically assessed and not have a diagnosis of glaucoma.",
-MYOC (HGNC:7610),PS2,Supporting,"1 confirmed de novo in POAG
-Use proposed SVI point recommendations for “phenotype consistent with the gene but not highly specific and with high genetic heterogeneity” for POAG. 
-
-
-
-
-Both maternity and paternity need to be proven for confirmed de novo variants. 
-
-
-Parents need to be clinically assessed and not have a diagnosis of glaucoma.",
-MYOC (HGNC:7610),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-MYOC (HGNC:7610),PS3,Strong,"Assays with OddsPath >18.7 as per the SVI recommendations
-
-
-
-
-Applies to the following functional studies: Solubility or secretion assays OR animal models that replicate the glaucoma phenotype.
-
-
-PS3 should only be applied if the assay includes both negative and positive controls and includes technical and/or biological replicates.
-
-
-If multiple results from functional assays are available for a single variant, then the evidence from the assay that is best validated should apply.
-
-
-Controls from the same general class of assay can be combined to calculate the odds of pathogenicity (OddsPath) as per the published SVI recommendations.
-
-
-If results from different assays are conflicting for a single variant, then the level of validation of each assay should be considered to decide whether the results from one assay can override the results from another.",
-MYOC (HGNC:7610),PS3,Moderate,"Assays with OddsPath >4.3 as per the SVI recommendations
-
-
-
-
-Applies to the following functional studies: Solubility or secretion assays OR animal models that replicate the glaucoma phenotype.
-
-
-PS3 should only be applied if the assay includes both negative and positive controls and includes technical and/or biological replicates.
-
-
-If multiple results from functional assays are available for a single variant, then the evidence from the assay that is best validated should apply.
-
-
-Controls from the same general class of assay can be combined to calculate the odds of pathogenicity (OddsPath) as per the published SVI recommendations.
-
-
-If results from different assays are conflicting for a single variant, then the level of validation of each assay should be considered to decide whether the results from one assay can override the results from another.",
-MYOC (HGNC:7610),PS3,Supporting,"Assays with OddsPath >2.1 as per the SVI recommendations
-
-
-
-
-Applies to the following functional studies: Solubility or secretion assays OR animal models that replicate the glaucoma phenotype.
-
-
-PS3 should only be applied if the assay includes both negative and positive controls and includes technical and/or biological replicates.
-
-
-If multiple results from functional assays are available for a single variant, then the evidence from the assay that is best validated should apply.
-
-
-Controls from the same general class of assay can be combined to calculate the odds of pathogenicity (OddsPath) as per the published SVI recommendations.
-
-
-If results from different assays are conflicting for a single variant, then the level of validation of each assay should be considered to decide whether the results from one assay can override the results from another.",
-MYOC (HGNC:7610),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-MYOC (HGNC:7610),PS4,Strong,"≥ 15 probands from multiple independent studies
-
-
-
-
-Probands counted should be clinically assessed and have a diagnosis of JOAG or POAG.
-
-
-PM2_Supporting must be met.",
-MYOC (HGNC:7610),PS4,Moderate,"≥ 6 probands from multiple independent studies
-
-
-
-
-Probands counted should be clinically assessed and have a diagnosis of JOAG or POAG.
-
-
-PM2_Supporting must be met.",
-MYOC (HGNC:7610),PS4,Supporting,"≥ 2 probands from multiple independent studies
-
-
-
-
-Probands counted should be clinically assessed and have a diagnosis of JOAG or POAG.
-
-
-PM2_Supporting must be met.",
-MYOC (HGNC:7610),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-MYOC (HGNC:7610),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-MYOC (HGNC:7610),PM2,Supporting,"Allele frequency ≤ 0.0001 in population databases
-
-
-
-
-The highest allele frequency in population databases should be used. 
-
-
-Only applies to populations of ≥ 10,000 alleles.",
-MYOC (HGNC:7610),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-MYOC (HGNC:7610),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-MYOC (HGNC:7610),PM4,Moderate,In-frame del/ins and truncating variants involving >10% of the protein and located within the conserved olfactomedin domain (AA 246-502),
-MYOC (HGNC:7610),PM4,Supporting,In-frame del/ins and truncating variants involving ≤10% of the protein and located within the conserved olfactomedin domain (AA 246-502),
-MYOC (HGNC:7610),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MYOC (HGNC:7610),PM5,Moderate,"Same residue as a previously established pathogenic variant (assessed independently of PM5) or 2 previously established likely pathogenic variants (both assessed independently of PM5)
-
-
-
-
-The novel change must not affect splicing (SpliceAI ≤ 0.2), must meet PP3 and have a Grantham score equal or greater than the previously established P/LP variants.",
-MYOC (HGNC:7610),PM5,Supporting,"Same residue as a previously established likely pathogenic variant (assessed independently of PM5)
-
-
-
-
-The novel change must not affect splicing (SpliceAI ≤ 0.2), must meet PP3 and have a Grantham score equal or greater than the previously established P/LP variants.",
-MYOC (HGNC:7610),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-MYOC (HGNC:7610),PM6,Moderate,"≥2 assumed de novo in JOAG
-Use proposed SVI point recommendations for “phenotype consistent with gene but not highly specific” for JOAG.
-
-
-
-
-Both maternity and paternity need to be proven for confirmed de novo variants.
-
-
-Parents need to be clinically assessed and not have a diagnosis of glaucoma.",
-MYOC (HGNC:7610),PM6,Supporting,"≥2 assumed de novo in POAG or 1 assumed de novo in JOAG
-Use proposed SVI point recommendations for “phenotype consistent with the gene but not highly specific and with high genetic heterogeneity” for POAG and “phenotype consistent with gene but not highly specific” for JOAG.
-
-
-
-
-Both maternity and paternity need to be proven for confirmed de novo variants.
-
-
-Parents need to be clinically assessed and not have a diagnosis of glaucoma.",
-MYOC (HGNC:7610),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-MYOC (HGNC:7610),PP1,Strong,"≥7 meioses in >1 family
-
-
-
-
-BA1 and BS1 must not be met.
-
-
-Only genotype positive/phenotype positive and obligate carriers/phenotype positive individuals should be counted as segregations.
-
-
-Phenotype positive need to be clinically assessed and either have a diagnosis of glaucoma or suspicious signs of glaucoma.",
-MYOC (HGNC:7610),PP1,Moderate,"≥ 5 meioses
-
-
-
-
-BA1 and BS1 must not be met.
-
-
-Only genotype positive/phenotype positive and obligate carriers/phenotype positive individuals should be counted as segregations.
-
-
-Phenotype positive need to be clinically assessed and either have a diagnosis of glaucoma or suspicious signs of glaucoma.",
-MYOC (HGNC:7610),PP1,Supporting,"≥ 3 meioses
-
-
-
-
-BA1 and BS1 must not be met.
-
-
-Only genotype positive/phenotype positive and obligate carriers/phenotype positive individuals should be counted as segregations.
-
-
-Phenotype positive need to be clinically assessed and either have a diagnosis of glaucoma or suspicious signs of glaucoma.",
-MYOC (HGNC:7610),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-MYOC (HGNC:7610),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-MYOC (HGNC:7610),PP3,Supporting,Applies to missense variants with a REVEL score of ≥ 0.7,
-MYOC (HGNC:7610),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-MYOC (HGNC:7610),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MYOC (HGNC:7610),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-MYOC (HGNC:7610),BA1,Stand Alone,"Allele frequency ≥ 0.01 in population databases
-
-
-
-
-The highest allele frequency in population databases should be used.
-
-
-Variant must be present in ≥ 5 alleles in any validated general continental population dataset of at least 2,000 observed alleles.",
-MYOC (HGNC:7610),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-MYOC (HGNC:7610),BS1,Strong,"Allele frequency ≥ 0.001 in population databases
-
-
-
-
-The highest allele frequency in population databases should be used. 
-
-
-Variant must be present in ≥ 5 alleles in any validated general continental population dataset of at least 2,000 observed alleles. 
-
-
-Does not apply to p.Gln368Ter.",
-MYOC (HGNC:7610),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",NA
-MYOC (HGNC:7610),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-MYOC (HGNC:7610),BS3,Moderate,"Applies to variants showing solubility or secretion in functional assays for studies with OddsPath <0.23 as per the SVI recommendations
-
-
-
-
-Only apply if the assay includes both negative and positive controls and includes technical and/or biological replicates.
-
-
-If multiple results from functional assays are available for a single variant, then the evidence from the assay that is best validated should apply.
-
-
-Controls from the same general class of assay can be combined to calculate the odds of pathogenicity (OddsPath) as per the published SVI recommendations.
-
-
-If results from different assays are conflicting for a single variant, then the level of validation of each assay should be considered to decide whether the results from one assay can override the results from another.",
-MYOC (HGNC:7610),BS3,Supporting,"Applies to variants showing solubility or secretion in functional assays for studies with OddsPath <0.48 as per the SVI recommendations
-
-
-
-
-Only apply if the assay includes both negative and positive controls and includes technical and/or biological replicates.
-
-
-If multiple results from functional assays are available for a single variant, then the evidence from the assay that is best validated should apply.
-
-
-Controls from the same general class of assay can be combined to calculate the odds of pathogenicity (OddsPath) as per the published SVI recommendations.
-
-
-If results from different assays are conflicting for a single variant, then the level of validation of each assay should be considered to decide whether the results from one assay can override the results from another.",
-MYOC (HGNC:7610),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",NA
-MYOC (HGNC:7610),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-MYOC (HGNC:7610),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-MYOC (HGNC:7610),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-MYOC (HGNC:7610),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-MYOC (HGNC:7610),BP4,Supporting,"Applies to:
-
-
-
-
-Missense variants with a REVEL score of ≤ 0.15
-
-
-Synonymous variants or noncoding variants with a CADD score of ≤ 10 AND SpliceAI ≤ 0.2",
-MYOC (HGNC:7610),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-MYOC (HGNC:7610),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MYOC (HGNC:7610),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-MYOC (HGNC:7610),BP7,Supporting,Applies to synonymous variants or noncoding variants with no impact on splicing (SpliceAI ≤ 0.2) and GERP <0 for conservation,
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenGlaucomaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYOCVersion2.0.0_version=2.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenGlaucomaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYOCVersion2.0.0_version=2.0.0.csv
deleted file mode 100644
index b6ed82567d306b2c2223c5e6932360d2b2353ccd..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenGlaucomaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYOCVersion2.0.0_version=2.0.0.csv
+++ /dev/null
@@ -1,103 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-MYOC (HGNC:7610),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-MYOC (HGNC:7610),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MYOC (HGNC:7610),PS1,Strong,Same amino acid change as previously established pathogenic variant,Clarification
-MYOC (HGNC:7610),PS1,Moderate,Same amino acid change as a previously established likely pathogenic variant,"Clarification,Strength"
-MYOC (HGNC:7610),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-MYOC (HGNC:7610),PS2,Strong,≥2 confirmed de novo in JOAG,Disease-specific
-MYOC (HGNC:7610),PS2,Moderate,"≥2 confirmed de novo in POAG
-
-
-Or 1 confirmed de novo in JOAG
-
-
-Or ≥2 assumed 
-de novo
- in JOAG","Disease-specific,Strength"
-MYOC (HGNC:7610),PS2,Supporting,"1 confirmed de novo in POAG
-
-
-Or ≥2 assumed 
-de novo
- in POAG
-
-
-Or 1 assumed 
-de novo
- in JOAG","Disease-specific,Strength"
-MYOC (HGNC:7610),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-MYOC (HGNC:7610),PS3,Strong,"Assays with OddsPath >18.7 as per the SVI recommendations.
-1","Disease-specific,Gene-specific"
-MYOC (HGNC:7610),PS3,Moderate,"Assays with OddsPath >4.3 as per the SVI recommendations.
-1","Disease-specific,Gene-specific,Strength"
-MYOC (HGNC:7610),PS3,Supporting,"Assays with OddsPath >2.1 as per the SVI recommendations.
-1","Disease-specific,Gene-specific,Strength"
-MYOC (HGNC:7610),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-MYOC (HGNC:7610),PS4,Strong,≥ 15 probands from multiple independent studies.,Gene-specific
-MYOC (HGNC:7610),PS4,Moderate,≥ 6 probands from multiple independent studies.,"Gene-specific,Strength"
-MYOC (HGNC:7610),PS4,Supporting,≥ 2 probands from multiple independent studies.,"Gene-specific,Strength"
-MYOC (HGNC:7610),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-MYOC (HGNC:7610),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-MYOC (HGNC:7610),PM2,Supporting,Allele frequency ≤ 0.0001 in population databases.,"Disease-specific,Gene-specific"
-MYOC (HGNC:7610),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-MYOC (HGNC:7610),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-MYOC (HGNC:7610),PM4,Moderate,"In-frame del/ins, stop-loss variants and truncating variants involving >10% of the protein and located within the conserved olfactomedin domain (AA 246-502).",Gene-specific
-MYOC (HGNC:7610),PM4,Supporting,"In-frame del/ins, stop-loss variants and truncating variants involving ≤10% of the protein and located within the conserved olfactomedin domain (AA 246-502).","Gene-specific,Strength"
-MYOC (HGNC:7610),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MYOC (HGNC:7610),PM5,Strong,Same residue as 2 previously established pathogenic variants (both assessed independently of PM5),"Clarification,Strength"
-MYOC (HGNC:7610),PM5,Moderate,Same residue as a previously established pathogenic variant (assessed independently of PM5) or 2 previously established likely pathogenic variants (both assessed independently of PM5),Clarification
-MYOC (HGNC:7610),PM5,Supporting,Same residue as a previously established likely pathogenic variant (assessed independently of PM5),"Clarification,Strength"
-MYOC (HGNC:7610),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-MYOC (HGNC:7610),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-MYOC (HGNC:7610),PP1,Strong,≥7 meioses in >1 family,"Clarification,Strength"
-MYOC (HGNC:7610),PP1,Moderate,≥ 5 meioses regardless of the number of families,"Clarification,Strength"
-MYOC (HGNC:7610),PP1,Supporting,≥ 3 meioses regardless of the number of families,Clarification
-MYOC (HGNC:7610),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-MYOC (HGNC:7610),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-MYOC (HGNC:7610),PP3,Strong,REVEL score of ≥ 0.932,"Clarification,Strength"
-MYOC (HGNC:7610),PP3,Moderate,REVEL score of 0.773-0.931,"Clarification,Strength"
-MYOC (HGNC:7610),PP3,Supporting,REVEL score of 0.644-0.772,Clarification
-MYOC (HGNC:7610),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-MYOC (HGNC:7610),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MYOC (HGNC:7610),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-MYOC (HGNC:7610),BA1,Stand Alone,Allele frequency ≥ 0.01 in population databases.,"Disease-specific,Gene-specific"
-MYOC (HGNC:7610),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-MYOC (HGNC:7610),BS1,Strong,Allele frequency ≥ 0.001 in population databases.,"Disease-specific,Gene-specific"
-MYOC (HGNC:7610),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",NA
-MYOC (HGNC:7610),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-MYOC (HGNC:7610),BS3,Moderate,Applies to variants showing solubility or secretion in functional assays for studies with OddsPath <0.23 as per the SVI recommendations.,"Gene-specific,Strength"
-MYOC (HGNC:7610),BS3,Supporting,Applies to variants showing solubility or secretion in functional assays for studies with OddsPath <0.48 as per the SVI recommendations.,"Gene-specific,Strength"
-MYOC (HGNC:7610),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",NA
-MYOC (HGNC:7610),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-MYOC (HGNC:7610),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-MYOC (HGNC:7610),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-MYOC (HGNC:7610),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-MYOC (HGNC:7610),BP4,Strong,REVEL score of ≤ 0.016,"Clarification,Strength"
-MYOC (HGNC:7610),BP4,Moderate,REVEL score of 0.017-0.183,"Clarification,Strength"
-MYOC (HGNC:7610),BP4,Supporting,"For missense variants: REVEL score of 0.184-0.290
-
-
-For all other variants located outside of donor/acceptor ±1,2 dinucleotide positions, when splicing assay is not available: SpliceAI ≤ 0.1",Clarification
-MYOC (HGNC:7610),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-MYOC (HGNC:7610),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MYOC (HGNC:7610),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-MYOC (HGNC:7610),BP7,Supporting,Apply to intronic/noncoding and synonymous (silent) exonic variants if BP4 is met,Clarification
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
deleted file mode 100644
index d146071c3610d2432fd65c2022d68ec1b36f7aff..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
+++ /dev/null
@@ -1,99 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-TECTA (HGNC:11720),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-TECTA (HGNC:11720),PVS1,Very Strong,"Null variant in a gene with established LOF as a disease mechanism; see PVS1_Strong, PVS1_Moderate, PVS1_Supporting for reduced evidence applications.",
-TECTA (HGNC:11720),PVS1,Strong,See PVS1 flow chart for PVS1_Strong variants in gene where LOF is a known mechanism of disease.,
-TECTA (HGNC:11720),PVS1,Moderate,See PVS1 flowchart for PVS1_Moderate variants in gene where LOF is a known mechanism of disease.,
-TECTA (HGNC:11720),PVS1,Supporting,See PVS1 flowchart for PVS1_Supporting variants in gene where LOF is a known mechanism of disease.,
-TECTA (HGNC:11720),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-TECTA (HGNC:11720),PS1,Strong,"Same amino acid change as an established pathogenic variant; OR
-splice variants at same nucleotide and with similar impact prediction as previously reported pathogenic variant.",
-TECTA (HGNC:11720),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-TECTA (HGNC:11720),PS2,Very Strong,"4 points per tables 5a and 5b:
-Examples: 2 proven de novo occurrences; OR 1 proven + 2 assumed de novo occurrences; OR 4 assumed de novo occurrences.",
-TECTA (HGNC:11720),PS2,Strong,"2 points per tables 5a and 5b:
-Examples: 1 proven de novo occurrence; OR 2 assumed de novo occurrences.",
-TECTA (HGNC:11720),PS2,Moderate,"1 point per tables 5a and 5b:
-Examples: 1 proven de novo occurrence (phenotype consistent but not specific to gene); OR 1 assumed de novo occurrence; OR 2 assumed de novo occurrences (phenotype/gene not specific).",
-TECTA (HGNC:11720),PS2,Supporting,"0.5 points per tables 5a and 5b:
-Example: 1 assumed de novo occurrence (phenotype/gene not specific).",
-TECTA (HGNC:11720),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-TECTA (HGNC:11720),PS3,Strong,Knock-in mouse model demonstrates the phenotype.,
-TECTA (HGNC:11720),PS3,Moderate,Validated functional studies show a deleterious effect (predefined list).,
-TECTA (HGNC:11720),PS3,Supporting,Functional studies with limited validation show a deleterious effect.,
-TECTA (HGNC:11720),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-TECTA (HGNC:11720),PS4,Strong,"Fisher Exact or Chi-Squared analysis shows statistical increase in cases over controls, OR Autosomal dominant: ≥15 probands with variant, and variant meets PM2.",
-TECTA (HGNC:11720),PS4,Moderate,"Autosomal dominant: ≥6 probands with variant, and variant meets PM2.",
-TECTA (HGNC:11720),PS4,Supporting,"Autosomal dominant: ≥2 probands with variant, and variant meets PM2.",
-TECTA (HGNC:11720),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-TECTA (HGNC:11720),PM1,Moderate,"Mutational hot spot or well-studied functional domain without benign variation (KCNQ4 pore-forming region; Gly residues in Gly-X-Y motifs of COL11A2, COL4A3, COL4A4, and COL4A5).",
-TECTA (HGNC:11720),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-TECTA (HGNC:11720),PM2,Moderate,"Absent/Rare in population databases (absent or ≤0.00007 (0.007%) for autosomal recessive, ≤0.00002 (0.002%) for autosomal dominant).",
-TECTA (HGNC:11720),PM2,Supporting,Low MAF in population databases <0.0007 (0.07%) for autosomal recessive.,
-TECTA (HGNC:11720),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-TECTA (HGNC:11720),PM3,Very Strong,"4 points awarded from tables 7a and 7b:
-Example: Detected in trans in ≥4 probands with a pathogenic variant (recessive).",
-TECTA (HGNC:11720),PM3,Strong,"2 points awarded from tables 7a and 7b:
-Example: Detected in trans in 2 probands with a pathogenic variant (recessive).",
-TECTA (HGNC:11720),PM3,Moderate,"1 point awarded from tables 7a and 7b:
-Example: Detected in trans with a pathogenic variant (recessive).",
-TECTA (HGNC:11720),PM3,Supporting,"0.5 points awarded from tables 7a and 7b:
-Examples: Two variants that meet PM2_Supporting detected in trans; OR a homozygous variant meeting PM2_Supporting.",
-TECTA (HGNC:11720),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-TECTA (HGNC:11720),PM4,Moderate,Protein length change due to an in-frame deletion or insertion that are not located in repetitive regions.,
-TECTA (HGNC:11720),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-TECTA (HGNC:11720),PM5,Strong,Missense change at same codon as two different pathogenic missense variants.,
-TECTA (HGNC:11720),PM5,Moderate,Missense change at same codon as another pathogenic missense variant.,
-TECTA (HGNC:11720),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-TECTA (HGNC:11720),PM6,Moderate,See PS2 above.,
-TECTA (HGNC:11720),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-TECTA (HGNC:11720),PP1,Strong,Segregation in three affected relatives for recessive and five affected relatives for dominant.,
-TECTA (HGNC:11720),PP1,Moderate,Segregation in two affected relatives for recessive and four affected relatives for dominant.,
-TECTA (HGNC:11720),PP1,Supporting,Segregation in one affected relative for recessive and two affected relatives for dominant.,
-TECTA (HGNC:11720),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-TECTA (HGNC:11720),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-TECTA (HGNC:11720),PP3,Supporting,"REVEL score ≥0.7, or predicted impact to splicing using MaxEntScan.",
-TECTA (HGNC:11720),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-TECTA (HGNC:11720),PP4,Supporting,Patient's phenotype highly specific for gene or fully sequenced gene set (see specifications in Table 7).,
-TECTA (HGNC:11720),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-TECTA (HGNC:11720),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-TECTA (HGNC:11720),BA1,Stand Alone,MAF of ≥0.005 (0.5%) for autosomal recessive; MAF of ≥0.001 (0.1%) for autosomal dominant.,
-TECTA (HGNC:11720),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-TECTA (HGNC:11720),BS1,Strong,"MAF of ≥0.003 (0.3%) for autosomal recessive; MAF of ≥0.0002 (0.02%) for autosomal dominant. Likely benign, provided there is no conflicting evidence.",
-TECTA (HGNC:11720),BS1,Supporting,MAF of ≥0.0007 (0.07%) for autosomal recessive. No BS1_Supporting criteria for autosomal dominant.,
-TECTA (HGNC:11720),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-TECTA (HGNC:11720),BS2,Strong,Observation of variant (biallelic with known pathogenic variant for recessive) in controls inconsistent with disease penetrance.,
-TECTA (HGNC:11720),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-TECTA (HGNC:11720),BS3,Supporting,Functional study shows no deleterious effect (predefined list).,
-TECTA (HGNC:11720),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-TECTA (HGNC:11720),BS4,Strong,Non-segregation with disease.,
-TECTA (HGNC:11720),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-TECTA (HGNC:11720),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-TECTA (HGNC:11720),BP2,Supporting,Observed in trans with a dominant variant/observed in cis with a pathogenic variant (use with caution).,
-TECTA (HGNC:11720),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-TECTA (HGNC:11720),BP3,Supporting,In-frame indels in repeat region without known function.,
-TECTA (HGNC:11720),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-TECTA (HGNC:11720),BP4,Supporting,Computational evidence suggests no impact; REVEL score ≤0.15 or no impact to splicing in MaxEntScan.,
-TECTA (HGNC:11720),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-TECTA (HGNC:11720),BP5,Supporting,Variant in an autosomal dominant gene found in a patient with an alternate explanation.,
-TECTA (HGNC:11720),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-TECTA (HGNC:11720),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-TECTA (HGNC:11720),BP7,Supporting,Silent variant with no predicted impact to splicing.,
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv
deleted file mode 100644
index b62326eaaedc823f64b7e9706fb01dd2c3d2acac..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv
+++ /dev/null
@@ -1,354 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-CDH23 (HGNC:13733),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-CDH23 (HGNC:13733),PVS1,Very Strong,"Null variant in a gene with established LOF as a disease mechanism; see PVS1_Strong, PVS1_Moderate, PVS1_Supporting for reduced evidence applications.",None
-CDH23 (HGNC:13733),PVS1,Strong,"See PVS1 flow chart for PVS1_Strong variants in gene where LOF is a known mechanism of disease.
-
-
-
-
-PVS1 should also be considered for the following genes with variants assessed in the Hearing Loss Variant Pilot: GJB2, CDH23, USH2A, SLC26A4, MYO6, MYO7A, TECTA, KCNQ4.
-
-
-For other genes, LOF must be an established disease mechanism, and the gene/disease association must be Strong or Definitive clinical validity level as outlined in Strande et al. 2017 (PMID: 28552198).
-
-
-If above criteria is met, follow PVS1 flowchart as recommended by the SVI.",None
-CDH23 (HGNC:13733),PVS1,Moderate,See PVS1 flowchart for PVS1_Moderate variants in gene where LOF is a known mechanism of disease.,None
-CDH23 (HGNC:13733),PVS1,Supporting,See PVS1 flowchart for PVS1_Supporting variants in gene where LOF is a known mechanism of disease.,None
-CDH23 (HGNC:13733),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-CDH23 (HGNC:13733),PS1,Strong,"Same amino acid change as an established pathogenic variant; OR
-splice variants at same nucleotide and with similar impact prediction as previously reported pathogenic variant.
-
-
-
-
-Established variant must meet criteria for pathogenicity by the HL specifications
-
-
-
-
-Can also use PS1 for splice variants located in the splice consensus sequence, at the same nucleotide position as a previously reported pathogenic variant
-
-
-
-
-Example: c.105+1G>C is known to be pathogenic, can use PS1 for c.105+1G>T
-
-
-
-
-No additional hearing loss specifications for missense variants. Follow recommendations as outlined in Richard 2015 and/or the Sequence Variant Interpretation working group within ClinGen.
-
-
-
-
-Caveat (from ACMG/AMP guidelines): Assess the possibility that the variant may act directly through the DNA change (e.g. through splicing disruption as assessed by at least computational analysis) instead of through the amino acid change)",None
-CDH23 (HGNC:13733),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-CDH23 (HGNC:13733),PS2,Very Strong,"4 points per tables 5a and 5b:
-Examples: 2 proven de novo occurrences; OR 1 proven + 2 assumed de novo occurrences; OR
-4 assumed de novo occurrences.",None
-CDH23 (HGNC:13733),PS2,Strong,"2 points per tables 5a and 5b:
-Examples: 1 proven de novo occurrence; OR 2 assumed de novo occurrences.",None
-CDH23 (HGNC:13733),PS2,Moderate,"1 point per tables 5a and 5b:
-Examples: 1 proven de novo occurrence (phenotype consistent but not specific to gene); OR
-1 assumed de novo occurrence; OR 2 assumed de novo occurrences (phenotype/gene not specific).",None
-CDH23 (HGNC:13733),PS2,Supporting,"0.5 points per tables 5a and 5b:
-Example: 1 assumed de novo occurrence (phenotype/gene not specific).",None
-CDH23 (HGNC:13733),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-CDH23 (HGNC:13733),PS3,Strong,Knock-in mouse model demonstrates the phenotype.,Disease-specific
-CDH23 (HGNC:13733),PS3,Moderate,"Validated functional studies show a deleterious effect (predefined list): GJB2: electrical coupling assays, dye transfer assays → PS3_Moderate
-
-
-
-
-Dye Transfer Assays: Expect results that compare the fluorescence of a variant-transfected cell to
-both a negative control (or H2O injected control) and a wildtype-transfected cell. PS3_Moderate
-would be applied if the variant results in no dye transfer or significantly different dye transfer when
-compared to the wildtype.
-
-
-Electrical Coupling Assays: Expect results comparing the current of the variant-transfected cells to both a negative control (i.e. H2O injected control) and a wildtype-transfected cell. PS3_Moderate would be applied if the variant results in significantly different current compared to the wildtype, and the current is comparable to background levels/negative control.",Disease-specific
-CDH23 (HGNC:13733),PS3,Supporting,"SLC26A4: Radio isotope and fluorescence assays → PS3_Supporting
-
-
-
-
-Radio Isotope Assays: PS3_Supporting would be applied when cells transfected with mutant SLC26A4 show a statistically significant decreased efflux of iodide compared to wildtype pendrin.
-
-
-Fluorescence Assays: PS3_Supporting would be applied when a cell transfected with the mutant SLC26A4 shows a statistically significant difference in fluorescence (ΔFmax %) compared to the wildtype protein, and when the fluorescence is not significantly different from that of an empty vector control.
-COCH: Localization, secretion, and dimerization studies performed using immunofluorescence and
-Western blotting techniques →PS3_Supporting
-
-
-Localization: PS3_Supporting would be applied if the mutant cochlin protein does not aggregate into extracellular deposits or in the perinuclear region, comparable to the localization of wildtype cochlin.
-
-
-Secretion: PS3_Supporting would be applied if cochlin protein containing the variant does not show secretion from transfected cells, but aggregates in cell regions such as the ER, Golgi and nucleus or is degraded.
-
-
-Dimerization: In a non-reducing environment, wildtype cochlin migrate quickly and appear smaller than in the reduced state because the structure is maintained by disulfide bonds. PS3_Supporting would be applied if the cochlin protein containing the variant forms more, or less, stable disulfide bonds when compared to the wildtype in non-reducing conditions.
-
-
-If not listed above, OK to use PS3_Supporting for other genes/functional analyses if
-
-
-The assay has been validated by a known pathogenic and benign variant AND  
-
-
-There is plausible reason that the function the assay is testing relates to the phenotype AND
-
-
-The assay conditions are likely to mimic the physiological environment.",Disease-specific
-CDH23 (HGNC:13733),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-CDH23 (HGNC:13733),PS4,Strong,"Fisher Exact or Chi-Squared analysis shows statistical increase in cases over controls, OR
-Autosomal dominant: ≥15 probands with variant, and variant meets PM2_Supporting.",Disease-specific
-CDH23 (HGNC:13733),PS4,Moderate,"Autosomal dominant: ≥6 probands with variant, and variant meets PM2_Supporting.",Disease-specific
-CDH23 (HGNC:13733),PS4,Supporting,"Autosomal dominant: ≥2 probands with variant, and variant meets PM2_Supporting.",Disease-specific
-CDH23 (HGNC:13733),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-CDH23 (HGNC:13733),PM1,Moderate,"Mutational hot spot or well-studied functional domain without benign variation (KCNQ4 pore-forming region).
-
-
-
-
-KCNQ4 (NM_004700.4) gene - missense variants located within amino acids 271-292 can be awarded PM1. This region is the pore-forming intramembrane region where many variants that cause autosomal dominant hearing loss are located (Naito et al. 2013, PMID: 23717403; 
-https://www.uniprot.org/uniprot/P56696
-). There are only two missense variants in this region in gnomAD, each with only single allele (
-http://gnomad.broadinstitute.org/
-; rs763326539: 1/33578 Latino chromosomes; rs55737429: 1/111720 European chromosomes).",Disease-specific
-CDH23 (HGNC:13733),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-CDH23 (HGNC:13733),PM2,Supporting,"Absent/Rare in population databases (absent or ≤0.00007 (0.007%) for autosomal recessive, ≤0.00002 (0.002%) for autosomal dominant).
-
-
-
-
-Background: Rarity or absence in the general population is not robust evidence for pathogenicity, particularly for autosomal recessive disorders. However, the ACMG/AMP Guidelines were devised in such a way that absence or rarity were considered moderate evidence towards pathogenicity, and the framework requires multiple pieces of evidence to classify a variant as likely pathogenic or pathogenic.",Strength
-CDH23 (HGNC:13733),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-CDH23 (HGNC:13733),PM3,Very Strong,"4 points awarded from tables 7a and 7b
-Example: Detected in trans in ≥4 probands with a pathogenic variant (recessive).",Strength
-CDH23 (HGNC:13733),PM3,Strong,"2 points awarded from tables 7a and 7b
-Example: Detected in trans in 2 probands with a pathogenic variant (recessive).",Strength
-CDH23 (HGNC:13733),PM3,Moderate,"1 point awarded from tables 7a and 7b.
-Example: Detected in trans with a pathogenic variant (recessive).",Strength
-CDH23 (HGNC:13733),PM3,Supporting,"0.5 points awarded from tables 7a and 7b
-Examples: Two variants that meet PM2_Supporting detected in trans; OR
-a homozygous variant meeting PM2_Supporting.",Strength
-CDH23 (HGNC:13733),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-CDH23 (HGNC:13733),PM4,Moderate,"Protein length change due to an in-frame deletion or insertion that are not located in repetitive regions.
-
-
-
-
-No changes. Follow recommendations as outlined in ACMG/AMP guidelines and/or Sequence Variant Interpretation working group.",None
-CDH23 (HGNC:13733),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-CDH23 (HGNC:13733),PM5,Strong,"Missense change at same codon as two different pathogenic missense variants.
-
-
-
-
-Located at an amino acid residue with known pathogenic variation (at least 2 other variants at the same site meet pathogenic criteria for based on independent data)
-
-
-Caveat: Assess whether the variants in question could have an impact at the DNA level, such as through splicing impacts.",None
-CDH23 (HGNC:13733),PM5,Moderate,"Missense change at same codon as another pathogenic missense variant.
-No changes. Follow recommendations as outlined in ACMG/AMP guidelines and/or Sequence Variant Interpretation working group.",None
-CDH23 (HGNC:13733),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-CDH23 (HGNC:13733),PM6,Moderate,See PS2 above,
-CDH23 (HGNC:13733),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-CDH23 (HGNC:13733),PP1,Strong,Segregation in three affected relatives for recessive and five affected relatives for dominant.,Strength
-CDH23 (HGNC:13733),PP1,Moderate,Segregation in two affected relatives for recessive and 4 affected relatives for dominant.,Strength
-CDH23 (HGNC:13733),PP1,Supporting,Segregation in one affected relative for recessive and two affected relatives for dominant.,Strength
-CDH23 (HGNC:13733),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-CDH23 (HGNC:13733),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-CDH23 (HGNC:13733),PP3,Supporting,"REVEL score ≥0.7, or predicted impact to splicing using MaxEntScan.
-
-
-
-
-Use REVEL and MAXENTSCAN.
-
-
-For missense variants, award PP3 if REVEL score is ≥0.7.
-
-
-If splicing is predicted to be impacted, either creation of a cryptic splice site, or disruption of a native splice site, award PP3.
-
-
-For splice variants (except for canonical -/+1 or 2), use MAXENTSCAN.
-
-
-For -/+ 1 or 2 splice variants, do not use PP3 if you are using PVS1.",Disease-specific
-CDH23 (HGNC:13733),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-CDH23 (HGNC:13733),PP4,Supporting,Patient's phenotype highly specific for gene or fully sequenced gene set (see specifications in Table 7).,Disease-specific
-CDH23 (HGNC:13733),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-CDH23 (HGNC:13733),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-CDH23 (HGNC:13733),BA1,Stand Alone,MAF of ≥0.005 (0.5%) for autosomal recessive; MAF of ≥0.001 (0.1%) for autosomal dominant.,
-CDH23 (HGNC:13733),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-CDH23 (HGNC:13733),BS1,Strong,"MAF of ≥0.003 (0.3%) for autosomal recessive; MAF of ≥0.0002 (0.02%) for autosomal dominant. Likely benign, provided there is no conflicting evidence.",Disease-specific
-CDH23 (HGNC:13733),BS1,Supporting,MAF of ≥0.0007 (0.07%) for autosomal recessive. No BS1_Supporting criteria for autosomal dominant.,Disease-specific
-CDH23 (HGNC:13733),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-CDH23 (HGNC:13733),BS2,Strong,"Observation of variant (biallelic with known pathogenic variant for recessive) in controls inconsistent with disease penetrance.
-
-
-
-
-Advise caution when using this rule, since most of hearing loss is autosomal recessive, and autosomal dominant hearing loss could display reduced penetrance or variable expression.
-
-
-However, if biallelic observations in controls are inconsistent with disease penetrance, this may be applicable.",None
-CDH23 (HGNC:13733),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-CDH23 (HGNC:13733),BS3,Supporting,"Functional study shows no deleterious effect (predefined list).
-
-
-
-
-Recommend that functional evidence is not used as strong evidence, due to the absence of well-established functional studies for hearing loss genes.
-
-
-Guidance on functional evidence at supporting level is as follows (see functional spreadsheets attached):
-
-
-GJB2: electrical coupling assays, dye transfer assays → BS3_Supporting
-
-
-Dye Transfer Assays: Expect results that compare the fluorescence of a variant-transfected cell to both a negative control (or H2O injected control) and a wildtype-transfected cell. BS2_Supporting can be applied if the variant results in dye transfer comparable to the wildtype.
-
-
-Electrical Coupling Assays: Expect results comparing the current of the variant-transfected cells to both a negative control (or H2O injected control) and a wildtype-transfected cell. BS2_Supporting would be applied if the variant results in a current comparable to the wildtype.
-
-
-SLC26A4: Radio isotope and fluorescence assays → BS3_Supporting
-
-
-Radio Isotope Assays: BS3_Supporting would be applied if the variant results in iodide efflux levels comparable to the wildtype.
-
-
-Fluorescence assay: BS3_Supporting would be applied if the variant results in fluorescence comparable to the wildtype
-
-
-COCH: Localization, secretion, and dimerization studies performed using immunofluorescence and Western blotting techniques → BS3_Supporting
-
-
-Localization: BS3_Supporting would be applied if the variant results in extracellular deposits comparable to the wildtype.
-
-
-Secretion: BS3_Supporting would be applied if the variant results in secretion comparable to the wildtype.
-
-
-Dimerization: In a non-reducing environment, wildtype cochlin migrate quickly and appear smaller than in the reduced state because the structure is maintained by disulfide bonds. BS3_Supporting would be applied if the variant results in molecular weight and size comparable to the wildtype.
-
-
-If not listed above, OK to use BS3_Supporting for other genes/functional analyses if
-
-
-The assay has been validated by a known pathogenic and benign variant AND
-
-
-There is plausible reason that the function the assay is testing relates to the phenotype AND
-
-
-The assay conditions are likely to mimic the physiological environment.",Disease-specific
-CDH23 (HGNC:13733),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-CDH23 (HGNC:13733),BS4,Strong,"Non-segregation with disease.
-
-
-
-
-Phenotype+/genotype-
-
-
-Strong evidence for benign.
-
-
-Be cautious when using this as the possibility for phenocopy is high. The hearing loss phenotype should be consistent within the family to consider it a non-segregation, though intra-familial variability has been reported. Factors to consider are:
-
-
-Age of onset (ie. congenital/early childhood vs. adult onset).
-
-
-Hearing loss prevalence increases significantly with age. A congenital hearing loss in a child and a late onset hearing loss in a grandparent would not be a consistent phenotype.
-
-
-Severity (ie - mild vs. profound).
-
-
-Minor differences may exist among family members.
-
-
-Keep in mind that progression in older individuals may account for a discrepancy between individuals.
-
-
-Sex -based differences (infertility, genes on X chromosomes)
-
-
-Audiogram shape.
-
-
-May not be completely consistent among family members even with same etiology.
-
-
-Genotype+/phenotype-
-
-
-Confounding variables to applying this rule: Age-related/sex-related penetrance, variable expressivity, etc.
-
-
-If the gene is associated with later onset and individual with the non-segregation is beyond the expected age that the hearing loss would occur, consider applying BS4_Supporting
-
-
-Recommend only using for fully penetrant genes (typically genes associated with AR hearing loss).
-
-
-Must be confident that patient is truly unaffected and a hearing loss is not missed or subclinical. Be cautious if only phenotyping was newborn hearing screening. Diagnostic audiometric testing (auditory brainstem response (ABR) or audiogram should be required).
-
-
-Any evidence for reduced penetrance, do not use BS4",Disease-specific
-CDH23 (HGNC:13733),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-CDH23 (HGNC:13733),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-CDH23 (HGNC:13733),BP2,Supporting,"Observed in trans with a dominant variant/observed in cis with a pathogenic variant (use with caution).
-Use with caution. For genes that are associated with both dominant and recessive hearing loss, consider whether an earlier onset/more severe phenotype could be present if variant is identified in trans with a dominant variant.",Disease-specific
-CDH23 (HGNC:13733),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-CDH23 (HGNC:13733),BP3,Supporting,"In-frame indels in repeat region without known function.
-No changes. Follow recommendations as outlined in Richard 2015 and/or ClinGen's Sequence Variant Interpretation working group.",None
-CDH23 (HGNC:13733),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-CDH23 (HGNC:13733),BP4,Supporting,Computational evidence suggests no impact; REVEL score ≤0.15 or no impact to splicing in MaxEntScan.,Disease-specific
-CDH23 (HGNC:13733),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-CDH23 (HGNC:13733),BP5,Supporting,"Variant in an autosomal dominant gene found in a patient with an alternate explanation.
-
-
-
-
-Autosomal recessive: Do not use. An individual could be carrier of pathogenic variant and have an alternate cause. Therefore, BP5 shouldn’t be used as evidence for benign in this case.
-
-
-
-
-Autosomal dominant: Can use BP5 as outlined by Richards 2015.
-
-
-
-
-Caveat: consider whether multiple pathogenic autosomal dominant variants could cause a more severe phenotype or whether multigenic inheritance is known to occur (example: Bardet-Biedl syndrome).",None
-CDH23 (HGNC:13733),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-CDH23 (HGNC:13733),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-CDH23 (HGNC:13733),BP7,Supporting,"Silent variant with no predicted impact to splicing.
-No changes. Follow recommendations as outlined in Richard 2015 and/or ClinGen's Sequence Variant Interpretation working group.",None
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforOTOFandMYO15AVersion1_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforOTOFandMYO15AVersion1_version=1.0.0.csv
deleted file mode 100644
index 3a75765094d35c1b37eddec1ca69031eefbafdce..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforOTOFandMYO15AVersion1_version=1.0.0.csv
+++ /dev/null
@@ -1,308 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-MYO15A (HGNC:7594),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-MYO15A (HGNC:7594),PVS1,Very Strong,"Null variant in a gene with established LOF as a disease mechanism; see PVS1_Strong, PVS1_Moderate, PVS1_Supporting for reduced evidence applications.
-PVS1 should also be considered for both of the genes OTOF and MYO15A with variants falling in two exons being exceptions to this rule: OTOF: NM_194248.2 Exon 46 (c.5841 to c.5994; PMID: 19250381) and MYO15A: NM_016239.3 Exon 8 (c.4033 to c. 4038; PMID: 10552926) and Exon 26 (c.5911 to c.5964; PMID: 30096381 and high frequency LOF variant 
-https://gnomad.broadinstitute.org/variant/17-18046894-G-A?dataset=gnomad_r2_1
-)",Disease-specific
-MYO15A (HGNC:7594),PVS1,Strong,See PVS1 flow chart for PVS1_Strong variants in gene where LOF is a known mechanism of disease.,None
-MYO15A (HGNC:7594),PVS1,Moderate,See PVS1 flowchart for PVS1_Moderate variants in gene where LOF is a known mechanism of disease.,None
-MYO15A (HGNC:7594),PVS1,Supporting,See PVS1 flowchart for PVS1_Supporting variants in gene where LOF is a known mechanism of disease.,None
-MYO15A (HGNC:7594),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MYO15A (HGNC:7594),PS1,Strong,"Same amino acid change as an established pathogenic variant; OR splice variants at same nucleotide and with similar impact prediction as previously reported pathogenic variant.
-
-
-
-
-Established variant must meet criteria for pathogenicity by the HL specifications.
-
-
-Can also use PS1 for splice variants located in the splice consensus sequence, at the same nucleotide position as a previously reported pathogenic variant.
-
-
-Example: c.105+1G>C is known to be pathogenic, can use PS1 for c.105+1G>T.
-
-
-
-
-
-
-No additional hearing loss specifications for missense variants. Follow recommendations as outlined in Richard 2015 and/or the Sequence Variant Interpretation working group within ClinGen.
-
-
-Caveat (from ACMG/AMP guidelines): Assess the possibility that the variant may act directly through the DNA change (e.g. through splicing disruption as assessed by at least computational analysis) instead of through the amino acid change).",None
-MYO15A (HGNC:7594),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-MYO15A (HGNC:7594),PS2,Very Strong,"4 points per tables 5a and 5b:
-Examples: 2 proven de novo occurrences; OR
-1 proven + 2 assumed de novo occurrences; OR
-4 assumed de novo occurrences.",None
-MYO15A (HGNC:7594),PS2,Strong,"2 points per tables 5a and 5b:
-Examples: 1 proven de novo occurrence; OR 2 assumed de novo occurrences.
-
-
-
-
-OTOF and MYO15A are associated with autosomal recessive conditions. Therefore, de novo variants are expected to be an unlikely occurrence. It is recommended that de novo evidence is only awarded when phase with another variant (VUS, Likely Pathogenic, or Pathogenic) can be confirmed in trans. This is to avoid inappropriately awarding de novo evidence, which would lead to potentially incorrect classification.
-
-
-
-
-Follow recommendations as specified by the Sequence Variant Interpretation working group within ClinGen, as outlined below
-
-
-
-
-Determine number of points per proband using table 1 below. Sum the total number of points for all probands, and determine the strength of the evidence by using table 2.
-
-
-
-
-Please note, the phenotype for de novo occurrences for MYO15A and OTOF are not considered “highly specific”.",None
-MYO15A (HGNC:7594),PS2,Moderate,"1 point per tables 5a and 5b:
-Examples: 1 proven de novo occurrence (phenotype consistent but not specific to gene); OR
-1 assumed de novo occurrence; OR 2 assumed de novo occurrences (phenotype/gene not specific).",None
-MYO15A (HGNC:7594),PS2,Supporting,"0.5 points per tables 5a and 5b:
-Example: 1 assumed de novo occurrence (phenotype/gene not specific).",None
-MYO15A (HGNC:7594),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-MYO15A (HGNC:7594),PS3,Strong,"Knock-in mouse model demonstrates the phenotype.
-
-
-
-
-Recommend that functional evidence, except for a variant specific mouse model, is not used as strong evidence, due to the absence of well-established functional studies for hearing loss genes.
-
-
-There are no specific assays for OTOF or MYO15A. However, PS3_Supporting can be applied for other functional analyses if
-
-
-The assay has been validated by a known pathogenic and benign variant AND
-
-
-There is plausible reason that the function the assay is testing relates to the phenotype AND
-
-
-The assay conditions are likely to mimic the physiological environment.",None
-MYO15A (HGNC:7594),PS3,Moderate,Validated functional studies show a deleterious effect (none are defined for OTOF and MYO15A).,None
-MYO15A (HGNC:7594),PS3,Supporting,Functional studies with limited validation show a deleterious effect.,None
-MYO15A (HGNC:7594),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-MYO15A (HGNC:7594),PS4,Very Strong,Fisher Exact or Chi-Squared analysis shows statistical increase in cases over controls.,Disease-specific
-MYO15A (HGNC:7594),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-MYO15A (HGNC:7594),PM1,Moderate,Mutational hot spot or well-studied functional domain without benign variation (None defined for OTOF and MYO15A).,None
-MYO15A (HGNC:7594),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-MYO15A (HGNC:7594),PM2,Supporting,Absent/Rare in population databases (absent or ≤0.00007 (0.007%) for autosomal recessive).,Disease-specific
-MYO15A (HGNC:7594),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-MYO15A (HGNC:7594),PM3,Very Strong,"4 points awarded from tables 7a and 7b.
-Example: Detected in trans in ≥4 probands with a pathogenic variant (recessive).",Strength
-MYO15A (HGNC:7594),PM3,Strong,"2 points awarded from tables 7a and 7b.
-Example: Detected in trans in 2 probands with a pathogenic variant (recessive).",Strength
-MYO15A (HGNC:7594),PM3,Moderate,"1 point awarded from tables 7a and 7b
-Example: Detected in trans with a pathogenic variant (recessive).",Strength
-MYO15A (HGNC:7594),PM3,Supporting,"0.5 points awarded from tables 7a and 7b
-Examples: 
-Two variants that meet PM2_Supporting detected in trans; OR
-a homozygous variant meeting PM2_Supporting.",Strength
-MYO15A (HGNC:7594),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-MYO15A (HGNC:7594),PM4,Moderate,"Protein length change due to an in-frame deletion or insertion that are not located in repetitive regions.
-No changes. Follow recommendations as outlined in ACMG/AMP guidelines and/or Sequence Variant Interpretation working group.",
-MYO15A (HGNC:7594),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MYO15A (HGNC:7594),PM5,Strong,"Missense change at same codon as two different pathogenic missense variants.
-Located at an amino acid residue with known pathogenic variation (at least 2 other variants at the same site meet pathogenic criteria for based on independent data).
-
-
-
-
-Caveat: Assess whether the variants in question could have an impact at the DNA level, such as through splicing impacts.",None
-MYO15A (HGNC:7594),PM5,Moderate,"Missense change at same codon as another pathogenic missense variant.
-No changes. Follow recommendations as outlined in ACMG/AMP guidelines and/or Sequence Variant Interpretation working group.",None
-MYO15A (HGNC:7594),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-MYO15A (HGNC:7594),PM6,Moderate,See PS2 above.,None
-MYO15A (HGNC:7594),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-MYO15A (HGNC:7594),PP1,Strong,Segregation in three affected relatives for recessive.,Strength
-MYO15A (HGNC:7594),PP1,Moderate,Segregation in two affected relatives for recessive.,Strength
-MYO15A (HGNC:7594),PP1,Supporting,Segregation in one affected relative for recessive.,Strength
-MYO15A (HGNC:7594),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-MYO15A (HGNC:7594),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-MYO15A (HGNC:7594),PP3,Supporting,"REVEL score ≥0.7, or predicted impact to splicing using MaxEntScan.
-
-
-
-
-Use REVEL and MAXENTSCAN
-
-
-For missense variants, award PP3 if REVEL score is ≥0.7
-
-
-If splicing is predicted to be impacted, either creation of a cryptic splice site, or disruption of a native splice site, award PP3
-
-
-For splice variants (except for canonical -/+1 or 2), use MAXENTSCAN.
-
-
-For -/+ 1 or 2 splice variants, do not use PP3 if you are using PVS1",Disease-specific
-MYO15A (HGNC:7594),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-MYO15A (HGNC:7594),PP4,Supporting,"Patient's phenotype highly specific for gene or fully sequenced gene set (see specifications in Table 7).
-
-
-
-
-The HL-EP applied this rule to HL syndromes if all causative genes have been sequenced and the detection rate at least doubles when the added clinical feature is present.
-
-
-See table below for applicable gene-disease phenotypes.
-
-
-Advise against using PP4 for patients with nonsyndromic or apparently nonsyndromic hearing loss, given genetic heterogeneity.",Disease-specific
-MYO15A (HGNC:7594),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MYO15A (HGNC:7594),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-MYO15A (HGNC:7594),BA1,Stand Alone,MAF of ≥0.005 (0.5%) for autosomal recessive.,Disease-specific
-MYO15A (HGNC:7594),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-MYO15A (HGNC:7594),BS1,Very Strong,"MAF of ≥0.003 (0.3%) for autosomal recessive. Likely benign, provided there is no conflicting evidence.",Disease-specific
-MYO15A (HGNC:7594),BS1,Supporting,MAF of ≥0.0007 (0.07%) for autosomal recessive.,Disease-specific
-MYO15A (HGNC:7594),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-MYO15A (HGNC:7594),BS2,Strong,"Observation of variant (biallelic with known pathogenic variant for recessive) in controls inconsistent with disease penetrance.
-
-
-
-
-Advise caution when using this rule, since most of hearing loss is autosomal recessive, and autosomal dominant hearing loss could display reduced penetrance or variable expression.
-
-
-However, if biallelic observations in controls are inconsistent with disease penetrance, this may be applicable. Ensure age of the unaffected individual is appropriate. MYO15A and OTOF are expected to cause congenital or childhood onset hearing loss. Therefore, an adult (ie >18 years) may be an appropriate individual to consider application of this criteria. Please see additional considerations listed under BS4 “Genotype+/phenotype-”.",Disease-specific
-MYO15A (HGNC:7594),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-MYO15A (HGNC:7594),BS3,Supporting,"Functional study shows no deleterious effect (none are defined for OTOF and MYO15A).
-
-
-
-
-Recommend that functional evidence is not used as strong evidence, due to the absence of well-established functional studies for hearing loss genes.
-
-
-
-
-No specific assays are listed for OTOF or MYO15A. However, BS3_Supporting can be used for functional analyses if
-
-
-
-
-The assay has been validated by a known pathogenic and benign variant AND
-
-
-There is plausible reason that the function the assay is testing relates to the phenotype AND
-
-
-The assay conditions are likely to mimic the physiological environment.",Disease-specific
-MYO15A (HGNC:7594),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-MYO15A (HGNC:7594),BS4,Strong,"Non-segregation with disease.
-
-
-
-
-Phenotype+/genotype-
-
-
-Strong evidence for benign.
-
-
-Be cautious when using this as the possibility for phenocopy is high. The hearing loss phenotype should be consistent within the family to consider it a non-segregation, though intra-familial variability has been reported. Factors to consider are:
-
-
-Age of onset (ie. congenital/early childhood vs. adult onset)
-
-
-Hearing loss prevalence increases significantly with age. A congenital hearing loss in a child and a late onset hearing loss in a grandparent would not be a consistent phenotype.
-
-
-Severity (ie - mild vs. profound)
-
-
-Minor differences may exist among family members.
-
-
-Keep in mind that progression in older individuals may account for a discrepancy between individuals.
-
-
-Audiogram shape
-
-
-May not be completely consistent among family members even with same etiology.
-
-
-
-
-
-
-Genotype+/phenotype-
-
-
-
-
-
-
-Confounding variables to applying this rule: Age-related penetrance, variable expressivity, etc.
-
-
-
-
-If the gene is associated with later onset and individual with the non-segregation is beyond the expected age that the hearing loss would occur, consider applying BS4_Supporting
-.
-
-
-
-
-Recommend only using for fully penetrant genes (typically genes associated with AR hearing loss)
-o Must be confident that patient is truly unaffected and a hearing loss is not missed or subclinical. Be cautious if only phenotyping was newborn hearing screening. Diagnostic audiometric testing (auditory brainstem response (ABR) or audiogram should be required).
-
-
-
-
-Any evidence for reduced penetrance, do not use BS4.",Disease-specific
-MYO15A (HGNC:7594),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-MYO15A (HGNC:7594),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-MYO15A (HGNC:7594),BP2,Supporting,"Observed in trans with a dominant variant/observed in cis with a pathogenic variant (use with caution).
-
-
-
-
-Use with caution. For genes that are associated with both dominant and recessive hearing loss, consider whether an earlier onset/more severe phenotype could be present if variant is identified in trans with a dominant variant.",None
-MYO15A (HGNC:7594),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-MYO15A (HGNC:7594),BP3,Supporting,"In-frame indels in repeat region without known function.
-
-
-
-
-No changes. Follow recommendations as outlined in Richard 2015 and/or ClinGen's Sequence Variant Interpretation working group.",None
-MYO15A (HGNC:7594),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-MYO15A (HGNC:7594),BP4,Supporting,"Computational evidence suggests no impact; REVEL score ≤0.15 or no impact to splicing in MaxEntScan.
-
-
-
-
-Use REVEL, award BP4 if score is 0.15 or lower. Make sure to also check MAXENTSCAN to rule out the creation of a cryptic splice site.",Disease-specific
-MYO15A (HGNC:7594),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-MYO15A (HGNC:7594),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MYO15A (HGNC:7594),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-MYO15A (HGNC:7594),BP7,Supporting,"Silent variant with no predicted impact to splicing.
-
-
-
-
-No changes. Follow recommendations as outlined in Richard 2015 and/or ClinGen's Sequence Variant Interpretation working group.",None
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHereditaryBreast,OvarianandPancreaticCancerExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforATMVersion1.1_version=1.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHereditaryBreast,OvarianandPancreaticCancerExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforATMVersion1.1_version=1.1.0.csv
deleted file mode 100644
index f090deb019d0c1c02bc2322af1d277e4b6a24b80..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHereditaryBreast,OvarianandPancreaticCancerExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforATMVersion1.1_version=1.1.0.csv
+++ /dev/null
@@ -1,78 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-ATM (HGNC:795),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-ATM (HGNC:795),PVS1,Very Strong,Use ATM PVS1 Decision Tree,"Gene-specific,Strength"
-ATM (HGNC:795),PVS1,Strong,Use ATM PVS1 Decision Tree.,"Gene-specific,Strength"
-ATM (HGNC:795),PVS1,Moderate,Use ATM PVS1 Decision Tree.,"Gene-specific,Strength"
-ATM (HGNC:795),PVS1,Supporting,Use ATM PVS1 Decision Tree,"Gene-specific,Strength"
-ATM (HGNC:795),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-ATM (HGNC:795),PS1,Strong,Use for protein changes as long as splicing is ruled-out for both alterations.,General recommendation
-ATM (HGNC:795),PS1,Moderate,Use for RNA changes as code PS1_RNA_Moderate if predictions or observations are similar or worse for the variant under consideration. Close matches must be VCEP approved LP/P variants.,"Strength,General recommendation"
-ATM (HGNC:795),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",NA
-ATM (HGNC:795),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-ATM (HGNC:795),PS3,Strong,Do not use as strong.,Gene-specific
-ATM (HGNC:795),PS3,Moderate,Use when a variant fails to rescue both an ATM specifc feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity.,"Gene-specific,Strength"
-ATM (HGNC:795),PS3,Supporting,"Use when a variant fails to rescue an ATM specifc feature, only (e.g. phosphorylation of ATM-specific targets). Do not use for radiosensitivity-only as that is not a feature specific to ATM deficiency","Gene-specific,Strength"
-ATM (HGNC:795),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-ATM (HGNC:795),PS4,Strong,"Use for case control studies that reflect an OR ≥2, p≤.05 and lower 95% CI ≥1.5.",General recommendation
-ATM (HGNC:795),PS4,Moderate,Do not use for proband counting.,"Gene-specific,Disease-specific"
-ATM (HGNC:795),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-ATM (HGNC:795),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-ATM (HGNC:795),PM2,Supporting,Frequency ≤.001% when N>1 in a large general population database (e.g. gnomAD 2.1.1),"Gene-specific,Strength"
-ATM (HGNC:795),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-ATM (HGNC:795),PM3,Very Strong,Use ATM PM3/BP2 table.,"Gene-specific,Disease-specific,Strength,General recommendation"
-ATM (HGNC:795),PM3,Strong,Use ATM PM3/BP2 table.,"Gene-specific,Disease-specific,Strength,General recommendation"
-ATM (HGNC:795),PM3,Moderate,Use ATM PM3/BP2 table.,"Gene-specific,Disease-specific,Strength,General recommendation"
-ATM (HGNC:795),PM3,Supporting,Use ATM PM3/BP2 table,"Gene-specific,Disease-specific,Strength,General recommendation"
-ATM (HGNC:795),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-ATM (HGNC:795),PM4,Moderate,Use for stop-loss variants.,"Gene-specific,General recommendation"
-ATM (HGNC:795),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-ATM (HGNC:795),PM5,Supporting,Use for genomic frameshift and truncating variants with PTC upstream of p.R3047. Do not use for splice or start-loss variants,"Gene-specific,Strength"
-ATM (HGNC:795),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-ATM (HGNC:795),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",NA
-ATM (HGNC:795),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-ATM (HGNC:795),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-ATM (HGNC:795),PP3,Supporting,Protein: REVEL >.7333; RNA: multiple in silico predictors agree to a smilar effect,
-ATM (HGNC:795),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-ATM (HGNC:795),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-ATM (HGNC:795),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-ATM (HGNC:795),BA1,Stand Alone,Filtering Allele Frequency >.5%.,
-ATM (HGNC:795),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-ATM (HGNC:795),BS1,Strong,Filtering Allele Frequency >.05%.,
-ATM (HGNC:795),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",NA
-ATM (HGNC:795),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-ATM (HGNC:795),BS3,Moderate,Use when a variant rescues both an ATM specifc feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity.,"Gene-specific,Disease-specific,Strength,General Recommendation"
-ATM (HGNC:795),BS3,Supporting,Use when a variant rescues EITHER an ATM specifc feature OR rescues radiosensitivity.,"Gene-specific,Disease-specific,Strength,General Recommendation"
-ATM (HGNC:795),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",NA
-ATM (HGNC:795),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-ATM (HGNC:795),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-ATM (HGNC:795),BP2,Strong,Use ATM PM3/BP2 table.,"Gene-specific,Disease-specific,Strength,General recommendation"
-ATM (HGNC:795),BP2,Moderate,Use ATM PM3/BP2 table.,"Gene-specific,Disease-specific,Strength,General recommendation"
-ATM (HGNC:795),BP2,Supporting,Use ATM PM3/BP2 table,"Gene-specific,Disease-specific,Strength,General recommendation"
-ATM (HGNC:795),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-ATM (HGNC:795),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-ATM (HGNC:795),BP4,Supporting,,
-ATM (HGNC:795),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-ATM (HGNC:795),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-ATM (HGNC:795),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-ATM (HGNC:795),BP7,Strong,Can be considered for BP7_O with curator discretion of quality.,General recommendation
-ATM (HGNC:795),BP7,Moderate,Can be considered for BP7_O with curator discretion of quality.,General recommendation
-ATM (HGNC:795),BP7,Supporting,"Can be considered for BP7_O with curator discretion of quality; Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -40 at donor and acceptor sites, respectively",General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHereditaryBreast,OvarianandPancreaticCancerExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforATMVersion1.2.0_version=1.2.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHereditaryBreast,OvarianandPancreaticCancerExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforATMVersion1.2.0_version=1.2.0.csv
deleted file mode 100644
index 1032018b5d462b691994f3187c8ea3cef5fa63ae..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHereditaryBreast,OvarianandPancreaticCancerExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforATMVersion1.2.0_version=1.2.0.csv
+++ /dev/null
@@ -1,88 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-ATM (HGNC:795),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-ATM (HGNC:795),PVS1,Very Strong,Use ATM PVS1 Decision Tree,"Gene-specific,Strength"
-ATM (HGNC:795),PVS1,Strong,Use ATM PVS1 Decision Tree.,"Gene-specific,Strength"
-ATM (HGNC:795),PVS1,Moderate,Use ATM PVS1 Decision Tree.,"Gene-specific,Strength"
-ATM (HGNC:795),PVS1,Supporting,Use ATM PVS1 Decision Tree,"Gene-specific,Strength"
-ATM (HGNC:795),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-ATM (HGNC:795),PS1,Strong,Use for protein changes as long as splicing is ruled-out for both alterations. Use ATM PS1 Splicing table for splicing variants with similar predictions or observations of splice defect.,General recommendation
-ATM (HGNC:795),PS1,Moderate,Use for protein changes as long as splicing is ruled-out for both alterations. Use ATM PS1 Splicing table for splicing variants with similar predictions or observations of splice defect.,"General recommendation,Strength"
-ATM (HGNC:795),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",NA
-ATM (HGNC:795),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-ATM (HGNC:795),PS3,Strong,Do not use as strong.,Gene-specific
-ATM (HGNC:795),PS3,Moderate,Use when a variant fails to rescue both an ATM specifc feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity.,"Gene-specific,Strength"
-ATM (HGNC:795),PS3,Supporting,"Use when a variant fails to rescue an ATM specifc feature, only (e.g. phosphorylation of ATM-specific targets). Do not use for radiosensitivity-only as that is not a feature specific to ATM deficiency","Gene-specific,Strength"
-ATM (HGNC:795),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-ATM (HGNC:795),PS4,Strong,"Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk  ≥2 OR lower 95% CI ≥1.5).",General recommendation
-ATM (HGNC:795),PS4,Moderate,Do not use for proband counting.,"Disease-specific,Gene-specific"
-ATM (HGNC:795),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-ATM (HGNC:795),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-ATM (HGNC:795),PM2,Supporting,"Frequency ≤.001% if n=1 in a single sub population, that is sufficiently rare and PM2_supporting would apply. n>1 in one or multiple subpopulations would not be considered rare and PM2_supporting would not apply","Gene-specific,Strength"
-ATM (HGNC:795),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-ATM (HGNC:795),PM3,Very Strong,Use ATM PM3/BP2 table.,"Disease-specific,General recommendation,Gene-specific,Strength"
-ATM (HGNC:795),PM3,Strong,Use ATM PM3/BP2 table.,"Disease-specific,General recommendation,Gene-specific,Strength"
-ATM (HGNC:795),PM3,Moderate,Use ATM PM3/BP2 table.,"Disease-specific,General recommendation,Gene-specific,Strength"
-ATM (HGNC:795),PM3,Supporting,Use ATM PM3/BP2 table,"Disease-specific,General recommendation,Gene-specific,Strength"
-ATM (HGNC:795),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-ATM (HGNC:795),PM4,Moderate,Use for stop-loss variants.,"General recommendation,Gene-specific"
-ATM (HGNC:795),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-ATM (HGNC:795),PM5,Supporting,Use for genomic frameshift and truncating variants with PTC upstream of p.R3047. Apply also to splice variants as PM5_supporting for splice variants can only be applied for variants premature termination codons upstream of p.Arg3047 where PVS1_VS(RNA) is applied based on high quality observed splicing impact and must be NMD prone. Do not use for start-loss variants,"Gene-specific,Strength"
-ATM (HGNC:795),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-ATM (HGNC:795),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",NA
-ATM (HGNC:795),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-ATM (HGNC:795),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-ATM (HGNC:795),PP3,Supporting,Protein: REVEL >.7333; RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing,Gene-specific
-ATM (HGNC:795),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-ATM (HGNC:795),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-ATM (HGNC:795),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-ATM (HGNC:795),BA1,Stand Alone,Filtering Allele Frequency >.5%.,Disease-specific
-ATM (HGNC:795),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-ATM (HGNC:795),BS1,Strong,Filtering Allele Frequency >.05%.,Disease-specific
-ATM (HGNC:795),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",NA
-ATM (HGNC:795),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-ATM (HGNC:795),BS3,Moderate,Use when a variant rescues both an ATM specifc feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity.,"Disease-specific,Gene-specific,Strength"
-ATM (HGNC:795),BS3,Supporting,Use when a variant rescues EITHER an ATM specifc feature OR rescues radiosensitivity.,"Disease-specific,Gene-specific,Strength"
-ATM (HGNC:795),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",NA
-ATM (HGNC:795),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-ATM (HGNC:795),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-ATM (HGNC:795),BP2,Strong,Use ATM PM3/BP2 table.,"Disease-specific,General recommendation,Gene-specific,Strength"
-ATM (HGNC:795),BP2,Moderate,Use ATM PM3/BP2 table.,"Disease-specific,General recommendation,Gene-specific,Strength"
-ATM (HGNC:795),BP2,Supporting,Use ATM PM3/BP2 table,"Disease-specific,General recommendation,Gene-specific,Strength"
-ATM (HGNC:795),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-ATM (HGNC:795),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-ATM (HGNC:795),BP4,Supporting,"Protein
- Analysis: Metapredictor REVEL score ≤.249
-
-
-RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing 
-
-
-NOTE: Splice analysis needs to be considered for all variant types (including missense, frameshift, nonsense, etc. as any variant has the potential to impact splicing which may preclude any expected protein effects) 
-
-
-NOTE: BP4 for splice predictions may not be applied in conjunction with BP7_Variable(RNA) (a lack of observed RNA defect) Use caution in applying the wrong type of computational evidence (protein vs. RNA) towards the cumulative body of evidence for the opposite mechanism.",General recommendation
-ATM (HGNC:795),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-ATM (HGNC:795),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-ATM (HGNC:795),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-ATM (HGNC:795),BP7,Strong,Can be considered for BP7_(RNA) with curator discretion of quality.,General recommendation
-ATM (HGNC:795),BP7,Moderate,Can be considered for BP7_(RNA) with curator discretion of quality.,General recommendation
-ATM (HGNC:795),BP7,Supporting,"Can be considered for BP7_(RNA) with curator discretion of quality; Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -40 at donor and acceptor sites, respectively",General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHereditaryBreast,OvarianandPancreaticCancerExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforATMVersion1.3.0_version=1.3.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHereditaryBreast,OvarianandPancreaticCancerExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforATMVersion1.3.0_version=1.3.0.csv
deleted file mode 100644
index 1032018b5d462b691994f3187c8ea3cef5fa63ae..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHereditaryBreast,OvarianandPancreaticCancerExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforATMVersion1.3.0_version=1.3.0.csv
+++ /dev/null
@@ -1,88 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-ATM (HGNC:795),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-ATM (HGNC:795),PVS1,Very Strong,Use ATM PVS1 Decision Tree,"Gene-specific,Strength"
-ATM (HGNC:795),PVS1,Strong,Use ATM PVS1 Decision Tree.,"Gene-specific,Strength"
-ATM (HGNC:795),PVS1,Moderate,Use ATM PVS1 Decision Tree.,"Gene-specific,Strength"
-ATM (HGNC:795),PVS1,Supporting,Use ATM PVS1 Decision Tree,"Gene-specific,Strength"
-ATM (HGNC:795),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-ATM (HGNC:795),PS1,Strong,Use for protein changes as long as splicing is ruled-out for both alterations. Use ATM PS1 Splicing table for splicing variants with similar predictions or observations of splice defect.,General recommendation
-ATM (HGNC:795),PS1,Moderate,Use for protein changes as long as splicing is ruled-out for both alterations. Use ATM PS1 Splicing table for splicing variants with similar predictions or observations of splice defect.,"General recommendation,Strength"
-ATM (HGNC:795),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",NA
-ATM (HGNC:795),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-ATM (HGNC:795),PS3,Strong,Do not use as strong.,Gene-specific
-ATM (HGNC:795),PS3,Moderate,Use when a variant fails to rescue both an ATM specifc feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity.,"Gene-specific,Strength"
-ATM (HGNC:795),PS3,Supporting,"Use when a variant fails to rescue an ATM specifc feature, only (e.g. phosphorylation of ATM-specific targets). Do not use for radiosensitivity-only as that is not a feature specific to ATM deficiency","Gene-specific,Strength"
-ATM (HGNC:795),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-ATM (HGNC:795),PS4,Strong,"Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk  ≥2 OR lower 95% CI ≥1.5).",General recommendation
-ATM (HGNC:795),PS4,Moderate,Do not use for proband counting.,"Disease-specific,Gene-specific"
-ATM (HGNC:795),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-ATM (HGNC:795),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-ATM (HGNC:795),PM2,Supporting,"Frequency ≤.001% if n=1 in a single sub population, that is sufficiently rare and PM2_supporting would apply. n>1 in one or multiple subpopulations would not be considered rare and PM2_supporting would not apply","Gene-specific,Strength"
-ATM (HGNC:795),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-ATM (HGNC:795),PM3,Very Strong,Use ATM PM3/BP2 table.,"Disease-specific,General recommendation,Gene-specific,Strength"
-ATM (HGNC:795),PM3,Strong,Use ATM PM3/BP2 table.,"Disease-specific,General recommendation,Gene-specific,Strength"
-ATM (HGNC:795),PM3,Moderate,Use ATM PM3/BP2 table.,"Disease-specific,General recommendation,Gene-specific,Strength"
-ATM (HGNC:795),PM3,Supporting,Use ATM PM3/BP2 table,"Disease-specific,General recommendation,Gene-specific,Strength"
-ATM (HGNC:795),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-ATM (HGNC:795),PM4,Moderate,Use for stop-loss variants.,"General recommendation,Gene-specific"
-ATM (HGNC:795),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-ATM (HGNC:795),PM5,Supporting,Use for genomic frameshift and truncating variants with PTC upstream of p.R3047. Apply also to splice variants as PM5_supporting for splice variants can only be applied for variants premature termination codons upstream of p.Arg3047 where PVS1_VS(RNA) is applied based on high quality observed splicing impact and must be NMD prone. Do not use for start-loss variants,"Gene-specific,Strength"
-ATM (HGNC:795),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-ATM (HGNC:795),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",NA
-ATM (HGNC:795),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-ATM (HGNC:795),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-ATM (HGNC:795),PP3,Supporting,Protein: REVEL >.7333; RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing,Gene-specific
-ATM (HGNC:795),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-ATM (HGNC:795),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-ATM (HGNC:795),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-ATM (HGNC:795),BA1,Stand Alone,Filtering Allele Frequency >.5%.,Disease-specific
-ATM (HGNC:795),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-ATM (HGNC:795),BS1,Strong,Filtering Allele Frequency >.05%.,Disease-specific
-ATM (HGNC:795),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",NA
-ATM (HGNC:795),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-ATM (HGNC:795),BS3,Moderate,Use when a variant rescues both an ATM specifc feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity.,"Disease-specific,Gene-specific,Strength"
-ATM (HGNC:795),BS3,Supporting,Use when a variant rescues EITHER an ATM specifc feature OR rescues radiosensitivity.,"Disease-specific,Gene-specific,Strength"
-ATM (HGNC:795),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",NA
-ATM (HGNC:795),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-ATM (HGNC:795),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-ATM (HGNC:795),BP2,Strong,Use ATM PM3/BP2 table.,"Disease-specific,General recommendation,Gene-specific,Strength"
-ATM (HGNC:795),BP2,Moderate,Use ATM PM3/BP2 table.,"Disease-specific,General recommendation,Gene-specific,Strength"
-ATM (HGNC:795),BP2,Supporting,Use ATM PM3/BP2 table,"Disease-specific,General recommendation,Gene-specific,Strength"
-ATM (HGNC:795),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-ATM (HGNC:795),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-ATM (HGNC:795),BP4,Supporting,"Protein
- Analysis: Metapredictor REVEL score ≤.249
-
-
-RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing 
-
-
-NOTE: Splice analysis needs to be considered for all variant types (including missense, frameshift, nonsense, etc. as any variant has the potential to impact splicing which may preclude any expected protein effects) 
-
-
-NOTE: BP4 for splice predictions may not be applied in conjunction with BP7_Variable(RNA) (a lack of observed RNA defect) Use caution in applying the wrong type of computational evidence (protein vs. RNA) towards the cumulative body of evidence for the opposite mechanism.",General recommendation
-ATM (HGNC:795),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-ATM (HGNC:795),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-ATM (HGNC:795),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-ATM (HGNC:795),BP7,Strong,Can be considered for BP7_(RNA) with curator discretion of quality.,General recommendation
-ATM (HGNC:795),BP7,Moderate,Can be considered for BP7_(RNA) with curator discretion of quality.,General recommendation
-ATM (HGNC:795),BP7,Supporting,"Can be considered for BP7_(RNA) with curator discretion of quality; Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -40 at donor and acceptor sites, respectively",General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHereditaryBreast,OvarianandPancreaticCancerExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforATMVersion1_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHereditaryBreast,OvarianandPancreaticCancerExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforATMVersion1_version=1.0.0.csv
deleted file mode 100644
index 38e59cfe7deed216b24f8767f9f381b87118705f..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHereditaryBreast,OvarianandPancreaticCancerExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforATMVersion1_version=1.0.0.csv
+++ /dev/null
@@ -1,77 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-ATM (HGNC:795),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-ATM (HGNC:795),PVS1,Very Strong,Use ATM PVS1 Decision Tree,"Gene-specific,Strength"
-ATM (HGNC:795),PVS1,Strong,Use ATM PVS1 Decision Tree.,"Gene-specific,Strength"
-ATM (HGNC:795),PVS1,Moderate,Use ATM PVS1 Decision Tree.,"Gene-specific,Strength"
-ATM (HGNC:795),PVS1,Supporting,Use ATM PVS1 Decision Tree,"Gene-specific,Strength"
-ATM (HGNC:795),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-ATM (HGNC:795),PS1,Strong,Use for protein changes as long as splicing is ruled-out for both alterations.,General recommendation
-ATM (HGNC:795),PS1,Moderate,Use for RNA changes as code PS1_RNA_Moderate if predictions or observations are similar or worse for the variant under consideration. Close matches must be VCEP approved LP/P variants.,"Strength,General recommendation"
-ATM (HGNC:795),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",NA
-ATM (HGNC:795),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-ATM (HGNC:795),PS3,Strong,Do not use as strong.,Gene-specific
-ATM (HGNC:795),PS3,Moderate,Use when a variant fails to rescue both an ATM specifc feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity.,"Gene-specific,Strength"
-ATM (HGNC:795),PS3,Supporting,"Use when a variant fails to rescue an ATM specifc feature, only (e.g. phosphorylation of ATM-specific targets). Do not use for radiosensitivity-only as that is not a feature specific to ATM deficiency","Gene-specific,Strength"
-ATM (HGNC:795),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-ATM (HGNC:795),PS4,Strong,"Use for case control studies that reflect an OR ≥2, p≤.05 and lower 95% CI ≥1.5.",General recommendation
-ATM (HGNC:795),PS4,Moderate,Do not use for proband counting.,"Gene-specific,Disease-specific"
-ATM (HGNC:795),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-ATM (HGNC:795),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-ATM (HGNC:795),PM2,Supporting,Frequency ≤.001% when N>1 in a large general population database (e.g. gnomAD 2.1.1),"Gene-specific,Strength"
-ATM (HGNC:795),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-ATM (HGNC:795),PM3,Very Strong,Use ATM PM3/BP2 table.,"Gene-specific,Disease-specific,Strength,General recommendation"
-ATM (HGNC:795),PM3,Strong,Use ATM PM3/BP2 table.,"Gene-specific,Disease-specific,Strength,General recommendation"
-ATM (HGNC:795),PM3,Moderate,Use ATM PM3/BP2 table.,"Gene-specific,Disease-specific,Strength,General recommendation"
-ATM (HGNC:795),PM3,Supporting,Use ATM PM3/BP2 table,"Gene-specific,Disease-specific,Strength,General recommendation"
-ATM (HGNC:795),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-ATM (HGNC:795),PM4,Moderate,Use for stop-loss variants.,"Gene-specific,General recommendation"
-ATM (HGNC:795),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-ATM (HGNC:795),PM5,Supporting,Use for genomic frameshift and truncating variants with PTC upstream of p.R3047. Do not use for splice or start-loss variants,"Gene-specific,Strength"
-ATM (HGNC:795),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-ATM (HGNC:795),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",NA
-ATM (HGNC:795),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-ATM (HGNC:795),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-ATM (HGNC:795),PP3,Supporting,Protein: REVEL >.7333; RNA: multiple in silico predictors agree to a smilar effect,
-ATM (HGNC:795),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-ATM (HGNC:795),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-ATM (HGNC:795),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-ATM (HGNC:795),BA1,Stand Alone,Filtering Allele Frequency >.5%.,
-ATM (HGNC:795),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-ATM (HGNC:795),BS1,Strong,Filtering Allele Frequency >.05%.,
-ATM (HGNC:795),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",NA
-ATM (HGNC:795),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-ATM (HGNC:795),BS3,Moderate,Use when a variant rescues both an ATM specifc feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity.,"Gene-specific,Disease-specific,Strength,General Recommendation"
-ATM (HGNC:795),BS3,Supporting,Use when a variant rescues EITHER an ATM specifc feature OR rescues radiosensitivity.,"Gene-specific,Disease-specific,Strength,General Recommendation"
-ATM (HGNC:795),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",NA
-ATM (HGNC:795),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-ATM (HGNC:795),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-ATM (HGNC:795),BP2,Strong,Use ATM PM3/BP2 table.,"Gene-specific,Disease-specific,Strength,General recommendation"
-ATM (HGNC:795),BP2,Moderate,Use ATM PM3/BP2 table.,"Gene-specific,Disease-specific,Strength,General recommendation"
-ATM (HGNC:795),BP2,Supporting,Use ATM PM3/BP2 table,"Gene-specific,Disease-specific,Strength,General recommendation"
-ATM (HGNC:795),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-ATM (HGNC:795),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",NA
-ATM (HGNC:795),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-ATM (HGNC:795),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-ATM (HGNC:795),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-ATM (HGNC:795),BP7,Strong,Can be considered for BP7_O with curator discretion of quality.,General recommendation
-ATM (HGNC:795),BP7,Moderate,Can be considered for BP7_O with curator discretion of quality.,General recommendation
-ATM (HGNC:795),BP7,Supporting,"Can be considered for BP7_O with curator discretion of quality; Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -40 at donor and acceptor sites, respectively",General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHereditaryBreast,OvarianandPancreaticCancerExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPALB2Version1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHereditaryBreast,OvarianandPancreaticCancerExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPALB2Version1.0.0_version=1.0.0.csv
deleted file mode 100644
index d94b197649b3ad2e24937dc7edce36ad65d5d49d..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHereditaryBreast,OvarianandPancreaticCancerExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPALB2Version1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,93 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-PALB2 (HGNC:26144),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-PALB2 (HGNC:26144),PVS1,Very Strong,Use PALB2 PVS1 Decision Tree,"Gene-specific,Strength"
-PALB2 (HGNC:26144),PVS1,Strong,Use PALB2 PVS1 Decision Tree.,"Gene-specific,Strength"
-PALB2 (HGNC:26144),PVS1,Moderate,Use PALB2 PVS1 Decision Tree.,"Gene-specific,Strength"
-PALB2 (HGNC:26144),PVS1,Supporting,Use PALB2 PVS1 Decision Tree,"Gene-specific,Strength"
-PALB2 (HGNC:26144),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-PALB2 (HGNC:26144),PS1,Strong,Use PALB2 PS1 Splicing table,General recommendation
-PALB2 (HGNC:26144),PS1,Moderate,Use PALB2 PS1 Splicing table,General recommendation
-PALB2 (HGNC:26144),PS1,Supporting,Use PALB2 PS1 Splicing table,General recommendation
-PALB2 (HGNC:26144),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",NA
-PALB2 (HGNC:26144),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",NA
-PALB2 (HGNC:26144),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-PALB2 (HGNC:26144),PS4,Strong,"Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk  ≥3 OR lower 95% CI ≥1.5).",Disease-specific
-PALB2 (HGNC:26144),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-PALB2 (HGNC:26144),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-PALB2 (HGNC:26144),PM2,Supporting,"Variant absent in gnomAD or present in ≤ 1/300,000 alleles","Gene-specific,Strength"
-PALB2 (HGNC:26144),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-PALB2 (HGNC:26144),PM3,Strong,Use Fanconi Anemia PM3 tables,"Disease-specific,Strength"
-PALB2 (HGNC:26144),PM3,Moderate,Use Fanconi Anemia PM3 tables,"Disease-specific,Strength"
-PALB2 (HGNC:26144),PM3,Supporting,Use Fanconi Anemia PM3 tables,"Disease-specific,Strength"
-PALB2 (HGNC:26144),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,NA
-PALB2 (HGNC:26144),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-PALB2 (HGNC:26144),PM5,Supporting,"Apply to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183, based on location of the most C-terminal known pathogenic variant, p.Tyr1183*","Gene-specific,Strength"
-PALB2 (HGNC:26144),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-PALB2 (HGNC:26144),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-PALB2 (HGNC:26144),PP1,Strong,LOD ≥1.26 or Bayes Factor (LR) ≥18:1,Gene-specific
-PALB2 (HGNC:26144),PP1,Moderate,LOD ≥.60 or Bayes Factor (LR) ≥4:1,Gene-specific
-PALB2 (HGNC:26144),PP1,Supporting,LOD ≥0.3 or Bayes Factor (LR) ≥2:1,Gene-specific
-PALB2 (HGNC:26144),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-PALB2 (HGNC:26144),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-PALB2 (HGNC:26144),PP3,Supporting,"Protein: Do not use.
-
-
-RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing",General recommendation
-PALB2 (HGNC:26144),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-PALB2 (HGNC:26144),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-PALB2 (HGNC:26144),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-PALB2 (HGNC:26144),BA1,Stand Alone,"GnomAD 
-Filtering Allele Frequency
- Allele frequency
-
-
->0.1%","Disease-specific,Gene-specific"
-PALB2 (HGNC:26144),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-PALB2 (HGNC:26144),BS1,Strong,"GnomAD 
-Filtering Allele Frequency
- greater than expected for disease
-
-
->.01%","Disease-specific,Gene-specific"
-PALB2 (HGNC:26144),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-PALB2 (HGNC:26144),BS2,Strong,Per Fanconi Anemia BS2 tables,Disease-specific
-PALB2 (HGNC:26144),BS2,Moderate,Per Fanconi Anemia BS2 tables,Disease-specific
-PALB2 (HGNC:26144),BS2,Supporting,Per Fanconi Anemia BS2 tables,Disease-specific
-PALB2 (HGNC:26144),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-PALB2 (HGNC:26144),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-PALB2 (HGNC:26144),BS4,Strong,LOD ≤ -1.28 or Bayes Factor (LR) LR≤.053:1,Gene-specific
-PALB2 (HGNC:26144),BS4,Moderate,LOD ≤ -.64 or Bayes Factor (LR) ≤.23,Gene-specific
-PALB2 (HGNC:26144),BS4,Supporting,LOD ≤-.32 or Bayes Factor (LR) ≤.48,Gene-specific
-PALB2 (HGNC:26144),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-PALB2 (HGNC:26144),BP1,Supporting,Apply to all missense variants.,Gene-specific
-PALB2 (HGNC:26144),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-PALB2 (HGNC:26144),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-PALB2 (HGNC:26144),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",NA
-PALB2 (HGNC:26144),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-PALB2 (HGNC:26144),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-PALB2 (HGNC:26144),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-PALB2 (HGNC:26144),BP7,Strong,BP7_Strong(RNA): Observed lack of aberrant RNA defect for silent substitutions and intronic variants. May reduce weight applied depending on assay quality.,General recommendation
-PALB2 (HGNC:26144),BP7,Moderate,BP7_Variable(RNA):Observed Lack of aberrant RNA defect with variable weight applied depending on assay quality,General recommendation
-PALB2 (HGNC:26144),BP7,Supporting,"BP7: Synonymous and deep intronic
-
-
-BP7_Variable(RNA): Observed Lack of aberrant RNA defect with variable weight applied depending on assay quality",General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHereditaryBreast,OvarianandPancreaticCancerExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPALB2Version1.1.0_version=1.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHereditaryBreast,OvarianandPancreaticCancerExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPALB2Version1.1.0_version=1.1.0.csv
deleted file mode 100644
index 2661610b41744e438c31b96ea958ecd01ee04875..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHereditaryBreast,OvarianandPancreaticCancerExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPALB2Version1.1.0_version=1.1.0.csv
+++ /dev/null
@@ -1,106 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-PALB2 (HGNC:26144),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-PALB2 (HGNC:26144),PVS1,Very Strong,Use PALB2 PVS1 Decision Tree,"Gene-specific,Strength"
-PALB2 (HGNC:26144),PVS1,Strong,Use PALB2 PVS1 Decision Tree.,"Gene-specific,Strength"
-PALB2 (HGNC:26144),PVS1,Moderate,Use PALB2 PVS1 Decision Tree.,"Gene-specific,Strength"
-PALB2 (HGNC:26144),PVS1,Supporting,Use PALB2 PVS1 Decision Tree,"Gene-specific,Strength"
-PALB2 (HGNC:26144),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-PALB2 (HGNC:26144),PS1,Strong,Use PALB2 PS1 Splicing table,General recommendation
-PALB2 (HGNC:26144),PS1,Moderate,Use PALB2 PS1 Splicing table,General recommendation
-PALB2 (HGNC:26144),PS1,Supporting,Use PALB2 PS1 Splicing table,General recommendation
-PALB2 (HGNC:26144),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",NA
-PALB2 (HGNC:26144),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",NA
-PALB2 (HGNC:26144),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-PALB2 (HGNC:26144),PS4,Strong,"Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk  ≥3 OR lower 95% CI ≥1.5).",Disease-specific
-PALB2 (HGNC:26144),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-PALB2 (HGNC:26144),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-PALB2 (HGNC:26144),PM2,Supporting,"Variant absent in gnomAD or present in ≤ 1/300,000 alleles","Gene-specific,Strength"
-PALB2 (HGNC:26144),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-PALB2 (HGNC:26144),PM3,Strong,Use Fanconi Anemia PM3 tables,"Disease-specific,Strength"
-PALB2 (HGNC:26144),PM3,Moderate,Use Fanconi Anemia PM3 tables,"Disease-specific,Strength"
-PALB2 (HGNC:26144),PM3,Supporting,Use Fanconi Anemia PM3 tables,"Disease-specific,Strength"
-PALB2 (HGNC:26144),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,NA
-PALB2 (HGNC:26144),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-PALB2 (HGNC:26144),PM5,Supporting,"Apply to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183, based on location of the most C-terminal known pathogenic variant, p.Tyr1183*","Gene-specific,Strength"
-PALB2 (HGNC:26144),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-PALB2 (HGNC:26144),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-PALB2 (HGNC:26144),PP1,Strong,LOD ≥1.26 or Bayes Factor (LR) ≥18:1,Gene-specific
-PALB2 (HGNC:26144),PP1,Moderate,LOD ≥.60 or Bayes Factor (LR) ≥4:1,Gene-specific
-PALB2 (HGNC:26144),PP1,Supporting,LOD ≥0.3 or Bayes Factor (LR) ≥2:1,Gene-specific
-PALB2 (HGNC:26144),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-PALB2 (HGNC:26144),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-PALB2 (HGNC:26144),PP3,Supporting,"Protein: Do not use.
-
-
-RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing",General recommendation
-PALB2 (HGNC:26144),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-PALB2 (HGNC:26144),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-PALB2 (HGNC:26144),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-PALB2 (HGNC:26144),BA1,Stand Alone,"GnomAD 
-Filtering Allele Frequency
- Allele frequency
-
-
->0.1%","Disease-specific,Gene-specific"
-PALB2 (HGNC:26144),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-PALB2 (HGNC:26144),BS1,Strong,"GnomAD 
-Filtering Allele Frequency
- greater than expected for disease
-
-
->.01%","Disease-specific,Gene-specific"
-PALB2 (HGNC:26144),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-PALB2 (HGNC:26144),BS2,Strong,Per Fanconi Anemia BS2 tables,Disease-specific
-PALB2 (HGNC:26144),BS2,Moderate,Per Fanconi Anemia BS2 tables,Disease-specific
-PALB2 (HGNC:26144),BS2,Supporting,Per Fanconi Anemia BS2 tables,Disease-specific
-PALB2 (HGNC:26144),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-PALB2 (HGNC:26144),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-PALB2 (HGNC:26144),BS4,Strong,LOD ≤ -1.28 or Bayes Factor (LR) LR≤.053:1,Gene-specific
-PALB2 (HGNC:26144),BS4,Moderate,LOD ≤ -.64 or Bayes Factor (LR) ≤.23,Gene-specific
-PALB2 (HGNC:26144),BS4,Supporting,LOD ≤-.32 or Bayes Factor (LR) ≤.48,Gene-specific
-PALB2 (HGNC:26144),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-PALB2 (HGNC:26144),BP1,Supporting,Apply to all missense variants.,Gene-specific
-PALB2 (HGNC:26144),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-PALB2 (HGNC:26144),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-PALB2 (HGNC:26144),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-PALB2 (HGNC:26144),BP4,Supporting,"● Protein: Do not use. So far, published predictors have yet to achieve functional outcome for PALB2 missense variants 
-
-
-● RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows no impact on splicing 
-
-
-o NOTE: Splice analysis needs to be considered for all variant types (including missense, frameshift, nonsense, etc. as any variant has the potential to impact splicing which may preclude any expected protein effects) 
-
-
-o NOTE: BP4 for splice predictions may not be applied in conjunction with BP7_Variable(RNA) (a lack of observed RNA defect) 
-
-
-o Use caution in applying the wrong type of computational evidence (protein vs. RNA) towards the cumulative body of evidence for the opposite mechanism.",General recommendation
-PALB2 (HGNC:26144),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-PALB2 (HGNC:26144),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-PALB2 (HGNC:26144),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-PALB2 (HGNC:26144),BP7,Strong,BP7_Strong(RNA): Observed lack of aberrant RNA defect for silent substitutions and intronic variants. May reduce weight applied depending on assay quality.,General recommendation
-PALB2 (HGNC:26144),BP7,Moderate,BP7_Variable(RNA):Observed Lack of aberrant RNA defect with variable weight applied depending on assay quality,General recommendation
-PALB2 (HGNC:26144),BP7,Supporting,"BP7: Synonymous and deep intronic
-
-
-BP7_Variable(RNA): Observed Lack of aberrant RNA defect with variable weight applied depending on assay quality",General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHereditaryHemorrhagicTelangiectasiaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforACVRL1Version1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHereditaryHemorrhagicTelangiectasiaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforACVRL1Version1.0.0_version=1.0.0.csv
deleted file mode 100644
index 52d2813087c68beb50a00937d385008b75f1bca2..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHereditaryHemorrhagicTelangiectasiaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforACVRL1Version1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,164 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-ACVRL1 (HGNC:175),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-ACVRL1 (HGNC:175),PVS1,Very Strong,Use ACVRL1 PVS1 Decision Tree (see attachments),"Gene-specific,Strength"
-ACVRL1 (HGNC:175),PVS1,Strong,Use ACVRL1 PVS1 Decision Tree (see attachments),"Gene-specific,Strength"
-ACVRL1 (HGNC:175),PVS1,Moderate,Use ACVRL1 PVS1 Decision Tree (see attachments),"Gene-specific,Strength"
-ACVRL1 (HGNC:175),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-ACVRL1 (HGNC:175),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",No change
-ACVRL1 (HGNC:175),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-ACVRL1 (HGNC:175),PS2,Strong,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Clarification,Disease-specific"
-ACVRL1 (HGNC:175),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-ACVRL1 (HGNC:175),PS3,Strong,"mRNA splicing assays can be used as strong functional evidence. 
-
-
-Note:
- level of evidence used may differ depending on whether the abnormal transcript is in-frame or out-of-frame, and whether there is complete or incomplete splicing impact.","Disease-specific,Strength"
-ACVRL1 (HGNC:175),PS3,Moderate,See PS3_Supporting and Instructions below.,"Disease-specific,Strength"
-ACVRL1 (HGNC:175),PS3,Supporting,"Protein expression assays: Metabolic label & IP, WB & FACS HUVECs/BOECs, FACs activated monocytes, cDNA transfect, WB & ML HEK293T/COS/NIH3T3, cDNA transfect & luciferase HepG2
-
-
-Note:
- Decreased protein expression can be used as supporting pathogenic evidence if experiment was not done in a single assay, and the corresponding densitometry of western blot reflects the conclusion drawn.
-
-
-
-
-
-
-Intracellular signaling assays: BRE/CAGA-luciferase, Gal4 Smad1/Smad3 for TGF-beta/BMP9 signaling
-
-
-Binding assays: BMP9 binding, transcription factor Sp1, BMP9 protein-protein interaction (BLI)
-
-
-Subcellular protein localization
-
-
-Morphology: Morphology & actin cytoskeleton, tubulogenesis
-
-
-Somatic variant 2
-nd
- hit: In vivo evidence can be obtained as supporting functional evidence by identification of somatic variants in telangiectases´ biopsies using NGS, suggesting a second-hit mechanism leading to biallelic LOF (PMID: 31630786).","Disease-specific,Strength"
-ACVRL1 (HGNC:175),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-ACVRL1 (HGNC:175),PS4,Strong,4+ probands with phenotype consistent with HHT.,Disease-specific
-ACVRL1 (HGNC:175),PS4,Moderate,2-3 probands with phenotype consistent with HHT.,Disease-specific
-ACVRL1 (HGNC:175),PS4,Supporting,1 proband with phenotype consistent with HHT.,Disease-specific
-ACVRL1 (HGNC:175),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-ACVRL1 (HGNC:175),PM1,Moderate,"Apply if variant is located in a critical residue:
-
-
-
-
-ACVRL1
-:
-
-
-glycine-rich loop: G209-V216
-
-
-phosphate anchor: K229
-
-
-C-helix E pairing the phosphate anchor: E242
-
-
-catalytic loop: R329-N335
-
-
-metal-binding loop: D348-L351
-
-
-BMP10
- interaction cluster
-
-
-(Cys46, Cys51, Val56, Arg61, His66, Asn71, Leu76, Pro81, Asn86, Asp91)",Gene-specific
-ACVRL1 (HGNC:175),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-ACVRL1 (HGNC:175),PM2,Supporting,<6 total alleles in gnomAD or <0.00004 (0.004%) in gnomAD subpopulations.,"Disease-specific,Strength"
-ACVRL1 (HGNC:175),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-ACVRL1 (HGNC:175),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-ACVRL1 (HGNC:175),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,None
-ACVRL1 (HGNC:175),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-ACVRL1 (HGNC:175),PM5,Strong,≥2 different missense changes at same codon have been determined to be likely pathogenic or pathogenic based on HHT VCEP rules.,"Disease-specific,Strength"
-ACVRL1 (HGNC:175),PM5,Moderate,A different missense change at same codon has been determined to be likely pathogenic or pathogenic based on HHT VCEP rules.,"Disease-specific,Strength"
-ACVRL1 (HGNC:175),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-ACVRL1 (HGNC:175),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-ACVRL1 (HGNC:175),PP1,Strong,5+ meioses (1/32 likelihood),"Disease-specific,Strength"
-ACVRL1 (HGNC:175),PP1,Moderate,4 meioses (1/16 likelihood),"Disease-specific,Strength"
-ACVRL1 (HGNC:175),PP1,Supporting,3 meioses (1/8 likelihood),"Disease-specific,Strength"
-ACVRL1 (HGNC:175),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-ACVRL1 (HGNC:175),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-ACVRL1 (HGNC:175),PP3,Supporting,"For missense variants: REVEL score ≥0.644 or SpliceAI score ≥0.2.
-
-
-For synonymous and intronic variants: SpliceAI score ≥0.2.",Disease-specific
-ACVRL1 (HGNC:175),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-ACVRL1 (HGNC:175),PP4,Moderate,"Patient's phenotype meets consensus clinical diagnostic (Curaçao) criteria for HHT, and sequencing and large deletion/duplication analysis was performed for both 
-ENG
- and 
-ACVRL1
- with any other identified variants ruled out.","Disease-specific,Strength"
-ACVRL1 (HGNC:175),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-ACVRL1 (HGNC:175),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-ACVRL1 (HGNC:175),BA1,Stand Alone,Allele frequency is ≥1% in general population databases (e.g. gnomAD) based on Popmax FAF.,Disease-specific
-ACVRL1 (HGNC:175),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-ACVRL1 (HGNC:175),BS1,Strong,">0.2% to <1% in general population databases (e.g. gnomAD) based on Popmax FAF, 
-or
- if variant meets BS1_Supporting and has ≥2 homozygotes.","Disease-specific,Strength"
-ACVRL1 (HGNC:175),BS1,Supporting,>0.08% to 0.2% (based on gnomAD Popmax FAF).,"Disease-specific,Strength"
-ACVRL1 (HGNC:175),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",NA
-ACVRL1 (HGNC:175),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-ACVRL1 (HGNC:175),BS3,Supporting,"mRNA splicing assays 
-
-
-Intracellular signaling assays: BRE/CAGA-luciferase, Gal4 Smad1/Smad3 for TGF-beta/BMP9 signaling
-
-
-Binding assays: BMP9 binding, transcription factor Sp1, BMP9 protein-protein interaction (BLI)
-
-
-Subcellular protein localization
-
-
-Morphology: Morphology & actin cytoskeleton, tubulogenesis","Disease-specific,Strength"
-ACVRL1 (HGNC:175),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-ACVRL1 (HGNC:175),BS4,Strong,Lack of segregation in affected members of a family.,"Clarification,Disease-specific"
-ACVRL1 (HGNC:175),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-ACVRL1 (HGNC:175),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-ACVRL1 (HGNC:175),BP2,Supporting,Observed in trans with a pathogenic or likely pathogenic variant based on HHT VCEP rules.,Disease-specific
-ACVRL1 (HGNC:175),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-ACVRL1 (HGNC:175),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-ACVRL1 (HGNC:175),BP4,Supporting,"For missense variants: REVEL score ≤0.15 and SpliceAI score ≤0.1.
-
-
-For synonymous and intronic variants: SpliceAI score ≤0.1.",Disease-specific
-ACVRL1 (HGNC:175),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-ACVRL1 (HGNC:175),BP5,Supporting,"Apply if a likely pathogenic or pathogenic variant (based on HHT VCEP rules) is found in 
-ENG
-.",Disease-specific
-ACVRL1 (HGNC:175),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-ACVRL1 (HGNC:175),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-ACVRL1 (HGNC:175),BP7,Supporting,A synonymous or intronic variant for which SpliceAI predicts no impact to the splice consensus sequence nor the creation of a new splice site. Can be used together with BP4 evidence.,Disease-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHereditaryHemorrhagicTelangiectasiaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforACVRL1Version1.1.0_version=1.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHereditaryHemorrhagicTelangiectasiaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforACVRL1Version1.1.0_version=1.1.0.csv
deleted file mode 100644
index b3056524bbefbf14b8c586c6837ae1c483ac5c2c..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHereditaryHemorrhagicTelangiectasiaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforACVRL1Version1.1.0_version=1.1.0.csv
+++ /dev/null
@@ -1,167 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-ACVRL1 (HGNC:175),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-ACVRL1 (HGNC:175),PVS1,Very Strong,Use ACVRL1 PVS1 Decision Tree (see attachments),"Gene-specific,Strength"
-ACVRL1 (HGNC:175),PVS1,Strong,Use ACVRL1 PVS1 Decision Tree (see attachments),"Gene-specific,Strength"
-ACVRL1 (HGNC:175),PVS1,Moderate,Use ACVRL1 PVS1 Decision Tree (see attachments),"Gene-specific,Strength"
-ACVRL1 (HGNC:175),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-ACVRL1 (HGNC:175),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",No change
-ACVRL1 (HGNC:175),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-ACVRL1 (HGNC:175),PS2,Strong,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Clarification,Disease-specific"
-ACVRL1 (HGNC:175),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-ACVRL1 (HGNC:175),PS3,Strong,"mRNA splicing assays can be used as strong functional evidence. 
-
-
-Note:
- level of evidence used may differ depending on whether the abnormal transcript is in-frame or out-of-frame, and whether there is complete or incomplete splicing impact.
-
-
-Do not use PS3 for splice variants that meet PVS1.","Disease-specific,Strength"
-ACVRL1 (HGNC:175),PS3,Moderate,See PS3_Supporting and Instructions below.,"Disease-specific,Strength"
-ACVRL1 (HGNC:175),PS3,Supporting,"Protein expression assays: Metabolic label & IP, WB & FACS HUVECs/BOECs, FACs activated monocytes, cDNA transfect, WB & ML HEK293T/COS/NIH3T3, cDNA transfect & luciferase HepG2
-
-
-Note:
- Decreased protein expression can be used as supporting pathogenic evidence if experiment was not done in a single assay, and the corresponding densitometry of western blot reflects the conclusion drawn.
-
-
-
-
-
-
-Intracellular signaling assays: BRE/CAGA-luciferase, Gal4 Smad1/Smad3 for TGF-beta/BMP9 signaling
-
-
-Binding assays: BMP9 binding, transcription factor Sp1, BMP9 protein-protein interaction (BLI)
-
-
-Subcellular protein localization
-
-
-Morphology: Morphology & actin cytoskeleton, tubulogenesis
-
-
-Somatic variant 2
-nd
- hit: In vivo evidence can be obtained as supporting functional evidence by identification of somatic variants in telangiectases´ biopsies using NGS, suggesting a second-hit mechanism leading to biallelic LOF (PMID: 31630786).","Disease-specific,Strength"
-ACVRL1 (HGNC:175),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-ACVRL1 (HGNC:175),PS4,Strong,4+ probands with phenotype consistent with HHT.,Disease-specific
-ACVRL1 (HGNC:175),PS4,Moderate,2-3 probands with phenotype consistent with HHT.,Disease-specific
-ACVRL1 (HGNC:175),PS4,Supporting,1 proband with phenotype consistent with HHT.,Disease-specific
-ACVRL1 (HGNC:175),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-ACVRL1 (HGNC:175),PM1,Moderate,"Apply if variant is located in a critical residue:
-
-
-
-
-ACVRL1
-:
-
-
-glycine-rich loop: G209-V216
-
-
-phosphate anchor: K229
-
-
-C-helix E pairing the phosphate anchor: E242
-
-
-catalytic loop: R329-N335
-
-
-metal-binding loop: D348-L351
-
-
-BMP10
- interaction cluster
-
-
-(His40, Val54, Val56, Arg57, Glu58, Glu59, His66, Asn71, Leu72, His73, Glu75, Leu76, Arg78, Gly79, Arg80, Thr82, Glu83, Phe84, Val85, His87)",Gene-specific
-ACVRL1 (HGNC:175),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-ACVRL1 (HGNC:175),PM2,Supporting,<6 total alleles in gnomAD or <0.00004 (0.004%) in gnomAD subpopulations.,"Disease-specific,Strength"
-ACVRL1 (HGNC:175),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-ACVRL1 (HGNC:175),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-ACVRL1 (HGNC:175),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,None
-ACVRL1 (HGNC:175),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-ACVRL1 (HGNC:175),PM5,Strong,≥2 different missense changes at same codon have been determined to be likely pathogenic or pathogenic based on HHT VCEP rules.,"Disease-specific,Strength"
-ACVRL1 (HGNC:175),PM5,Moderate,A different missense change at same codon has been determined to be likely pathogenic or pathogenic based on HHT VCEP rules.,"Disease-specific,Strength"
-ACVRL1 (HGNC:175),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-ACVRL1 (HGNC:175),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-ACVRL1 (HGNC:175),PP1,Strong,5+ meioses (1/32 likelihood),"Disease-specific,Strength"
-ACVRL1 (HGNC:175),PP1,Moderate,4 meioses (1/16 likelihood),"Disease-specific,Strength"
-ACVRL1 (HGNC:175),PP1,Supporting,3 meioses (1/8 likelihood),"Disease-specific,Strength"
-ACVRL1 (HGNC:175),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-ACVRL1 (HGNC:175),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-ACVRL1 (HGNC:175),PP3,Supporting,"For missense variants: REVEL score ≥0.644 or SpliceAI score ≥0.2.
-
-
-For synonymous and intronic variants: SpliceAI score ≥0.2.",Disease-specific
-ACVRL1 (HGNC:175),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-ACVRL1 (HGNC:175),PP4,Moderate,"Patient's phenotype meets consensus clinical diagnostic (Curaçao) criteria for HHT, and sequencing and large deletion/duplication analysis was performed for both 
-ENG
- and 
-ACVRL1
- with any other identified variants ruled out.","Disease-specific,Strength"
-ACVRL1 (HGNC:175),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-ACVRL1 (HGNC:175),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-ACVRL1 (HGNC:175),BA1,Stand Alone,Allele frequency is ≥1% in general population databases (e.g. gnomAD) based on Popmax FAF.,Disease-specific
-ACVRL1 (HGNC:175),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-ACVRL1 (HGNC:175),BS1,Strong,">0.2% to <1% in general population databases (e.g. gnomAD) based on Popmax FAF, 
-or
- if variant meets BS1_Supporting and has ≥2 homozygotes.","Disease-specific,Strength"
-ACVRL1 (HGNC:175),BS1,Supporting,>0.08% to 0.2% (based on gnomAD Popmax FAF).,"Disease-specific,Strength"
-ACVRL1 (HGNC:175),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",NA
-ACVRL1 (HGNC:175),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-ACVRL1 (HGNC:175),BS3,Supporting,"mRNA splicing assays 
-
-
-Intracellular signaling assays: BRE/CAGA-luciferase, Gal4 Smad1/Smad3 for TGF-beta/BMP9 signaling
-
-
-Binding assays: BMP9 binding, transcription factor Sp1, BMP9 protein-protein interaction (BLI)
-
-
-Subcellular protein localization
-
-
-Morphology: Morphology & actin cytoskeleton, tubulogenesis","Disease-specific,Strength"
-ACVRL1 (HGNC:175),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-ACVRL1 (HGNC:175),BS4,Strong,Lack of segregation in affected members of a family.,"Clarification,Disease-specific"
-ACVRL1 (HGNC:175),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-ACVRL1 (HGNC:175),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-ACVRL1 (HGNC:175),BP2,Supporting,Observed in trans with a pathogenic or likely pathogenic variant based on HHT VCEP rules.,Disease-specific
-ACVRL1 (HGNC:175),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-ACVRL1 (HGNC:175),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-ACVRL1 (HGNC:175),BP4,Supporting,"For missense variants: REVEL score ≤0.15 and SpliceAI score ≤0.1.
-
-
-For synonymous and intronic variants: SpliceAI score ≤0.1.",Disease-specific
-ACVRL1 (HGNC:175),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-ACVRL1 (HGNC:175),BP5,Supporting,"Apply if a likely pathogenic or pathogenic variant (based on HHT VCEP rules) is found in 
-ENG
-.",Disease-specific
-ACVRL1 (HGNC:175),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-ACVRL1 (HGNC:175),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-ACVRL1 (HGNC:175),BP7,Supporting,A synonymous or intronic variant for which SpliceAI predicts no impact to the splice consensus sequence nor the creation of a new splice site. Can be used together with BP4 evidence.,Disease-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHereditaryHemorrhagicTelangiectasiaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforENGVersion1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHereditaryHemorrhagicTelangiectasiaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforENGVersion1.0.0_version=1.0.0.csv
deleted file mode 100644
index 46d067840511692e5d9ee3f42c54a85bf4461b46..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHereditaryHemorrhagicTelangiectasiaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforENGVersion1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,169 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-ENG (HGNC:3349),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-ENG (HGNC:3349),PVS1,Very Strong,Use ENG PVS1 Decision Tree (see attachments),"Gene-specific,Strength"
-ENG (HGNC:3349),PVS1,Strong,Use ENG PVS1 Decision Tree (see attachments),"Gene-specific,Strength"
-ENG (HGNC:3349),PVS1,Moderate,Use ENG PVS1 Decision Tree (see attachments),"Gene-specific,Strength"
-ENG (HGNC:3349),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-ENG (HGNC:3349),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",No change
-ENG (HGNC:3349),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-ENG (HGNC:3349),PS2,Strong,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Clarification,Disease-specific"
-ENG (HGNC:3349),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-ENG (HGNC:3349),PS3,Strong,"mRNA splicing assays can be used as strong functional evidence. 
-
-
-Note:
- level of evidence used may differ depending on whether the abnormal transcript is in-frame or out-of-frame, and whether there is complete or incomplete splicing impact.","Disease-specific,Strength"
-ENG (HGNC:3349),PS3,Moderate,See PS3_Supporting and Instructions below.,"Disease-specific,Strength"
-ENG (HGNC:3349),PS3,Supporting,"Protein expression assays: Metabolic label & IP, WB & FACS HUVECs/BOECs, FACs activated monocytes, cDNA transfect, WB & ML HEK293T/COS/NIH3T3, cDNA transfect & luciferase HepG2
-
-
-Note:
- Decreased protein expression can be used as supporting pathogenic evidence if experiment was not done in a single assay, and the corresponding densitometry of western blot reflects the conclusion drawn.
-
-
-
-
-
-
-Intracellular signaling assays: BRE/CAGA-luciferase, Gal4 Smad1/Smad3 for TGF-beta/BMP9 signaling
-
-
-Binding assays: BMP9 binding, transcription factor Sp1, BMP9 protein-protein interaction (BLI)
-
-
-Subcellular protein localization
-
-
-Morphology: Morphology & actin cytoskeleton, tubulogenesis
-
-
-Somatic variant 2
-nd
- hit: In vivo evidence can be obtained as supporting functional evidence by identification of somatic variants in telangiectases´ biopsies using NGS, suggesting a second-hit mechanism leading to biallelic LOF (PMID: 31630786).","Disease-specific,Strength"
-ENG (HGNC:3349),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-ENG (HGNC:3349),PS4,Strong,4+ probands with phenotype consistent with HHT.,Disease-specific
-ENG (HGNC:3349),PS4,Moderate,2-3 probands with phenotype consistent with HHT.,Disease-specific
-ENG (HGNC:3349),PS4,Supporting,1 proband with phenotype consistent with HHT.,Disease-specific
-ENG (HGNC:3349),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-ENG (HGNC:3349),PM1,Moderate,"Apply if variant is located in a critical residue:
-
-
-
-
-ENG:
-
-
-BMP9 binding sites: S278, F282 (PMIDs 28564608, 25312062)
-
-
-Cysteine residues either previously reported to be likely pathogenic or pathogenic:
-
-
-C207, C363, C382, C412, C549
-
-
-
-
-
-
-Or cysteine residues known to be important for ENG function:
-
-
-C350 (C350-C382 disulfide in ZP-N domain of ENG is required for secretion of its ZP module)
-
-
-C394 (makes a disulfide bond with C412 which is reported to be a mutated residue)
-
-
-C516 (involved in forming intermolecular disulfides that hold ENG homodimer together)
-
-
-C582 (involved in forming intermolecular disulfides that hold ENG homodimer together)",Gene-specific
-ENG (HGNC:3349),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-ENG (HGNC:3349),PM2,Supporting,<6 total alleles in gnomAD or <0.00004 (0.004%) in gnomAD subpopulations.,"Disease-specific,Strength"
-ENG (HGNC:3349),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-ENG (HGNC:3349),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-ENG (HGNC:3349),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,None
-ENG (HGNC:3349),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-ENG (HGNC:3349),PM5,Strong,≥2 different missense changes at same codon have been determined to be likely pathogenic or pathogenic based on HHT VCEP rules.,"Disease-specific,Strength"
-ENG (HGNC:3349),PM5,Moderate,A different missense change at same codon has been determined to be likely pathogenic or pathogenic based on HHT VCEP rules.,"Disease-specific,Strength"
-ENG (HGNC:3349),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-ENG (HGNC:3349),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-ENG (HGNC:3349),PP1,Strong,5+ meioses (1/32 likelihood),"Disease-specific,Strength"
-ENG (HGNC:3349),PP1,Moderate,4 meioses (1/16 likelihood),"Disease-specific,Strength"
-ENG (HGNC:3349),PP1,Supporting,3 meioses (1/8 likelihood),"Disease-specific,Strength"
-ENG (HGNC:3349),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-ENG (HGNC:3349),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-ENG (HGNC:3349),PP3,Supporting,"For missense variants: REVEL score ≥0.644 or SpliceAI score ≥0.2.
-
-
-For synonymous and intronic variants: SpliceAI score ≥0.2.",Disease-specific
-ENG (HGNC:3349),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-ENG (HGNC:3349),PP4,Moderate,"Patient's phenotype meets consensus clinical diagnostic (Curaçao) criteria for HHT, and sequencing and large deletion/duplication analysis was performed for both 
-ENG
- and 
-ACVRL1
- with any other identified variants ruled out.","Disease-specific,Strength"
-ENG (HGNC:3349),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-ENG (HGNC:3349),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-ENG (HGNC:3349),BA1,Stand Alone,Allele frequency is ≥1% in general population databases (e.g. gnomAD) based on Popmax FAF.,Disease-specific
-ENG (HGNC:3349),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-ENG (HGNC:3349),BS1,Strong,">0.2% to <1% in general population databases (e.g. gnomAD) based on Popmax FAF, 
-or
- if variant meets BS1_Supporting and has ≥2 homozygotes.","Disease-specific,Strength"
-ENG (HGNC:3349),BS1,Supporting,>0.08% to 0.2% (based on gnomAD Popmax FAF).,"Disease-specific,Strength"
-ENG (HGNC:3349),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",NA
-ENG (HGNC:3349),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-ENG (HGNC:3349),BS3,Supporting,"mRNA splicing assays 
-
-
-Intracellular signaling assays: BRE/CAGA-luciferase, Gal4 Smad1/Smad3 for TGF-beta/BMP9 signaling
-
-
-Binding assays: BMP9 binding, transcription factor Sp1, BMP9 protein-protein interaction (BLI)
-
-
-Subcellular protein localization
-
-
-Morphology: Morphology & actin cytoskeleton, tubulogenesis","Disease-specific,Strength"
-ENG (HGNC:3349),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-ENG (HGNC:3349),BS4,Strong,Lack of segregation in affected members of a family.,"Clarification,Disease-specific"
-ENG (HGNC:3349),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-ENG (HGNC:3349),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-ENG (HGNC:3349),BP2,Supporting,Observed in trans with a pathogenic or likely pathogenic variant based on HHT VCEP rules.,Disease-specific
-ENG (HGNC:3349),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-ENG (HGNC:3349),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-ENG (HGNC:3349),BP4,Supporting,"For missense variants: REVEL score ≤0.15 and SpliceAI score ≤0.1.
-
-
-For synonymous and intronic variants: SpliceAI score ≤0.1.",Disease-specific
-ENG (HGNC:3349),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-ENG (HGNC:3349),BP5,Supporting,"Apply if a likely pathogenic or pathogenic variant (based on HHT VCEP rules) is found in 
-ACVRL1
-.",Disease-specific
-ENG (HGNC:3349),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-ENG (HGNC:3349),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-ENG (HGNC:3349),BP7,Supporting,A synonymous or intronic variant for which SpliceAI predicts no impact to the splice consensus sequence nor the creation of a new splice site. Can be used together with BP4 evidence.,Disease-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHereditaryHemorrhagicTelangiectasiaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforENGVersion1.1.0_version=1.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHereditaryHemorrhagicTelangiectasiaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforENGVersion1.1.0_version=1.1.0.csv
deleted file mode 100644
index fa4ce1e8fbb52cef0bd5d18d479de9a997b6b950..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenHereditaryHemorrhagicTelangiectasiaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforENGVersion1.1.0_version=1.1.0.csv
+++ /dev/null
@@ -1,172 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-ENG (HGNC:3349),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-ENG (HGNC:3349),PVS1,Very Strong,Use ENG PVS1 Decision Tree (see attachments),"Gene-specific,Strength"
-ENG (HGNC:3349),PVS1,Strong,Use ENG PVS1 Decision Tree (see attachments),"Gene-specific,Strength"
-ENG (HGNC:3349),PVS1,Moderate,Use ENG PVS1 Decision Tree (see attachments),"Gene-specific,Strength"
-ENG (HGNC:3349),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-ENG (HGNC:3349),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",No change
-ENG (HGNC:3349),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-ENG (HGNC:3349),PS2,Strong,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.","Clarification,Disease-specific"
-ENG (HGNC:3349),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-ENG (HGNC:3349),PS3,Strong,"mRNA splicing assays can be used as strong functional evidence. 
-
-
-Note:
- level of evidence used may differ depending on whether the abnormal transcript is in-frame or out-of-frame, and whether there is complete or incomplete splicing impact.
-
-
-Do not use PS3 for splice variants that meet PVS1.","Disease-specific,Strength"
-ENG (HGNC:3349),PS3,Moderate,See PS3_Supporting and Instructions below.,"Disease-specific,Strength"
-ENG (HGNC:3349),PS3,Supporting,"Protein expression assays: Metabolic label & IP, WB & FACS HUVECs/BOECs, FACs activated monocytes, cDNA transfect, WB & ML HEK293T/COS/NIH3T3, cDNA transfect & luciferase HepG2
-
-
-Note:
- Decreased protein expression can be used as supporting pathogenic evidence if experiment was not done in a single assay, and the corresponding densitometry of western blot reflects the conclusion drawn.
-
-
-
-
-
-
-Intracellular signaling assays: BRE/CAGA-luciferase, Gal4 Smad1/Smad3 for TGF-beta/BMP9 signaling
-
-
-Binding assays: BMP9 binding, transcription factor Sp1, BMP9 protein-protein interaction (BLI)
-
-
-Subcellular protein localization
-
-
-Morphology: Morphology & actin cytoskeleton, tubulogenesis
-
-
-Somatic variant 2
-nd
- hit: In vivo evidence can be obtained as supporting functional evidence by identification of somatic variants in telangiectases´ biopsies using NGS, suggesting a second-hit mechanism leading to biallelic LOF (PMID: 31630786).","Disease-specific,Strength"
-ENG (HGNC:3349),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-ENG (HGNC:3349),PS4,Strong,4+ probands with phenotype consistent with HHT.,Disease-specific
-ENG (HGNC:3349),PS4,Moderate,2-3 probands with phenotype consistent with HHT.,Disease-specific
-ENG (HGNC:3349),PS4,Supporting,1 proband with phenotype consistent with HHT.,Disease-specific
-ENG (HGNC:3349),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-ENG (HGNC:3349),PM1,Moderate,"Apply if variant is located in a critical residue:
-
-
-
-
-ENG:
-
-
-BMP9 binding sites: S278, F282 (PMIDs 28564608, 25312062)
-
-
-Cysteine residues either previously reported to be likely pathogenic or pathogenic:
-
-
-C207, C363, C382, C412, C549
-
-
-
-
-
-
-Or cysteine residues known to be important for ENG function:
-
-
-C350 (C350-C382 disulfide in ZP-N domain of ENG is required for secretion of its ZP module)
-
-
-C394 (makes a disulfide bond with C412 which is reported to be a mutated residue)
-
-
-C516 (involved in forming intermolecular disulfides that hold ENG homodimer together)
-
-
-C582 (involved in forming intermolecular disulfides that hold ENG homodimer together)",Gene-specific
-ENG (HGNC:3349),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-ENG (HGNC:3349),PM2,Supporting,<6 total alleles in gnomAD or <0.00004 (0.004%) in gnomAD subpopulations.,"Disease-specific,Strength"
-ENG (HGNC:3349),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-ENG (HGNC:3349),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-ENG (HGNC:3349),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,None
-ENG (HGNC:3349),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-ENG (HGNC:3349),PM5,Strong,≥2 different missense changes at same codon have been determined to be likely pathogenic or pathogenic based on HHT VCEP rules.,"Disease-specific,Strength"
-ENG (HGNC:3349),PM5,Moderate,A different missense change at same codon has been determined to be likely pathogenic or pathogenic based on HHT VCEP rules.,"Disease-specific,Strength"
-ENG (HGNC:3349),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-ENG (HGNC:3349),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-ENG (HGNC:3349),PP1,Strong,5+ meioses (1/32 likelihood),"Disease-specific,Strength"
-ENG (HGNC:3349),PP1,Moderate,4 meioses (1/16 likelihood),"Disease-specific,Strength"
-ENG (HGNC:3349),PP1,Supporting,3 meioses (1/8 likelihood),"Disease-specific,Strength"
-ENG (HGNC:3349),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-ENG (HGNC:3349),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-ENG (HGNC:3349),PP3,Supporting,"For missense variants: REVEL score ≥0.644 or SpliceAI score ≥0.2.
-
-
-For synonymous and intronic variants: SpliceAI score ≥0.2.",Disease-specific
-ENG (HGNC:3349),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-ENG (HGNC:3349),PP4,Moderate,"Patient's phenotype meets consensus clinical diagnostic (Curaçao) criteria for HHT, and sequencing and large deletion/duplication analysis was performed for both 
-ENG
- and 
-ACVRL1
- with any other identified variants ruled out.","Disease-specific,Strength"
-ENG (HGNC:3349),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-ENG (HGNC:3349),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-ENG (HGNC:3349),BA1,Stand Alone,Allele frequency is ≥1% in general population databases (e.g. gnomAD) based on Popmax FAF.,Disease-specific
-ENG (HGNC:3349),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-ENG (HGNC:3349),BS1,Strong,">0.2% to <1% in general population databases (e.g. gnomAD) based on Popmax FAF, 
-or
- if variant meets BS1_Supporting and has ≥2 homozygotes.","Disease-specific,Strength"
-ENG (HGNC:3349),BS1,Supporting,>0.08% to 0.2% (based on gnomAD Popmax FAF).,"Disease-specific,Strength"
-ENG (HGNC:3349),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",NA
-ENG (HGNC:3349),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-ENG (HGNC:3349),BS3,Supporting,"mRNA splicing assays 
-
-
-Intracellular signaling assays: BRE/CAGA-luciferase, Gal4 Smad1/Smad3 for TGF-beta/BMP9 signaling
-
-
-Binding assays: BMP9 binding, transcription factor Sp1, BMP9 protein-protein interaction (BLI)
-
-
-Subcellular protein localization
-
-
-Morphology: Morphology & actin cytoskeleton, tubulogenesis","Disease-specific,Strength"
-ENG (HGNC:3349),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-ENG (HGNC:3349),BS4,Strong,Lack of segregation in affected members of a family.,"Clarification,Disease-specific"
-ENG (HGNC:3349),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-ENG (HGNC:3349),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-ENG (HGNC:3349),BP2,Supporting,Observed in trans with a pathogenic or likely pathogenic variant based on HHT VCEP rules.,Disease-specific
-ENG (HGNC:3349),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-ENG (HGNC:3349),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-ENG (HGNC:3349),BP4,Supporting,"For missense variants: REVEL score ≤0.15 and SpliceAI score ≤0.1.
-
-
-For synonymous and intronic variants: SpliceAI score ≤0.1.",Disease-specific
-ENG (HGNC:3349),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-ENG (HGNC:3349),BP5,Supporting,"Apply if a likely pathogenic or pathogenic variant (based on HHT VCEP rules) is found in 
-ACVRL1
-.",Disease-specific
-ENG (HGNC:3349),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-ENG (HGNC:3349),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-ENG (HGNC:3349),BP7,Supporting,A synonymous or intronic variant for which SpliceAI predicts no impact to the splice consensus sequence nor the creation of a new splice site. Can be used together with BP4 evidence.,Disease-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforAPCVersion1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforAPCVersion1.0.0_version=1.0.0.csv
deleted file mode 100644
index 85e1b929aa515071e5af6b4795c0f96890c5995d..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforAPCVersion1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,375 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-APC (HGNC:583),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-APC (HGNC:583),PVS1,Very Strong,"Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (
-Figure 1
-) [Reference 1].","Gene-specific,Strength"
-APC (HGNC:583),PVS1,Strong,"Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (
-Figure 1
-) [Reference 1].","Gene-specific,Strength"
-APC (HGNC:583),PVS1,Moderate,"Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (
-Figure 1
-) [Reference 1].","Gene-specific,Strength"
-APC (HGNC:583),PVS1,Supporting,"Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (
-Figure 1
-) [Reference 1].","Gene-specific,Strength"
-APC (HGNC:583),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-APC (HGNC:583),PS1,Strong,"The previously established variant was classified as Pathogenic according to the _APC_-specific modifications.
-
-
-This criterion can be applied to both missense and splice variants in 
-APC
-. 
-
-
-Missense variants:
- when the variant under assessment results in the same amino acid change as previously established (Likely) Pathogenic variant(s). 
-
-
-There are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). Other variants leading to the same missense change at these positions meet PS1_Moderate. No missense variant has been classified as Pathogenic based on current evidence. 
-
-
-Splice variants
-: when the variant under assessment affects splicing at the same nucleotide as a previously established (Likely) Pathogenic variant. The splice prediction must be above defined thresholds 
-1
- or similar to the previously established variant by multiple 
-in silico
- predictors.
-
-
-1
- See Supplemental material - Evaluation of canonical ±1 or 2 splice sites","Gene-specific,Strength"
-APC (HGNC:583),PS1,Moderate,"The previously established variant was classified as Likely Pathogenic according to the _APC_-specific modifications.
-
-
-This criterion can be applied to both missense and splice variants in 
-APC
-. 
-
-
-Missense variants:
- when the variant under assessment results in the same amino acid change as previously established (Likely) Pathogenic variant(s). 
-
-
-There are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). Other variants leading to the same missense change at these positions meet PS1_Moderate. No missense variant has been classified as Pathogenic based on current evidence. 
-
-
-Splice variants
-: when the variant under assessment affects splicing at the same nucleotide as a previously established (Likely) Pathogenic variant. The splice prediction must be above defined thresholds 
-1
- or similar to the previously established variant by multiple 
-in silico
- predictors.
-
-
-1
- See Supplemental material - Evaluation of canonical ±1 or 2 splice sites","Gene-specific,Strength"
-APC (HGNC:583),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-APC (HGNC:583),PS2,Very Strong,"≥ 4 
-de novo
- scores. For curation of 
-de novo
- score see 
-Tables 1
- and 
-2
-.","Gene-specific,Strength"
-APC (HGNC:583),PS2,Strong,"2-3 
-de novo
- scores. For curation of 
-de novo
- score see 
-Tables 1
- and 
-2
-.","Gene-specific,Strength"
-APC (HGNC:583),PS2,Moderate,"1 
-de novo
- score. For curation of 
-de novo
- score see 
-Tables 1
- and 
-2
-.","Gene-specific,Strength"
-APC (HGNC:583),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-APC (HGNC:583),PS3,Very Strong,"RNA assays
- show
-
-
-
-
-a premature stop codon
-OR
-
-
-inframe skipping of exon 13 or 14
-
-
-
-
-AND
- the absence of full-length transcript.","Gene-specific,Strength"
-APC (HGNC:583),PS3,Strong,"RNA assays
- show
-
-
-
-
-a premature stop codon
-OR
-
-
-inframe skipping of exon 13 or 14
-
-
-
-
-AND
- < 10% of full-length transcript.","Gene-specific,Strength"
-APC (HGNC:583),PS3,Moderate,"RNA assays
- show 
-
-
-
-
-a premature stop codon
-OR
-
-
-inframe skipping of exon 13 or 14
-OR
-
-
-other inframe skipping AND absent or < 10% full-length transcript.","Gene-specific,Strength"
-APC (HGNC:583),PS3,Supporting,"RNA assays
- show 
-
-
-
-
-inframe skipping of of exons other than exon 13 or 14
-OR
-
-
-over-expression of an alternative transcript
-
-
-
-
-Protein assays
- show
-
-
-Increased β-catenin regulated transcription activity and/or decreased binding to β-catenin by surface plasmon resonance (only for variants within the β-catenin binding domain, which refers to codons 959-2129 of 
-APC
-) [Reference 2].","Gene-specific,Strength"
-APC (HGNC:583),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-APC (HGNC:583),PS4,Very Strong,"≥ 16 phenotype points. For phenotype points curation see 
-Table 1
-.","Gene-specific,Strength"
-APC (HGNC:583),PS4,Strong,"4-15 phenotype points. For phenotype points curation see 
-Table 1
-.","Gene-specific,Strength"
-APC (HGNC:583),PS4,Moderate,"2-3 phenotype points. For phenotype points curation see 
-Table 1
-.","Gene-specific,Strength"
-APC (HGNC:583),PS4,Supporting,"1 phenotype point. For phenotype points curation see 
-Table 1
-.","Gene-specific,Strength"
-APC (HGNC:583),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-APC (HGNC:583),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-APC (HGNC:583),PM2,Supporting,Rare in controls is defined by an allele frequency ≤ 0.0003% (0.000003).,"Gene-specific,Strength"
-APC (HGNC:583),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-APC (HGNC:583),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,NA
-APC (HGNC:583),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-APC (HGNC:583),PM5,Moderate,"The reported missense variant was determined to be Pathogenic according to the _APC_-specific modifications.
-
-
-There are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). Other different missense variants at these positions meet PM5_supporting. No missense variant has been classified as Pathogenic based on current evidence. 
-
-
-Grantham´s distance of the variant under assessment must have an equal or higher score than the reported variant [Reference 3].","Gene-specific,Strength"
-APC (HGNC:583),PM5,Supporting,"The reported missense variant was determined to be Likely Pathogenic according to the _APC_-specific modifications.
-
-
-There are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). Other different missense variants at these positions meet PM5_supporting. No missense variant has been classified as Pathogenic based on current evidence. 
-
-
-Grantham´s distance of the variant under assessment must have an equal or higher score than the reported variant [Reference 3].","Gene-specific,Strength"
-APC (HGNC:583),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-APC (HGNC:583),PM6,Strong,"2-3 
-de novo
- scores. For curation of 
-de novo
- score see 
-Tables 1
- and 
-2
-.","Gene-specific,Strength"
-APC (HGNC:583),PM6,Moderate,"1 
-de novo
- scores. For curation of 
-de novo
- score see 
-Tables 1
- and 
-2
-.","Gene-specific,Strength"
-APC (HGNC:583),PM6,Supporting,"0.5 
-de novo
- scores. For curation of 
-de novo
- score see 
-Tables 1
- and 
-2
-.","Gene-specific,Strength"
-APC (HGNC:583),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-APC (HGNC:583),PP1,Strong,Variant segregates in ≥ 7 meioses in ≥ 2 families.,Strength
-APC (HGNC:583),PP1,Moderate,Variant segregates in 5-6 meioses in ≥ 1 family.,Strength
-APC (HGNC:583),PP1,Supporting,Variant segregates in 3-4 meioses in ≥ 1 familiy.,Strength
-APC (HGNC:583),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-APC (HGNC:583),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-APC (HGNC:583),PP3,Supporting,"This criterion can be applied to missense and non-canonical splicing variants.
-
-
-Missense variants:
- Do not use computational prediction models for conservation, evolution, etc. 
-In silico
- splicing predictors should be used for presumed missense variants to reveal possible splicing effects.
-
-
-Non-canonical splicing variants:
- Multiple 
-in silico
- splicing predictors support a deleterious effect.","Gene-specific,Strength"
-APC (HGNC:583),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-APC (HGNC:583),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-APC (HGNC:583),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-APC (HGNC:583),BA1,Stand Alone,"Allele frequency 
-≥ 0.1%
- (0.001).",Gene-specific
-APC (HGNC:583),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-APC (HGNC:583),BS1,Strong,"Allele frequency 
-≥ 0.001%
- (0.00001).",Gene-specific
-APC (HGNC:583),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-APC (HGNC:583),BS2,Strong,"≥ 10 points for healthy individuals 
-OR
- ≥ 2 times in homozygous state.
-
-
-A 
-healthy individual
- worth 1 point is defined by:
-
-
-Age ≥ 50 years 
-+ Less than 5 adenomatous polyps in a colonoscopy 
-+ Absence of features in Table 1
-
-
-OR
-
-
-Age ≥ 50 years 
-+ Colorectal cancer/polyposis was not the indication for testing
-
-
-A 
-healthy individual
- worth 0.5 points is defined by keywords including control, non-cancer, normal, unaffected population.","Gene-specific,Strength"
-APC (HGNC:583),BS2,Supporting,"≥ 3 points for healthy individuals.
-
-
-A 
-healthy individual
- worth 1 point is defined by:
-
-
-Age ≥ 50 years 
-+ Less than 5 adenomatous polyps in a colonoscopy 
-+ Absence of features in Table 1
-
-
-OR
-
-
-Age ≥ 50 years 
-+ Colorectal cancer/polyposis was not the indication for testing
-
-
-A 
-healthy individual
- worth 0.5 points is defined by keywords including control, non-cancer, normal, unaffected population.","Gene-specific,Strength"
-APC (HGNC:583),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-APC (HGNC:583),BS3,Strong,"RNA assay
- of a synonymous or intronic variant in constitutional patient sample demonstrates no mRNA aberration
-
-
-AND
-
-
-if biallelic expression is shown and/or nonsense-mediated decay inhibition was used.","Gene-specific,Strength"
-APC (HGNC:583),BS3,Supporting,"RNA assay
- of a synonymous or intronic variant in constitutional patient sample demonstrates no mRNA aberration
-
-
-OR
-
-
-Protein assay
- show retention of β-catenin regulated transcription activity comparable to wild-type (only for variants within the β-catenin binding domain, which refers to codons 959-2129 of 
-APC
-, see PMID: 33348689)","Gene-specific,Strength"
-APC (HGNC:583),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-APC (HGNC:583),BS4,Strong,"Affected member without the variant must score at least 1 phenotype point or at least two affected members without the variant must each score at least 0.5 phenotype points (see 
-Table 1
-).","Gene-specific,Strength"
-APC (HGNC:583),BS4,Supporting,"Affected member without the variant must score at least 0.5 phenotype points (see 
-Table 1
-).","Gene-specific,Strength"
-APC (HGNC:583),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-APC (HGNC:583),BP1,Supporting,Exception: not applicable to missense variants located in the first 15-amino acid repeat of the β-catenin binding domain (codon 1021-1035) [Reference 3].,No change
-APC (HGNC:583),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-APC (HGNC:583),BP2,Supporting,"Observed 
-in trans
- with a (Likely) Pathogenic 
-APC
- variant 
-OR
- ≥ 3 times in an unknown phase with different (Likely) Pathogenic 
-APC
- variants.",Gene-specific
-APC (HGNC:583),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-APC (HGNC:583),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-APC (HGNC:583),BP4,Supporting,"Missense variants:
- BP4 is not applicable.
-
-
-Synonymous (silent) or intronic variants
-: Multiple in silico splicing predictors suggest no impact on gene or gene product.",Gene-specific
-APC (HGNC:583),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-APC (HGNC:583),BP5,Supporting,Only applicable for an alternate genetic basis of the colorectal polyposis phenotype.,No change
-APC (HGNC:583),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-APC (HGNC:583),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-APC (HGNC:583),BP7,Supporting,A synonymous (silent) or intronic variant at or beyond +7/–21 for which multiple splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforAPCVersion2.0.3_version=2.0.3.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforAPCVersion2.0.3_version=2.0.3.csv
deleted file mode 100644
index dc14aa072a0d2b3af8341a0fb9162ca514385195..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforAPCVersion2.0.3_version=2.0.3.csv
+++ /dev/null
@@ -1,372 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-APC (HGNC:583),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-APC (HGNC:583),PVS1,Very Strong,"Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (
-Figure 1
-) [Reference 1].","Gene-specific,Strength"
-APC (HGNC:583),PVS1,Strong,"Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (
-Figure 1
-) [Reference 1].","Gene-specific,Strength"
-APC (HGNC:583),PVS1,Moderate,"Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (
-Figure 1
-) [Reference 1].","Gene-specific,Strength"
-APC (HGNC:583),PVS1,Supporting,"Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (
-Figure 1
-) [Reference 1].","Gene-specific,Strength"
-APC (HGNC:583),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-APC (HGNC:583),PS1,Strong,"The previously established variant was classified as Pathogenic according to the APC-specific modifications.
-
-
-This criterion can be applied to both missense and splice variants in 
-APC
-. 
-
-
-Missense variants:
- when the variant under assessment results in the same amino acid change as previously established Pathogenic variant(s). 
-
-
-There are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). Other variants leading to the same missense change at these positions meet PS1_Moderate. No missense variant has been classified as Pathogenic based on current evidence. 
-
-
-Splice variants
-: when the variant under assessment affects splicing at the same nucleotide as a previously established Pathogenic variant. The splice prediction must be above defined thresholds 
-1
- or similar to the previously established variant by multiple 
-in silico
- predictors.
-
-
-1
- See Supplemental material - Evaluation of canonical ±1 or 2 splice sites","Gene-specific,Strength"
-APC (HGNC:583),PS1,Moderate,"The previously established variant was classified as Likely Pathogenic according to the APC-specific modifications.
-
-
-This criterion can be applied to both missense and splice variants in 
-APC
-. 
-
-
-Missense variants:
- when the variant under assessment results in the same amino acid change as previously established Likely Pathogenic variant(s). 
-
-
-There are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). Other variants leading to the same missense change at these positions meet PS1_Moderate. No missense variant has been classified as Pathogenic based on current evidence. 
-
-
-Splice variants
-: when the variant under assessment affects splicing at the same nucleotide as a previously established Likely Pathogenic variant. The splice prediction must be above defined thresholds 
-1
- or similar to the previously established variant by multiple 
-in silico
- predictors.
-
-
-1
- See Supplemental material - Evaluation of canonical ±1 or 2 splice sites","Gene-specific,Strength"
-APC (HGNC:583),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-APC (HGNC:583),PS2,Very Strong,"≥ 4 
-de novo
- scores. For curation of 
-de novo
- score see 
-Tables 1
- and 
-2
-.","Gene-specific,Strength"
-APC (HGNC:583),PS2,Strong,"2-3.5 
-de novo
- scores. For curation of 
-de novo
- score see 
-Tables 1
- and 
-2
-.","Gene-specific,Strength"
-APC (HGNC:583),PS2,Moderate,"1-1.5 
-de novo
- score. For curation of 
-de novo
- score see 
-Tables 1
- and 
-2
-.","Gene-specific,Strength"
-APC (HGNC:583),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-APC (HGNC:583),PS3,Very Strong,"RNA assays
- show
-
-
-
-
-a premature stop codon
-OR
-
-
-inframe skipping of exon 13 or 14
-
-
-
-
-AND
- the absence of full-length transcript.","Gene-specific,Strength"
-APC (HGNC:583),PS3,Strong,"RNA assays
- show
-
-
-
-
-a premature stop codon
-OR
-
-
-inframe skipping of exon 13 or 14
-
-
-
-
-AND
- < 10% of full-length transcript.","Gene-specific,Strength"
-APC (HGNC:583),PS3,Moderate,"RNA assays
- show 
-
-
-
-
-a premature stop codon AND reports of exon deletion/skipping/loss, insertion of intronic nucleotides
-OR
-
-
-inframe skipping of exon 13 or 14 AND reports of exon deletion/skipping/loss, insertion of intronic nucleotides
-OR
-
-
-other inframe skipping AND absent or < 10% full-length transcript.","Gene-specific,Strength"
-APC (HGNC:583),PS3,Supporting,"RNA assays
- show 
-
-
-
-
-inframe skipping of exons other than exon 13 or 14 AND reports of exon deletion/skipping/loss, insertion of intronic nucleotides
-OR
-
-
-over-expression of an alternative transcript (exons 10, 11 or 15)
-
-
-
-
-Protein assays
- show
-
-
-Increased β-catenin regulated transcription activity and/or decreased binding to β-catenin by surface plasmon resonance (only for variants within the β-catenin binding domain, which refers to codons 959-2129 of 
-APC
-) [Reference 2].","Gene-specific,Strength"
-APC (HGNC:583),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-APC (HGNC:583),PS4,Very Strong,"≥ 16 phenotype points. For phenotype points curation see 
-Table 1
-.","Gene-specific,Strength"
-APC (HGNC:583),PS4,Strong,"4-15.5 phenotype points. For phenotype points curation see 
-Table 1
-.","Gene-specific,Strength"
-APC (HGNC:583),PS4,Moderate,"2-3.5 phenotype points. For phenotype points curation see 
-Table 1
-.","Gene-specific,Strength"
-APC (HGNC:583),PS4,Supporting,"1-1.5 phenotype point. For phenotype points curation see 
-Table 1
-.","Gene-specific,Strength"
-APC (HGNC:583),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-APC (HGNC:583),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-APC (HGNC:583),PM2,Supporting,"Rare in controls, defined by an allele frequency ≤ 0.0003% (0.000003) if the allele count is > 1 OR by an allele frequency < 0.001% (0.00001) if the allele count is ≤ 1.","Gene-specific,Strength"
-APC (HGNC:583),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-APC (HGNC:583),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,NA
-APC (HGNC:583),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-APC (HGNC:583),PM5,Moderate,"The reported missense variant was determined to be Pathogenic according to the APC-specific modifications.
-
-
-There are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). Other different missense variants at these positions meet PM5_supporting. No missense variant has been classified as Pathogenic based on current evidence. 
-
-
-Grantham´s distance of the variant under assessment must have an equal or higher score than the reported variant [Reference 3].","Gene-specific,Strength"
-APC (HGNC:583),PM5,Supporting,"The reported missense variant was determined to be Likely Pathogenic according to the APC-specific modifications.
-
-
-There are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). Other different missense variants at these positions meet PM5_supporting. No missense variant has been classified as Pathogenic based on current evidence. 
-
-
-Grantham´s distance of the variant under assessment must have an equal or higher score than the reported variant [Reference 3].","Gene-specific,Strength"
-APC (HGNC:583),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-APC (HGNC:583),PM6,Strong,"2-3.5 
-de novo
- scores. For curation of 
-de novo
- score see 
-Tables 1
- and 
-2
-.","Gene-specific,Strength"
-APC (HGNC:583),PM6,Moderate,"1-1.5 
-de novo
- scores. For curation of 
-de novo
- score see 
-Tables 1
- and 
-2
-.","Gene-specific,Strength"
-APC (HGNC:583),PM6,Supporting,"0.5 
-de novo
- scores. For curation of 
-de novo
- score see 
-Tables 1
- and 
-2
-.","Gene-specific,Strength"
-APC (HGNC:583),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-APC (HGNC:583),PP1,Strong,Variant segregates in ≥ 7 meioses in ≥ 2 families.,Strength
-APC (HGNC:583),PP1,Moderate,Variant segregates in 5-6 meioses in ≥ 1 family.,Strength
-APC (HGNC:583),PP1,Supporting,Variant segregates in 3-4 meioses in ≥ 1 family.,Strength
-APC (HGNC:583),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-APC (HGNC:583),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-APC (HGNC:583),PP3,Supporting,"Missense variants:
- Do not use computational prediction models for conservation, evolution, etc. 
-In silico
- splicing predictors should be used for presumed missense variants to reveal possible splicing effects.
-
-
-Non-canonical splicing variants:
- Multiple 
-in silico
- splicing predictors support a deleterious effect.","Gene-specific,Strength"
-APC (HGNC:583),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-APC (HGNC:583),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-APC (HGNC:583),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-APC (HGNC:583),BA1,Stand Alone,"GnomAD Popmax Filtering Allele Frequency (AF) 
-≥ 0.1%
- (0.001).",Gene-specific
-APC (HGNC:583),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-APC (HGNC:583),BS1,Strong,"GnomAD Popmax Filtering Allele Frequency (AF) 
-≥ 0.001%
- (0.00001).",Gene-specific
-APC (HGNC:583),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-APC (HGNC:583),BS2,Strong,"≥ 10 points for healthy individuals 
-OR
- ≥ 2 times in homozygous state.
-
-
-A 
-healthy individual
- worth 1 point is defined by:
-
-
-Age ≥ 50 years 
-+ Less than 5 adenomatous polyps in a colonoscopy 
-+ Absence of features in Table 1
-
-
-OR
-
-
-Age ≥ 50 years 
-+ Colorectal cancer/polyposis was not the indication for testing
-
-
-A 
-healthy individual
- worth 0.5 points is defined by keywords including control, non-cancer, normal, unaffected population.","Gene-specific,Strength"
-APC (HGNC:583),BS2,Supporting,"≥ 3 points for healthy individuals.
-
-
-A 
-healthy individual
- worth 1 point is defined by:
-
-
-Age ≥ 50 years 
-+ Less than 5 adenomatous polyps in a colonoscopy 
-+ Absence of features in Table 1
-
-
-OR
-
-
-Age ≥ 50 years 
-+ Colorectal cancer/polyposis was not the indication for testing
-
-
-A 
-healthy individual
- worth 0.5 points is defined by keywords including control, non-cancer, normal, unaffected population.","Gene-specific,Strength"
-APC (HGNC:583),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-APC (HGNC:583),BS3,Strong,"RNA assay
- of a synonymous or intronic variant in constitutional patient sample demonstrates no mRNA aberration
-
-
-AND
-
-
-biallelic expression is shown and/or nonsense-mediated decay inhibition was used.","Gene-specific,Strength"
-APC (HGNC:583),BS3,Supporting,"RNA assay
- of a synonymous or intronic variant in constitutional patient sample demonstrates no mRNA aberration, without demonstration of biallelic expression or use of nonsense-mediated decay inhibition
-
-
-OR
-
-
-Protein assay
- show retention of β-catenin regulated transcription activity comparable to wild-type (only for variants within the β-catenin binding domain, which refers to codons 959-2129 of 
-APC
-, see PMID: 33348689)","Gene-specific,Strength"
-APC (HGNC:583),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-APC (HGNC:583),BS4,Strong,"Affected member without the variant must score at least 1 phenotype point or at least two affected members without the variant must each score at least 0.5 phenotype points (see 
-Table 1
-).","Gene-specific,Strength"
-APC (HGNC:583),BS4,Supporting,"Affected member without the variant must score at least 0.5 phenotype points (see 
-Table 1
-).","Gene-specific,Strength"
-APC (HGNC:583),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-APC (HGNC:583),BP1,Supporting,BP1 is applicable to APC with the exception of missense variants located in the first 15-amino acid repeat of the β-catenin binding domain (codon 1021-1035) [Reference 3].,No change
-APC (HGNC:583),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-APC (HGNC:583),BP2,Supporting,"Observed 
-in trans
- with a (Likely) Pathogenic 
-APC
- variant 
-OR
- ≥ 3 times in an unknown phase with different (Likely) Pathogenic 
-APC
- variants.",Gene-specific
-APC (HGNC:583),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-APC (HGNC:583),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-APC (HGNC:583),BP4,Supporting,"Missense variants:
- BP4 is not applicable.
-
-
-Synonymous (silent) or intronic variants
-: Multiple in silico splicing predictors suggest no impact on gene or gene product.",Gene-specific
-APC (HGNC:583),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-APC (HGNC:583),BP5,Supporting,Only applicable for an alternate genetic basis of the colorectal polyposis phenotype.,No change
-APC (HGNC:583),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-APC (HGNC:583),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-APC (HGNC:583),BP7,Supporting,A synonymous (silent) or intronic variant at or beyond +7/–21 for which multiple splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforAPCVersion2.1.0_version=2.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforAPCVersion2.1.0_version=2.1.0.csv
deleted file mode 100644
index 0ad58c33233686fcb8f9dfb778550786d839489d..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforAPCVersion2.1.0_version=2.1.0.csv
+++ /dev/null
@@ -1,360 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-APC (HGNC:583),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-APC (HGNC:583),PVS1,Very Strong,"Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (
-Figure 1
-) [Reference 1].","Gene-specific,Strength"
-APC (HGNC:583),PVS1,Strong,"Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (
-Figure 1
-) [Reference 1].","Gene-specific,Strength"
-APC (HGNC:583),PVS1,Moderate,"Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (
-Figure 1
-) [Reference 1].","Gene-specific,Strength"
-APC (HGNC:583),PVS1,Supporting,"Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (
-Figure 1
-) [Reference 1].","Gene-specific,Strength"
-APC (HGNC:583),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-APC (HGNC:583),PS1,Strong,"The previously established variant was classified as Pathogenic according to the APC-specific modifications.
-
-
-This criterion can be applied to both missense and splice variants in 
-APC
-. 
-
-
-Missense variants:
- when the variant under assessment results in the same amino acid change as previously established Pathogenic variant(s). 
-
-
-There are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). Other variants leading to the same missense change at these positions meet PS1_Moderate. No missense variant has been classified as Pathogenic based on current evidence. 
-
-
-Splice variants
-: when the variant under assessment affects splicing at the same nucleotide as a previously established Pathogenic variant. The splice prediction must be above defined thresholds (see instructions) or similar to the previously established variant by multiple 
-in silico
- predictors.","Gene-specific,Strength"
-APC (HGNC:583),PS1,Moderate,"The previously established variant was classified as Likely Pathogenic according to the APC-specific modifications.
-
-
-This criterion can be applied to both missense and splice variants in 
-APC
-. 
-
-
-Missense variants:
- when the variant under assessment results in the same amino acid change as previously established Likely Pathogenic variant(s). 
-
-
-There are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). Other variants leading to the same missense change at these positions meet PS1_Moderate. No missense variant has been classified as Pathogenic based on current evidence. 
-
-
-Splice variants
-: when the variant under assessment affects splicing at the same nucleotide as a previously established Likely Pathogenic variant. The splice prediction must be above defined thresholds (see instructions) or similar to the previously established variant by multiple 
-in silico
- predictors.","Gene-specific,Strength"
-APC (HGNC:583),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-APC (HGNC:583),PS2,Very Strong,"≥ 4 
-de novo
- scores. For curation of 
-de novo
- score see 
-Tables 1
- and 
-2
-.","Gene-specific,Strength"
-APC (HGNC:583),PS2,Strong,"2-3.5 
-de novo
- scores. For curation of 
-de novo
- score see 
-Tables 1
- and 
-2
-.","Gene-specific,Strength"
-APC (HGNC:583),PS2,Moderate,"1-1.5 
-de novo
- score. For curation of 
-de novo
- score see 
-Tables 1
- and 
-2
-.","Gene-specific,Strength"
-APC (HGNC:583),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-APC (HGNC:583),PS3,Very Strong,"RNA assays
- show
-
-
-
-
-a premature stop codon
-OR
-
-
-inframe skipping of exon 13 or 14
-
-
-
-
-AND
- the absence of full-length transcript.","Gene-specific,Strength"
-APC (HGNC:583),PS3,Strong,"RNA assays
- show
-
-
-
-
-a premature stop codon
-OR
-
-
-inframe skipping of exon 13 or 14
-
-
-
-
-AND
- < 10% of full-length transcript.","Gene-specific,Strength"
-APC (HGNC:583),PS3,Moderate,"RNA assays
- show 
-
-
-
-
-a premature stop codon AND reports of exon deletion/skipping/loss, insertion of intronic nucleotides
-OR
-
-
-inframe skipping of exon 13 or 14 AND reports of exon deletion/skipping/loss, insertion of intronic nucleotides
-OR
-
-
-other inframe skipping AND absent or < 10% full-length transcript.","Gene-specific,Strength"
-APC (HGNC:583),PS3,Supporting,"RNA assays
- show 
-
-
-
-
-inframe skipping of exons other than exon 13 or 14 AND reports of exon deletion/skipping/loss, insertion of intronic nucleotides
-OR
-
-
-over-expression of an alternative transcript (exons 10, 11 or 15)
-
-
-
-
-Protein assays
- show
-
-
-Increased β-catenin regulated transcription activity and/or decreased binding to β-catenin by surface plasmon resonance (only for variants within the β-catenin binding domain, which refers to codons 959-2129 of 
-APC
-) [Reference 2].","Gene-specific,Strength"
-APC (HGNC:583),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-APC (HGNC:583),PS4,Very Strong,"≥ 16 phenotype points. For phenotype points curation see 
-Table 1
-.","Gene-specific,Strength"
-APC (HGNC:583),PS4,Strong,"4-15.5 phenotype points. For phenotype points curation see 
-Table 1
-.","Gene-specific,Strength"
-APC (HGNC:583),PS4,Moderate,"2-3.5 phenotype points. For phenotype points curation see 
-Table 1
-.","Gene-specific,Strength"
-APC (HGNC:583),PS4,Supporting,"1-1.5 phenotype point. For phenotype points curation see 
-Table 1
-.","Gene-specific,Strength"
-APC (HGNC:583),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-APC (HGNC:583),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-APC (HGNC:583),PM2,Supporting,"Rare in controls, defined by an allele frequency ≤ 0.0003% (0.000003) if the allele count is > 1 OR by an allele frequency < 0.001% (0.00001) if the allele count is ≤ 1.","Gene-specific,Strength"
-APC (HGNC:583),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-APC (HGNC:583),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,NA
-APC (HGNC:583),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-APC (HGNC:583),PM5,Moderate,"The reported missense variant was determined to be Pathogenic according to the APC-specific modifications.
-
-
-There are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). Other different missense variants at these positions meet PM5_supporting. No missense variant has been classified as Pathogenic based on current evidence. 
-
-
-Grantham´s distance of the variant under assessment must have an equal or higher score than the reported variant [Reference 3].","Gene-specific,Strength"
-APC (HGNC:583),PM5,Supporting,"The reported missense variant was determined to be Likely Pathogenic according to the APC-specific modifications.
-
-
-There are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). Other different missense variants at these positions meet PM5_supporting. No missense variant has been classified as Pathogenic based on current evidence. 
-
-
-Grantham´s distance of the variant under assessment must have an equal or higher score than the reported variant [Reference 3].","Gene-specific,Strength"
-APC (HGNC:583),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-APC (HGNC:583),PM6,Strong,"2-3.5 
-de novo
- scores. For curation of 
-de novo
- score see 
-Tables 1
- and 
-2
-.","Gene-specific,Strength"
-APC (HGNC:583),PM6,Moderate,"1-1.5 
-de novo
- scores. For curation of 
-de novo
- score see 
-Tables 1
- and 
-2
-.","Gene-specific,Strength"
-APC (HGNC:583),PM6,Supporting,"0.5 
-de novo
- scores. For curation of 
-de novo
- score see 
-Tables 1
- and 
-2
-.","Gene-specific,Strength"
-APC (HGNC:583),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-APC (HGNC:583),PP1,Strong,Variant segregates in ≥ 7 meioses in ≥ 2 families.,Strength
-APC (HGNC:583),PP1,Moderate,Variant segregates in 5-6 meioses in ≥ 1 family.,Strength
-APC (HGNC:583),PP1,Supporting,Variant segregates in 3-4 meioses in ≥ 1 family.,Strength
-APC (HGNC:583),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-APC (HGNC:583),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-APC (HGNC:583),PP3,Supporting,"Missense variants:
- Do not use computational prediction models for conservation, evolution, etc. 
-In silico
- splicing predictors should be used for presumed missense variants to reveal possible splicing effects.
-
-
-Non-canonical splicing variants:
- Multiple 
-in silico
- splicing predictors support a deleterious effect.","Gene-specific,Strength"
-APC (HGNC:583),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-APC (HGNC:583),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-APC (HGNC:583),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-APC (HGNC:583),BA1,Stand Alone,"GnomAD Popmax Filtering Allele Frequency (AF) 
-≥ 0.1%
- (0.001).",Gene-specific
-APC (HGNC:583),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-APC (HGNC:583),BS1,Strong,"GnomAD Popmax Filtering Allele Frequency (AF) 
-≥ 0.001%
- (0.00001).",Gene-specific
-APC (HGNC:583),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-APC (HGNC:583),BS2,Strong,"≥ 10 points for healthy individuals 
-OR
- ≥ 2 times in homozygous state.
-
-
-A 
-healthy individual
- worth 1 point is defined by:
-
-
-Age ≥ 50 years 
-+ Less than 5 adenomatous polyps in a colonoscopy 
-+ Absence of features in Table 1
-
-
-OR
-
-
-Age ≥ 50 years 
-+ Colorectal cancer/polyposis was not the indication for testing
-
-
-A 
-healthy individual
- worth 0.5 points is defined by keywords including control, non-cancer, normal, unaffected population.","Gene-specific,Strength"
-APC (HGNC:583),BS2,Supporting,"≥ 3 points for healthy individuals.
-
-
-A 
-healthy individual
- worth 1 point is defined by:
-
-
-Age ≥ 50 years 
-+ Less than 5 adenomatous polyps in a colonoscopy 
-+ Absence of features in Table 1
-
-
-OR
-
-
-Age ≥ 50 years 
-+ Colorectal cancer/polyposis was not the indication for testing
-
-
-A 
-healthy individual
- worth 0.5 points is defined by keywords including control, non-cancer, normal, unaffected population.","Gene-specific,Strength"
-APC (HGNC:583),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-APC (HGNC:583),BS3,Strong,"RNA assay
- of a synonymous or intronic variant in constitutional patient sample demonstrates no mRNA aberration
-
-
-AND
-
-
-biallelic expression is shown and/or nonsense-mediated decay inhibition was used.","Gene-specific,Strength"
-APC (HGNC:583),BS3,Supporting,"RNA assay
- of a synonymous or intronic variant in constitutional patient sample demonstrates no mRNA aberration, without demonstration of biallelic expression or use of nonsense-mediated decay inhibition
-
-
-OR
-
-
-Protein assay
- show retention of β-catenin regulated transcription activity comparable to wild-type (only for variants within the β-catenin binding domain, which refers to codons 959-2129 of 
-APC
-, see PMID: 33348689)","Gene-specific,Strength"
-APC (HGNC:583),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-APC (HGNC:583),BS4,Strong,"Affected member without the variant must score at least 1 phenotype point or at least two affected members without the variant must each score at least 0.5 phenotype points (see 
-Table 1
-).","Gene-specific,Strength"
-APC (HGNC:583),BS4,Supporting,"Affected member without the variant must score at least 0.5 phenotype points (see 
-Table 1
-).","Gene-specific,Strength"
-APC (HGNC:583),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-APC (HGNC:583),BP1,Supporting,BP1 is applicable to APC with the exception of missense variants located in the first 15-amino acid repeat of the β-catenin binding domain (codon 1021-1035).,No change
-APC (HGNC:583),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-APC (HGNC:583),BP2,Supporting,"Observed 
-in trans
- with a (Likely) Pathogenic 
-APC
- variant 
-OR
- ≥ 3 times in an unknown phase with different (Likely) Pathogenic 
-APC
- variants.",Gene-specific
-APC (HGNC:583),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-APC (HGNC:583),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-APC (HGNC:583),BP4,Supporting,"Missense variants:
- BP4 is not applicable.
-
-
-Synonymous (silent) or intronic variants
-: Multiple in silico splicing predictors suggest no impact on gene or gene product.",Gene-specific
-APC (HGNC:583),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-APC (HGNC:583),BP5,Supporting,Only applicable for an alternate genetic basis of the colorectal polyposis phenotype.,No change
-APC (HGNC:583),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-APC (HGNC:583),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-APC (HGNC:583),BP7,Supporting,A synonymous (silent) or intronic variant at or beyond +7/–21 for which multiple splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMLH1Version1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMLH1Version1.0.0_version=1.0.0.csv
deleted file mode 100644
index 615acf39f2b7baec2b3901e7d6efac0b68723ab6..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMLH1Version1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,259 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-MLH1 (HGNC:7127),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-MLH1 (HGNC:7127),PVS1,Very Strong,"Nonsense/frameshift variant introducing Premature Termination Codon (PTC)
-a
-  at or before codon 753 in 
-MLH1.
-
-
-OR
-
-
-Large genomic alterations
-a
- of single or multi-exon size.
-
-
-OR
-
-
-Variants at IVS±1 or IVS±2​
-a,c
- where exon skipping or use of a cryptic splice site disrupts reading frame and is predicted to undergo NMD. Not to be combined with PP3 and not to be used for a confirmed splice defect (see PVS1 for variants where patient mRNA assays indicate splicing aberration). If exon skipping or use of a cryptic splice site preserves reading frame and the altered region is critical to protein function
-b
- then use PVS1_Strong. If exon skipping or use of a cryptic splice site disrupts reading frame and is NOT predicted to undergo NMD then use PVS1_Moderate.
-
-
-OR
-
-
-Variants where mRNA assays using RNA derived from patient constitutional biological samples indicate that the variant allele results in a splicing aberration (with evidence that the variant allele produces no full-length/reference transcript) leading to premature stop codon or in-frame deletion disrupting a functional domain
-b
- or protein conformation. Splicing aberration must be confirmed in a minigene assay or an additional RNA assay from an independent laboratory if it is a non-canonical splice site variant.
-
-
-OR
-
-
-Variants in the initiation codon of 
-MLH1
-.",General recommendation
-MLH1 (HGNC:7127),PVS1,Strong,"Presumed by default in tandem duplication of ≥1 exon resulting in a frameshift before the last splice junction. This rule does not apply for variants that involve the UTR (i.e. exon 1 or last exon) and whole gene duplications.
-
-
-OR
-
-
-G>non-G at last base of exon if first 6 bases of the intron are not GTRRGT. If confirmed to cause a splice defect, then PVS1 should be used instead.
-
-
-OR
-
-
-Variants at IVS±1 or IVS±2​
-a,c
- where exon skipping or use of a cryptic splice site preserves reading frame and the altered region is critical to protein function
-b
-. Not to be combined with PP3 and not to be used for a confirmed splice defect (see PVS1 for variants where patient mRNA assays indicate splicing aberration).",General recommendation
-MLH1 (HGNC:7127),PVS1,Moderate,"Nonsense/frameshift variant introducing premature termination codon in codons 754, 755 or 756 in 
-MLH1.
- Refer to Appendix for details.",Gene-specific
-MLH1 (HGNC:7127),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MLH1 (HGNC:7127),PS1,Strong,"A predicted missense substitution that encodes the same amino acid change with a different underlying nucleotide change previously established by this VCEP as Pathogenic (not a predicted or confirmed splice defect).
-
-
-OR
-
-
-Variants affecting the same non-canonical splice nucleotide as a confirmed pathogenic splice variant with similar or worse splicing in silico prediction using SpliceAI.",General recommendation
-MLH1 (HGNC:7127),PS1,Moderate,"A predicted missense substitution that encodes the same amino acid change with a different underlying nucleotide change as a previously established Likely Pathogenic missense variant with normal RNA result*, and PM2_supporting is met.
-
-
-*Otherwise, if the previously established Likely pathogenic missense variant truly is a splice defect, the new missense variant also has to be investigated on a functional level for RNA splicing.",General recommendation
-MLH1 (HGNC:7127),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-MLH1 (HGNC:7127),PS2,Very Strong,"≥ 4 
-de novo
- points",Disease-specific
-MLH1 (HGNC:7127),PS2,Strong,"2 or 3 
-de novo
- points",Disease-specific
-MLH1 (HGNC:7127),PS2,Moderate,"1 
-de novo
- point",Disease-specific
-MLH1 (HGNC:7127),PS2,Supporting,"0.5 
-de novo
- points",Disease-specific
-MLH1 (HGNC:7127),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-MLH1 (HGNC:7127),PS3,Strong,Calibrated functional assays with functional odds for Pathogenicity > 18.7,General recommendation
-MLH1 (HGNC:7127),PS3,Moderate,"Calibrated functional assays with functional odds for pathogenicity >4.3 and <= 18.7
-
-
-OR 
-
-
-MMR function defect following functional assay flowchart*
-
-
-OR 
-
-
-Variants with monoallelic expression: complete loss of expression (<10% of wild-type in cDNA without puromycin) of the variant allele. Full-length transcript should be analysed with and without NMD block.",General recommendation
-MLH1 (HGNC:7127),PS3,Supporting,Calibrated functional odds for Pathogenicity >2.08 and <= 4.3,General recommendation
-MLH1 (HGNC:7127),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",NA
-MLH1 (HGNC:7127),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-MLH1 (HGNC:7127),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-MLH1 (HGNC:7127),PM2,Supporting,"Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset",General recommendation
-MLH1 (HGNC:7127),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-MLH1 (HGNC:7127),PM3,Very Strong,≥ 4 points,Disease-specific
-MLH1 (HGNC:7127),PM3,Strong,≥ 2 and < 4 points,Disease-specific
-MLH1 (HGNC:7127),PM3,Moderate,≥1 and < 2 points,Disease-specific
-MLH1 (HGNC:7127),PM3,Supporting,= 0.5 points,Disease-specific
-MLH1 (HGNC:7127),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,NA
-MLH1 (HGNC:7127),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MLH1 (HGNC:7127),PM5,Moderate,Missense change at an amino acid residue where a different missense change was classified by this VCEP as Pathogenic on the protein level and not due to aberrant splicing. Only use PM5 if PP3 is supporting for the missense change. Use PM5_Supporting if other variant is Likely Pathogenic due to a missense alteration.,General recommendation
-MLH1 (HGNC:7127),PM5,Supporting,Missense change at an amino acid residue where a different missense change was classified as Likely Pathogenic on the protein level and not due to aberrant splicing. Only use PM5_Supporting if PP3 is supporting for the missense change. Use PM5 if other variant is Pathogenic due to a missense alteration.,General recommendation
-MLH1 (HGNC:7127),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-MLH1 (HGNC:7127),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-MLH1 (HGNC:7127),PP1,Strong,"Co-segregation with disease in pedigree(s) with a combined* Bayes Likelihood Ratio
-h
- >18.7​ in ≥2 families.",General recommendation
-MLH1 (HGNC:7127),PP1,Moderate,"Co-segregation with disease in pedigree(s) with a combined* Bayes Likelihood Ratio​
-h
- >4.3 & ≤18.7.",General recommendation
-MLH1 (HGNC:7127),PP1,Supporting,"Co-segregation with disease in pedigree(s) with a combined* Bayes Likelihood Ratio
-h
- >2.08 & ≤4.3.",General recommendation
-MLH1 (HGNC:7127),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-MLH1 (HGNC:7127),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-MLH1 (HGNC:7127),PP3,Moderate,"Missense variant with HCI prior probability for pathogenicity >0.81 as per 
-https://hci-priors.hci.utah.edu/PRIORS",General recommendation
-MLH1 (HGNC:7127),PP3,Supporting,"Missense variant with HCI prior probability for pathogenicity >0.68 & ≤0.81 as per 
-https://hci-priors.hci.utah.edu/PRIORS
-
-
-OR
-
-
-Predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score >= 0.2 as per Walker et al 2023.",General recommendation
-MLH1 (HGNC:7127),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-MLH1 (HGNC:7127),PP4,Strong,"≥3 independent CRC/Endometrial MSI-H tumors in ≥2 families using a standard panel of 5-10 markers
-g 
- or tumor genome 
-and/or
-​ loss of MMR protein expression consistent with the variant location. MSI-H tumor with inconsistent protein expression does not meet PP4_Strong. For 
-MLH1
- variants, 
-MLH1
- promoter methylation is to be excluded in the tumors. Independent tumors can be from the same patient/family.",Disease-specific
-MLH1 (HGNC:7127),PP4,Moderate,"2 independent CRC/Endometrial MSI-H tumors using a standard panel of 5-10 markers
-g
- or tumor genome ​
-and/or
-​ loss of MMR protein expression consistent with the variant location. MSI-H tumor with inconsistent protein expression does not meet PP4_Moderate. For 
-MLH1
- variants, 
-MLH1
- promoter methylation is to be excluded in the tumors. Independent tumors can be from the same patient/family.",Disease-specific
-MLH1 (HGNC:7127),PP4,Supporting,"1 CRC/Endometrial MSI-H tumor using a standard panel of 5-10 markers
-g 
- or tumor genome ​
-and/or
-​ loss of MMR protein expression consistent with the variant location. MSI-H tumor with inconsistent protein expression does not meet PP4. For 
-MLH1
- variants, 
-MLH1
- promoter methylation is to be excluded in the tumor.",Disease-specific
-MLH1 (HGNC:7127),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MLH1 (HGNC:7127),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-MLH1 (HGNC:7127),BA1,Stand Alone,GnomAD v4 Grpmax filtering allele frequency ≥ 0.001 (0.1%) and variant is excluded as founder pathogenic variant.,Gene-specific
-MLH1 (HGNC:7127),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-MLH1 (HGNC:7127),BS1,Strong,GnomAD v4 Grpmax filtering allele frequency ≥ 0.0001 and < 0.001 (0.01-0.1%) and variant is excluded as founder pathogenic variant.,Gene-specific
-MLH1 (HGNC:7127),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-MLH1 (HGNC:7127),BS2,Strong,"Co-occurrence ​
-in trans​
- with a known pathogenic sequence variant in the same gene in a patient with colorectal cancer after age 45 (or other LS cancer above the median age of onset for that cancer in LS
-​f
-​), and who has no previous or current evidence of clinical manifestations of CMMRD as per Aronson et al 2022 (Refer to 'Table for CMMRD diagnosis.pdf'). Confirmation of phase requires testing of parents or offspring.",Disease-specific
-MLH1 (HGNC:7127),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-MLH1 (HGNC:7127),BS3,Strong,"Calibrated functional assays with functional odds for Pathogenicity ≤ 0.05
-
-
-OR
-
-
-Synonymous substitutions and intronic variants with no associated mRNA aberration (either splicing or allelic imbalance) as determined by laboratory assays conducted with nonsense-mediated decay inhibition. Whenever abnormal transcripts are identified at similar levels in controls they will be considered naturally occurring isoforms and not mRNA aberrations.",General recommendation
-MLH1 (HGNC:7127),BS3,Supporting,"Calibrated functional assays with functional odds for Pathogenicity >0.05 & ≤0.48
-
-
-OR
-
-
-Variant-specific proficient function in protein and mRNA-based lab assays as per MMR functional assay flowchart*.",General recommendation
-MLH1 (HGNC:7127),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-MLH1 (HGNC:7127),BS4,Strong,"Lack of co-segregation with disease in pedigree(s) with a combined* Bayes Likelihood Ratio
-h
- <0.05​.",General recommendation
-MLH1 (HGNC:7127),BS4,Supporting,"Lack of co-segregation with disease in pedigree(s) with a combined* Bayes Likelihood Ratio
-h
- >0.05 & ≤0.48.",General recommendation
-MLH1 (HGNC:7127),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-MLH1 (HGNC:7127),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-MLH1 (HGNC:7127),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-MLH1 (HGNC:7127),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-MLH1 (HGNC:7127),BP4,Supporting,"Missense variant with HCI-prior probability of pathogenicity <0.11 as per 
-https://hci-priors.hci.utah.edu/PRIORS
-
-
-OR
-
-
-For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score <= 0.1 as per Walker et al 2023",General recommendation
-MLH1 (HGNC:7127),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-MLH1 (HGNC:7127),BP5,Strong,"​≥ 4 tumors: CRC/Endometrial tumors with MSS ​and/or​ no ​loss of MMR protein expression​ ​and/or LS spectrum tumors
-f
- with loss of MMR protein(s) that is inconsistent with the gene demonstrating genetic variation
-
-
-OR
-
-
-≥2 BRAF V600E (CRC only)/
-MLH1
- methylation (in LS spectrum tumor only) with MSI-H/
-MLH1
- loss.",Disease-specific
-MLH1 (HGNC:7127),BP5,Supporting,"2 or 3 tumors: CRC/Endometrial tumors with MSS and/or no loss of MMR protein expression and/or LS spectrum tumors
-f
- with loss of MMR protein(s) that is inconsistent with the gene demonstrating genetic variation.
-
-
-OR 
-
-
-1 BRAF V600E (Colon only)/
-MLH1
- methylation (in LS spectrum tumor only) with MSI-H/
-MLH1
- loss.",Disease-specific
-MLH1 (HGNC:7127),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MLH1 (HGNC:7127),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-MLH1 (HGNC:7127),BP7,Supporting,A synonymous (silent) or intronic variant at or beyond -21/+7 (5′/3′ exonic). Variants may satisfy both BP7 and BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMSH2Version1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMSH2Version1.0.0_version=1.0.0.csv
deleted file mode 100644
index 4560e662ea6ec25a71344a834fb0f4e021f5683a..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMSH2Version1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,238 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-MSH2 (HGNC:7325),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-MSH2 (HGNC:7325),PVS1,Very Strong,"Nonsense/frameshift variant introducing Premature Termination Codon (PTC)
-a
- ≤ codon 891 in 
-MSH2.
- Refer to Appendix for details.
-
-
-OR
-
-
-Large genomic alterations
-a
- of single or multi-exon size.
-
-
-OR
-
-
-Variants at IVS±1 or IVS±2​
-a,c
- where exon skipping or use of a cryptic splice site disrupts reading frame and is predicted to undergo NMD. Not to be combined with PP3 and not to be used for a confirmed splice defect (see PVS1 for variants where patient mRNA assays indicate splicing aberration). If exon skipping or use of a cryptic splice site preserves reading frame and the altered region is critical to protein function
-b
- then use PVS1_Strong. If exon skipping or use of a cryptic splice site disrupts reading frame and is NOT predicted to undergo NMD then use PVS1_Moderate.
-
-
-OR
-
-
-Variants where mRNA assays using RNA derived from patient constitutional biological samples indicate that the variant allele results in a splicing aberration (with evidence that the variant allele produces no full-length/reference transcript) leading to premature stop codon or in-frame deletion disrupting a functional domain
-b
- or protein conformation. Splicing aberration must be confirmed in a minigene assay or an additional RNA assay from an independent laboratory if it is a non-canonical splice site variant.",General recommendation
-MSH2 (HGNC:7325),PVS1,Strong,"Presumed by default in tandem duplication of ≥1 exon resulting in a frameshift before the last splice junction. This rule does not apply for variants that involve the UTR (i.e. exon 1 or last exon) and whole gene duplications.
-
-
-OR
-
-
-G>non-G at last base of exon if first 6 bases of the intron are not GTRRGT. If confirmed to cause a splice defect, then PVS1 should be used instead.
-
-
-OR
-
-
-Variants at IVS±1 or IVS±2​
-a,c
- where exon skipping or use of a cryptic splice site preserves reading frame and the altered region is critical to protein function
-b
-. Not to be combined with PP3 and not to be used for a confirmed splice defect (see PVS1 for variants where patient mRNA assays indicate splicing aberration).",General recommendation
-MSH2 (HGNC:7325),PVS1,Moderate,"Nonsense/frameshift variant introducing premature termination codon between codons 892 & 934 in 
-MSH2
-. Refer to Appendix for details.",Gene-specific
-MSH2 (HGNC:7325),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MSH2 (HGNC:7325),PS1,Strong,"A predicted missense substitution that encodes the same amino acid change with a different underlying nucleotide change previously established by this VCEP as Pathogenic (not a predicted or confirmed splice defect).
-
-
-OR
-
-
-Variants affecting the same non-canonical splice nucleotide as a confirmed pathogenic splice variant with similar or worse splicing in silico prediction using SpliceAI.",General recommendation
-MSH2 (HGNC:7325),PS1,Moderate,"A predicted missense substitution that encodes the same amino acid change with a different underlying nucleotide change as a previously established Likely Pathogenic missense variant with normal RNA result*, and PM2_supporting is met.
-
-
-*Otherwise, if the previously established Likely pathogenic missense variant truly is a splice defect, the new missense variant also has to be investigated on a functional level for RNA splicing.",General recommendation
-MSH2 (HGNC:7325),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-MSH2 (HGNC:7325),PS2,Very Strong,"≥ 4 
-de novo
- points",Disease-specific
-MSH2 (HGNC:7325),PS2,Strong,"2 or 3 
-de novo
- points",Disease-specific
-MSH2 (HGNC:7325),PS2,Moderate,"1 
-de novo
- point",Disease-specific
-MSH2 (HGNC:7325),PS2,Supporting,"0.5 
-de novo
- points",Disease-specific
-MSH2 (HGNC:7325),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-MSH2 (HGNC:7325),PS3,Strong,Calibrated functional assays with functional odds for Pathogenicity > 18.7,General recommendation
-MSH2 (HGNC:7325),PS3,Moderate,"Calibrated functional assays with functional odds for pathogenicity >4.3 and <= 18.7
-
-
-OR 
-
-
-MMR function defect following functional assay flowchart*
-
-
-OR 
-
-
-Variants with monoallelic expression: complete loss of expression (<10% of wild-type in cDNA without puromycin) of the variant allele. Full-length transcript should be analysed with and without NMD block.",General recommendation
-MSH2 (HGNC:7325),PS3,Supporting,Calibrated functional odds for Pathogenicity >2.08 and <= 4.3,General recommendation
-MSH2 (HGNC:7325),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",NA
-MSH2 (HGNC:7325),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-MSH2 (HGNC:7325),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-MSH2 (HGNC:7325),PM2,Supporting,"Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset",General recommendation
-MSH2 (HGNC:7325),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-MSH2 (HGNC:7325),PM3,Very Strong,≥ 4 points,Disease-specific
-MSH2 (HGNC:7325),PM3,Strong,≥ 2 and < 4 points,Disease-specific
-MSH2 (HGNC:7325),PM3,Moderate,≥1 and < 2 points,Disease-specific
-MSH2 (HGNC:7325),PM3,Supporting,= 0.5 points,Disease-specific
-MSH2 (HGNC:7325),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,NA
-MSH2 (HGNC:7325),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MSH2 (HGNC:7325),PM5,Moderate,Missense change at an amino acid residue where a different missense change was classified by this VCEP as Pathogenic on the protein level and not due to aberrant splicing. Only use PM5 if PP3 is supporting for the missense change. Use PM5_Supporting if other variant is Likely Pathogenic due to a missense alteration.,General recommendation
-MSH2 (HGNC:7325),PM5,Supporting,Missense change at an amino acid residue where a different missense change was classified as Likely Pathogenic on the protein level and not due to aberrant splicing. Only use PM5_Supporting if PP3 is supporting for the missense change. Use PM5 if other variant is Pathogenic due to a missense alteration.,General recommendation
-MSH2 (HGNC:7325),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-MSH2 (HGNC:7325),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-MSH2 (HGNC:7325),PP1,Strong,"Co-segregation with disease in pedigree(s) with a combined* Bayes Likelihood Ratio
-h
- >18.7​ in ≥2 families.",General recommendation
-MSH2 (HGNC:7325),PP1,Moderate,"Co-segregation with disease in pedigree(s) with a combined* Bayes Likelihood Ratio​
-h
- >4.3 & ≤18.7.",General recommendation
-MSH2 (HGNC:7325),PP1,Supporting,"Co-segregation with disease in pedigree(s) with a combined* Bayes Likelihood Ratio
-h
- >2.08 & ≤4.3.",General recommendation
-MSH2 (HGNC:7325),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-MSH2 (HGNC:7325),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-MSH2 (HGNC:7325),PP3,Moderate,"Missense variant with HCI prior probability for pathogenicity >0.81 as per 
-https://hci-priors.hci.utah.edu/PRIORS",General recommendation
-MSH2 (HGNC:7325),PP3,Supporting,"Missense variant with HCI prior probability for pathogenicity >0.68 & ≤0.81 as per 
-https://hci-priors.hci.utah.edu/PRIORS
-
-
-OR
-
-
-Predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score >= 0.2 as per Walker et al 2023.",General recommendation
-MSH2 (HGNC:7325),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-MSH2 (HGNC:7325),PP4,Strong,"≥3 independent CRC/Endometrial MSI-H tumors in ≥2 families using a standard panel of 5-10 markers​
-g
- ​or tumor genome 
-and/or
-​ loss of MMR protein expression consistent with the variant location. MSI-H tumor with inconsistent protein expression does not meet PP4_Strong. Independent tumors can be from the same patient/family.",Disease-specific
-MSH2 (HGNC:7325),PP4,Moderate,"2 independent CRC/Endometrial MSI-H tumors using a standard panel of 5-10 markers
-g
- or tumor genome ​
-and/or
-​ loss of MMR protein expression consistent with the variant location. MSI-H tumor with inconsistent protein expression does not meet PP4_Moderate. Independent tumors can be from the same patient/family.",Disease-specific
-MSH2 (HGNC:7325),PP4,Supporting,"1 CRC/Endometrial MSI-H tumor using a standard panel of 5-10 markers
-g
- or tumor genome ​
-and/or
-​ loss of MMR protein expression consistent with the variant location. MSI-H tumor with inconsistent protein expression does not meet PP4.",Disease-specific
-MSH2 (HGNC:7325),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MSH2 (HGNC:7325),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-MSH2 (HGNC:7325),BA1,Stand Alone,GnomAD v4 Grpmax filtering allele frequency ≥ 0.001 (0.1%) and variant is excluded as founder pathogenic variant.,Gene-specific
-MSH2 (HGNC:7325),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-MSH2 (HGNC:7325),BS1,Strong,GnomAD v4 Grpmax filtering allele frequency ≥ 0.0001 and < 0.001 (0.01-0.1%) and variant is excluded as founder pathogenic variant.,Gene-specific
-MSH2 (HGNC:7325),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-MSH2 (HGNC:7325),BS2,Strong,"Co-occurrence 
-​in trans​
- with a known pathogenic sequence variant in the same gene in a patient with colorectal cancer after age 45 (or other LS cancer above the median age of onset for that cancer in LS​f​), and who has no previous or current evidence of clinical manifestations of CMMRD as per Aronson et al 2022 (Refer to 'Table for CMMRD diagnosis.pdf'). Confirmation of phase requires testing of parents or offspring.",Disease-specific
-MSH2 (HGNC:7325),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-MSH2 (HGNC:7325),BS3,Strong,"Calibrated functional assays with functional odds for Pathogenicity ≤ 0.05
-
-
-OR
-
-
-Synonymous substitutions and intronic variants with no associated mRNA aberration (either splicing or allelic imbalance) as determined by laboratory assays conducted with nonsense-mediated decay inhibition. Whenever abnormal transcripts are identified at similar levels in controls they will be considered naturally occurring isoforms and not mRNA aberrations.",General recommendation
-MSH2 (HGNC:7325),BS3,Supporting,"Calibrated functional assays with functional odds for Pathogenicity >0.05 & ≤0.48
-
-
-OR
-
-
-Variant-specific proficient function in protein and mRNA-based lab assays as per MMR functional assay flowchart.",General recommendation
-MSH2 (HGNC:7325),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-MSH2 (HGNC:7325),BS4,Strong,"Lack of co-segregation with disease in pedigree(s) with a combined* Bayes Likelihood Ratio
-h
- <0.05​.",General recommendation
-MSH2 (HGNC:7325),BS4,Supporting,"Lack of co-segregation with disease in pedigree(s) with a combined* Bayes Likelihood Ratio
-h
- >0.05 & ≤0.48.",General recommendation
-MSH2 (HGNC:7325),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-MSH2 (HGNC:7325),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-MSH2 (HGNC:7325),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-MSH2 (HGNC:7325),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-MSH2 (HGNC:7325),BP4,Supporting,"Missense variant with HCI-prior probability of pathogenicity <0.11 as per 
-https://hci-priors.hci.utah.edu/PRIORS
-
-
-OR
-
-
-For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score <= 0.1 as per Walker et al 2023.",General recommendation
-MSH2 (HGNC:7325),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-MSH2 (HGNC:7325),BP5,Strong,"​≥ 4 tumors: CRC/Endometrial tumors with MSS ​and/or​ no ​loss of MMR protein expression​ ​and/or LS spectrum tumors
-f
- with loss of MMR protein(s) that is inconsistent with the gene demonstrating genetic variation
-
-
-OR
-
-
-≥2 BRAF V600E (CRC only)/
-MLH1
- methylation (in LS spectrum tumor only) with MSI-H/
-MLH1
- loss.",Disease-specific
-MSH2 (HGNC:7325),BP5,Supporting,"2 or 3 tumors: CRC/Endometrial tumors with MSS and/or no loss of MMR protein expression and/or LS spectrum tumors
-f
- with loss of MMR protein(s) that is inconsistent with the gene demonstrating genetic variation.
-
-
-OR 
-
-
-1 BRAF V600E (Colon only)/
-MLH1
- methylation (in LS spectrum tumor only) with MSI-H/
-MLH1
- loss.",Disease-specific
-MSH2 (HGNC:7325),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MSH2 (HGNC:7325),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-MSH2 (HGNC:7325),BP7,Supporting,A synonymous (silent) or intronic variant at or beyond -21/+7 (5′/3′ exonic). Variants may satisfy both BP7 and BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMSH6Version1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMSH6Version1.0.0_version=1.0.0.csv
deleted file mode 100644
index 618581aa53cda950fc8caee9076245fd894741bc..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMSH6Version1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,247 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-MSH6 (HGNC:7329),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-MSH6 (HGNC:7329),PVS1,Very Strong,"Nonsense/frameshift variant introducing Premature Termination Codon (PTC)
-a
- ≤ codon 1341 in 
-MSH6
-. Refer to Appendix for details.
-
-
-OR
-
-
-Large genomic alterations
-a
- of single or multi-exon size.
-
-
-OR
-
-
-Variants at IVS±1 or IVS±2​
-a,c
- where exon skipping or use of a cryptic splice site disrupts reading frame and is predicted to undergo NMD. Not to be combined with PP3 and not to be used for a confirmed splice defect (see PVS1 for variants where patient mRNA assays indicate splicing aberration). If exon skipping or use of a cryptic splice site preserves reading frame and the altered region is critical to protein function
-b
- then use PVS1_Strong. If exon skipping or use of a cryptic splice site disrupts reading frame and is NOT predicted to undergo NMD then use PVS1_Moderate.
-
-
-OR
-
-
-Variants where mRNA assays using RNA derived from patient constitutional biological samples indicate that the variant allele results in a splicing aberration (with evidence that the variant allele produces no full-length/reference transcript) leading to premature stop codon or in-frame deletion disrupting a functional domain
-b
- or protein conformation. Splicing aberration must be confirmed in a minigene assay or an additional RNA assay from an independent laboratory if it is a non-canonical splice site variant.",General recommendation
-MSH6 (HGNC:7329),PVS1,Strong,"Variants in the initiation codon of 
-MSH6
-.
-
-
-OR 
-
-
-Presumed by default in tandem duplication of ≥1 exon resulting in a frameshift before the last splice junction. This rule does not apply for variants that involve the UTR (i.e. exon 1 or last exon) and whole gene duplications.
-
-
-OR
-
-
-G>non-G at last base of exon if first 6 bases of the intron are not GTRRGT. If confirmed to cause a splice defect, then PVS1 should be used instead.
-
-
-OR
-
-
-Variants at IVS±1 or IVS±2​
-a,c
- where exon skipping or use of a cryptic splice site preserves reading frame and the altered region is critical to protein function
-b
-. Not to be combined with PP3 and not to be used for a confirmed splice defect (see PVS1 for variants where patient mRNA assays indicate splicing aberration).",General recommendation
-MSH6 (HGNC:7329),PVS1,Moderate,Nonsense/frameshift variant introducing premature termination codon  between codons 1342 & 1360 in MSH6. Refer to Appendix for details.,Gene-specific
-MSH6 (HGNC:7329),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MSH6 (HGNC:7329),PS1,Strong,"A predicted missense substitution that encodes the same amino acid change with a different underlying nucleotide change previously established by this VCEP as Pathogenic (not a predicted or confirmed splice defect).
-
-
-OR
-
-
-Variants affecting the same non-canonical splice nucleotide as a confirmed pathogenic splice variant with similar or worse splicing in silico prediction using SpliceAI.",General recommendation
-MSH6 (HGNC:7329),PS1,Moderate,"A predicted missense substitution that encodes the same amino acid change with a different underlying nucleotide change as a previously established Likely Pathogenic missense variant with normal RNA result*, and PM2_supporting is met.
-
-
-*Otherwise, if the previously established Likely pathogenic missense variant truly is a splice defect, the new missense variant also has to be investigated on a functional level for RNA splicing.",General recommendation
-MSH6 (HGNC:7329),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-MSH6 (HGNC:7329),PS2,Very Strong,"≥ 4 
-de novo
- points",Disease-specific
-MSH6 (HGNC:7329),PS2,Strong,"2 or 3 
-de novo
- points",Disease-specific
-MSH6 (HGNC:7329),PS2,Moderate,"1 
-de novo
- point",Disease-specific
-MSH6 (HGNC:7329),PS2,Supporting,"0.5 
-de novo
- points",Disease-specific
-MSH6 (HGNC:7329),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-MSH6 (HGNC:7329),PS3,Strong,Calibrated functional assays with functional odds for Pathogenicity > 18.7,General recommendation
-MSH6 (HGNC:7329),PS3,Moderate,"Calibrated functional assays with functional odds for pathogenicity >4.3 and <= 18.7
-
-
-OR 
-
-
-MMR function defect following functional assay flowchart*
-
-
-OR 
-
-
-Variants with monoallelic expression: complete loss of expression (<10% of wild-type in cDNA without puromycin) of the variant allele. Full-length transcript should be analysed with and without NMD block.",General recommendation
-MSH6 (HGNC:7329),PS3,Supporting,Calibrated functional odds for Pathogenicity >2.08 and <= 4.3,General recommendation
-MSH6 (HGNC:7329),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",NA
-MSH6 (HGNC:7329),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-MSH6 (HGNC:7329),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-MSH6 (HGNC:7329),PM2,Supporting,"Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset",General recommendation
-MSH6 (HGNC:7329),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-MSH6 (HGNC:7329),PM3,Very Strong,≥ 4 points,Disease-specific
-MSH6 (HGNC:7329),PM3,Strong,≥ 2 and < 4 points,Disease-specific
-MSH6 (HGNC:7329),PM3,Moderate,≥1 and < 2 points,Disease-specific
-MSH6 (HGNC:7329),PM3,Supporting,= 0.5 points,Disease-specific
-MSH6 (HGNC:7329),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,NA
-MSH6 (HGNC:7329),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MSH6 (HGNC:7329),PM5,Moderate,Missense change at an amino acid residue where a different missense change was classified by this VCEP as Pathogenic on the protein level and not due to aberrant splicing. Only use PM5 if PP3 is supporting for the missense change. Use PM5_Supporting if other variant is Likely Pathogenic due to a missense alteration.,General recommendation
-MSH6 (HGNC:7329),PM5,Supporting,Missense change at an amino acid residue where a different missense change was classified as Likely Pathogenic on the protein level and not due to aberrant splicing. Only use PM5_Supporting if PP3 is supporting for the missense change. Use PM5 if other variant is Pathogenic due to a missense alteration.,General recommendation
-MSH6 (HGNC:7329),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-MSH6 (HGNC:7329),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-MSH6 (HGNC:7329),PP1,Strong,"Co-segregation with disease in pedigree(s) with a combined* Bayes Likelihood Ratio
-h
- >18.7​ in ≥2 families.",General recommendation
-MSH6 (HGNC:7329),PP1,Moderate,"Co-segregation with disease in pedigree(s) with a combined* Bayes Likelihood Ratio​
-h
- >4.3 & ≤18.7.",General recommendation
-MSH6 (HGNC:7329),PP1,Supporting,"Co-segregation with disease in pedigree(s) with a combined* Bayes Likelihood Ratio
-h
- >2.08 & ≤4.3.",General recommendation
-MSH6 (HGNC:7329),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-MSH6 (HGNC:7329),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-MSH6 (HGNC:7329),PP3,Moderate,"Missense variant with HCI prior probability for pathogenicity >0.81 as per 
-https://hci-priors.hci.utah.edu/PRIORS",General recommendation
-MSH6 (HGNC:7329),PP3,Supporting,"Missense variant with HCI prior probability for pathogenicity >0.68 & ≤0.81 as per 
-https://hci-priors.hci.utah.edu/PRIORS
- 
-
-
-OR
-
-
-Predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score >= 0.2 as per Walker et al 2023.",General recommendation
-MSH6 (HGNC:7329),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-MSH6 (HGNC:7329),PP4,Strong,"≥3 independent CRC/Endometrial MSI-H tumors in ≥2 families using a standard panel of 5-10 markers​
-g
- ​or tumor genome 
-and/or
-​ loss of MMR protein expression consistent with the variant location. MSI-H tumor with inconsistent protein expression does not meet PP4_Strong.  Independent tumors can be from the same patient/family.",Disease-specific
-MSH6 (HGNC:7329),PP4,Moderate,"2 independent CRC/Endometrial MSI-H tumors using a standard panel of 5-10 markers​
-g
- or tumor genome ​
-and/or
-​ loss of MMR protein expression consistent with the variant location. MSI-H tumor with inconsistent protein expression does not meet PP4_Moderate.",Disease-specific
-MSH6 (HGNC:7329),PP4,Supporting,"1 CRC/Endometrial MSI-H tumor using a standard panel of 5-10 markers​
-g
- or tumor genome ​
-and/or
-​ loss of MMR protein expression consistent with the variant location. MSI-H tumor with inconsistent protein expression does not meet PP4.",Disease-specific
-MSH6 (HGNC:7329),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MSH6 (HGNC:7329),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-MSH6 (HGNC:7329),BA1,Stand Alone,GnomAD v4 Grpmax filtering allele frequency ≥ 0.0022 (0.22%) and variant is excluded as founder pathogenic variant.,Gene-specific
-MSH6 (HGNC:7329),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-MSH6 (HGNC:7329),BS1,Strong,GnomAD v4 Grpmax filtering allele frequency ≥ 0.00022 and < 0.0022 (0.022-0.22%) and variant is excluded as founder pathogenic variant.,Gene-specific
-MSH6 (HGNC:7329),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-MSH6 (HGNC:7329),BS2,Strong,"Co-occurrence 
-​in trans
- with a known pathogenic sequence variant in the same gene in a patient with colorectal cancer after age 45 (or other LS cancer above the median age of onset for that cancer in LS
-​f​
-), and who has no previous or current evidence of clinical manifestations of CMMRD as per Aronson et al 2022 (Refer to 'Table for CMMRD diagnosis.pdf'). Confirmation of phase requires testing of parents or offspring.",Disease-specific
-MSH6 (HGNC:7329),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-MSH6 (HGNC:7329),BS3,Strong,"Calibrated functional assays with functional odds for Pathogenicity ≤ 0.05
-
-
-OR
-
-
-Synonymous substitutions and intronic variants with no associated mRNA aberration (either splicing or allelic imbalance) as determined by laboratory assays conducted with nonsense-mediated decay inhibition. Whenever abnormal transcripts are identified at similar levels in controls they will be considered naturally occurring isoforms and not mRNA aberrations.",General recommendation
-MSH6 (HGNC:7329),BS3,Supporting,"Calibrated functional assays with functional odds for Pathogenicity >0.05 & ≤0.48
-
-
-OR
-
-
-Variant-specific proficient function in protein and mRNA-based lab assays as per MMR functional assay flowchart.",General recommendation
-MSH6 (HGNC:7329),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-MSH6 (HGNC:7329),BS4,Strong,"Lack of co-segregation with disease in pedigree(s) with a combined* Bayes Likelihood Ratio
-h
- <0.05​.",General recommendation
-MSH6 (HGNC:7329),BS4,Supporting,"Lack of co-segregation with disease in pedigree(s) with a combined* Bayes Likelihood Ratio
-h
- >0.05 & ≤0.48.",General recommendation
-MSH6 (HGNC:7329),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-MSH6 (HGNC:7329),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-MSH6 (HGNC:7329),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-MSH6 (HGNC:7329),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-MSH6 (HGNC:7329),BP4,Supporting,"Missense variant with HCI-prior probability of pathogenicity <0.11 as per 
-https://hci-priors.hci.utah.edu/PRIORS
-
-
-OR
-
-
-For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score <= 0.1 as per Walker et al 2023.",General recommendation
-MSH6 (HGNC:7329),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-MSH6 (HGNC:7329),BP5,Strong,"​≥ 4 tumors: CRC/Endometrial tumors with MSS ​and/or​ no ​loss of MMR protein expression​ ​and/or LS spectrum tumors
-f
- with loss of MMR protein(s) that is inconsistent with the gene demonstrating genetic variation
-
-
-OR
-
-
-≥2 BRAF V600E (CRC only)/
-MLH1
- methylation (in LS spectrum tumor only) with MSI-H/
-MLH1
- loss.",Disease-specific
-MSH6 (HGNC:7329),BP5,Supporting,"2 or 3 tumors: CRC/Endometrial tumors with MSS and/or no loss of MMR protein expression and/or LS spectrum tumors
-f
- with loss of MMR protein(s) that is inconsistent with the gene demonstrating genetic variation.
-
-
-OR 
-
-
-1 BRAF V600E (Colon only)/
-MLH1
- methylation (in LS spectrum tumor only) with MSI-H/
-MLH1
- loss.",Disease-specific
-MSH6 (HGNC:7329),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MSH6 (HGNC:7329),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-MSH6 (HGNC:7329),BP7,Supporting,A synonymous (silent) or intronic variant at or beyond -21/+7 (5′/3′ exonic). Variants may satisfy both BP7 and BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPMS2Version1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPMS2Version1.0.0_version=1.0.0.csv
deleted file mode 100644
index 17af41f7811c3dace300fca0699d578bcc13c486..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPMS2Version1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,255 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-PMS2 (HGNC:9122),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-PMS2 (HGNC:9122),PVS1,Very Strong,"Nonsense/frameshift variant introducing Premature Termination Codon (PTC)
-a 
- ≤ codon 798 in 
-PMS2
-. Refer to Appendix for details.
-
-
-OR
-
-
-Large genomic alterations
-a
- of single or multi-exon size.
-
-
-OR
-
-
-Variants at IVS±1 or IVS±2​**
-a,c 
- ** where exon skipping or use of a cryptic splice site disrupts reading frame and is predicted to undergo NMD. Not to be combined with PP3 and not to be used for a confirmed splice defect (see PVS1 for variants where patient mRNA assays indicate splicing aberration). If exon skipping or use of a cryptic splice site preserves reading frame and the altered region is critical to protein function
-b
- then use PVS1_Strong. If exon skipping or use of a cryptic splice site disrupts reading frame and is NOT predicted to undergo NMD then use PVS1_Moderate.
-
-
-OR
-
-
-Variants where mRNA assays using RNA derived from patient constitutional biological samples indicate that the variant allele results in a splicing aberration (with evidence that the variant allele produces no full-length/reference transcript) leading to premature stop codon or in-frame deletion disrupting a functional domain
-b
- or protein conformation. Splicing aberration must be confirmed in a minigene assay or an additional RNA assay from an independent laboratory if it is a non-canonical splice site variant.",General recommendation
-PMS2 (HGNC:9122),PVS1,Strong,"Variants in the initiation codon of 
-PMS2
-
-
-OR 
-
-
-Presumed by default in tandem duplication of ≥1 exon resulting in a frameshift before the last splice junction. This rule does not apply for variants that involve the UTR (i.e. exon 1 or last exon) and whole gene duplications.
-
-
-OR
-
-
-G>non-G at last base of exon if first 6 bases of the intron are not GTRRGT. If confirmed to cause a splice defect, then PVS1 should be used instead.
-
-
-OR
-
-
-Variants at IVS±1 or IVS±2​
-a,c
- where exon skipping or use of a cryptic splice site preserves reading frame and the altered region is critical to protein function
-b
-. Not to be combined with PP3 and not to be used for a confirmed splice defect (see PVS1 for variants where patient mRNA assays indicate splicing aberration).",General recommendation
-PMS2 (HGNC:9122),PVS1,Moderate,"Nonsense/frameshift variant introducing premature termination codon between codons 799 & 862 in 
-PMS2
-. Refer to Appendix for details.",Gene-specific
-PMS2 (HGNC:9122),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-PMS2 (HGNC:9122),PS1,Strong,"A predicted missense substitution that encodes the same amino acid change with a different underlying nucleotide change previously established by this VCEP as Pathogenic (not a predicted or confirmed splice defect).
-
-
-OR
-
-
-Variants affecting the same non-canonical splice nucleotide as a confirmed pathogenic splice variant with similar or worse splicing in silico prediction using SpliceAI.",General recommendation
-PMS2 (HGNC:9122),PS1,Moderate,"A predicted missense substitution that encodes the same amino acid change with a different underlying nucleotide change as a previously established Likely Pathogenic missense variant with normal RNA result*, and PM2_supporting is met.
-
-
-*Otherwise, if the previously established Likely pathogenic missense variant truly is a splice defect, the new missense variant also has to be investigated on a functional level for RNA splicing.",General recommendation
-PMS2 (HGNC:9122),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-PMS2 (HGNC:9122),PS2,Very Strong,"≥ 4 
-de novo
- points",Disease-specific
-PMS2 (HGNC:9122),PS2,Strong,"2 or 3 
-de novo
- points",Disease-specific
-PMS2 (HGNC:9122),PS2,Moderate,"1 
-de novo
- point",Disease-specific
-PMS2 (HGNC:9122),PS2,Supporting,"0.5 
-de novo
- points",Disease-specific
-PMS2 (HGNC:9122),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-PMS2 (HGNC:9122),PS3,Strong,Calibrated functional assays with functional odds for Pathogenicity > 18.7,General recommendation
-PMS2 (HGNC:9122),PS3,Moderate,"Calibrated functional assays with functional odds for pathogenicity >4.3 and <= 18.7
-
-
-OR 
-
-
-MMR function defect following functional assay flowchart*
-
-
-OR 
-
-
-Variants with monoallelic expression: complete loss of expression (<10% of wild-type in cDNA without puromycin) of the variant allele. Full-length transcript should be analysed with and without NMD block.",General recommendation
-PMS2 (HGNC:9122),PS3,Supporting,Calibrated functional odds for Pathogenicity >2.08 and <= 4.3,General recommendation
-PMS2 (HGNC:9122),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",NA
-PMS2 (HGNC:9122),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-PMS2 (HGNC:9122),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-PMS2 (HGNC:9122),PM2,Supporting,"Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset",General recommendation
-PMS2 (HGNC:9122),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-PMS2 (HGNC:9122),PM3,Very Strong,≥ 4 points,Disease-specific
-PMS2 (HGNC:9122),PM3,Strong,≥ 2 and < 4 points,Disease-specific
-PMS2 (HGNC:9122),PM3,Moderate,≥1 and < 2 points,Disease-specific
-PMS2 (HGNC:9122),PM3,Supporting,= 0.5 points,Disease-specific
-PMS2 (HGNC:9122),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,NA
-PMS2 (HGNC:9122),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-PMS2 (HGNC:9122),PM5,Moderate,Missense change at an amino acid residue where a different missense change was classified by this VCEP as Pathogenic on the protein level and not due to aberrant splicing. Only use PM5 if PP3 is supporting for the missense change. Use PM5_Supporting if other variant is Likely Pathogenic due to a missense alteration.,General recommendation
-PMS2 (HGNC:9122),PM5,Supporting,Missense change at an amino acid residue where a different missense change was classified as Likely Pathogenic on the protein level and not due to aberrant splicing. Only use PM5_Supporting if PP3 is supporting for the missense change. Use PM5 if other variant is Pathogenic due to a missense alteration.,General recommendation
-PMS2 (HGNC:9122),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-PMS2 (HGNC:9122),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-PMS2 (HGNC:9122),PP1,Strong,"Co-segregation with disease in pedigree(s) with a combined* Bayes Likelihood Ratio
-h
- >18.7​ in ≥2 families.",General recommendation
-PMS2 (HGNC:9122),PP1,Moderate,"Co-segregation with disease in pedigree(s) with a combined* Bayes Likelihood Ratio​
-h
- >4.3 & ≤18.7.",General recommendation
-PMS2 (HGNC:9122),PP1,Supporting,"Co-segregation with disease in pedigree(s) with a combined* Bayes Likelihood Ratio
-h
- >2.08 & ≤4.3.",General recommendation
-PMS2 (HGNC:9122),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-PMS2 (HGNC:9122),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-PMS2 (HGNC:9122),PP3,Moderate,"Missense variant with HCI prior probability for pathogenicity >0.81 as per 
-https://hci-priors.hci.utah.edu/PRIORS",General recommendation
-PMS2 (HGNC:9122),PP3,Supporting,"Missense variant with “MAPP/PP2 Prior P” score  >0.68 & ≤0.81 from 
-http://hci-lovd.hci.utah.edu/variants.php?select_db=PMS2_priors&action=search_unique
- 
-
-
-OR
-
-
-Predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score >= 0.2 as per Walker et al 2023.",General recommendation
-PMS2 (HGNC:9122),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-PMS2 (HGNC:9122),PP4,Strong,"≥3 independent CRC/Endometrial MSI-H tumors in ≥2 families using a standard panel of 5-10 markers​
-g
- ​or tumor genome 
-and/or
-​ loss of MMR protein expression consistent with the variant location. MSI-H tumor with inconsistent protein expression does not meet PP4_Strong. Independent tumors can be from the same patient/family.",Disease-specific
-PMS2 (HGNC:9122),PP4,Moderate,"2 independent CRC/Endometrial MSI-H tumors using a standard panel of 5-10 markers​
-g
- or tumor genome ​
-and/or
-​ loss of MMR protein expression consistent with the variant location. MSI-H tumor with inconsistent protein expression does not meet PP4_Moderate.",Disease-specific
-PMS2 (HGNC:9122),PP4,Supporting,"1 CRC/Endometrial MSI-H tumor using a standard panel of 5-10 markers​
-g
- or tumor genome ​
-and/or
-​ loss of MMR protein expression consistent with the variant location. MSI-H tumor with inconsistent protein expression does not meet PP4.",Disease-specific
-PMS2 (HGNC:9122),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-PMS2 (HGNC:9122),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-PMS2 (HGNC:9122),BA1,Stand Alone,GnomAD v4 Grpmax filtering allele frequency ≥ 0.0028 (0.28%) and variant is excluded as founder pathogenic variant.,Gene-specific
-PMS2 (HGNC:9122),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-PMS2 (HGNC:9122),BS1,Strong,GnomAD v4 Grpmax filtering allele frequency ≥ 0.0001 and < 0.001 (0.01-0.1%) and variant is excluded as founder pathogenic variant.,Gene-specific
-PMS2 (HGNC:9122),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-PMS2 (HGNC:9122),BS2,Strong,"Co-occurrence 
-​in trans​
- with a known pathogenic sequence variant in the same gene in a patient with colorectal cancer after age 45 (or other LS cancer above the median age of onset for that cancer in LS​f​), and who has no previous or current evidence of clinical manifestations of CMMRD as per Aronson et al 2022 (Refer to 'Table for CMMRD diagnosis.pdf'). Confirmation of phase requires testing of parents or offspring.",Disease-specific
-PMS2 (HGNC:9122),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-PMS2 (HGNC:9122),BS3,Strong,"Calibrated functional assays with functional odds for Pathogenicity ≤ 0.05
-
-
-OR
-
-
-Synonymous substitutions and intronic variants with no associated mRNA aberration (either splicing or allelic imbalance) as determined by laboratory assays conducted with nonsense-mediated decay inhibition. Whenever abnormal transcripts are identified at similar levels in controls they will be considered naturally occurring isoforms and not mRNA aberrations.",General recommendation
-PMS2 (HGNC:9122),BS3,Supporting,"Calibrated functional assays with functional odds for Pathogenicity >0.05 & ≤0.48
-
-
-OR
-
-
-Variant-specific proficient function in protein and mRNA-based lab assays as per MMR functional assay flowchart.",General recommendation
-PMS2 (HGNC:9122),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-PMS2 (HGNC:9122),BS4,Strong,"Lack of co-segregation with disease in pedigree(s) with a combined* Bayes Likelihood Ratio
-h
- <0.05​. 
-
-
-*For multiple pedigrees, results are combined. Recommended segregation analysis tool: COOL (COsegregation OnLine) v2 
-http://fengbj-laboratory.org/cool2/manual.html",General recommendation
-PMS2 (HGNC:9122),BS4,Supporting,"Lack of co-segregation with disease in pedigree(s) with a combined* Bayes Likelihood Ratio
-h
- >0.05 & ≤0.48.  
-
-
-*with multiple pedigrees, results are combined. Recommended segregation analysis tool: COOL (COsegregation OnLine) v2 
-http://fengbj-laboratory.org/cool2/manual.html",General recommendation
-PMS2 (HGNC:9122),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-PMS2 (HGNC:9122),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-PMS2 (HGNC:9122),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-PMS2 (HGNC:9122),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-PMS2 (HGNC:9122),BP4,Supporting,"Missense variant with “MAPP/PP2 Prior P” score  <0.11 from 
-http://hci-lovd.hci.utah.edu/variants.php?select_db=PMS2_priors&action=search_unique
- 
-
-
-OR
-
-
-For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score <= 0.1 as per Walker et al 2023.",General recommendation
-PMS2 (HGNC:9122),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-PMS2 (HGNC:9122),BP5,Strong,"​≥ 4 tumors: CRC/Endometrial tumors with MSS ​and/or​ no ​loss of MMR protein expression​ ​and/or LS spectrum tumors
-f
- with loss of MMR protein(s) that is inconsistent with the gene demonstrating genetic variation
-
-
-OR
-
-
-≥2 BRAF V600E (CRC only)/
-MLH1
- methylation (in LS spectrum tumor only) with MSI-H/
-MLH1
- loss.",Disease-specific
-PMS2 (HGNC:9122),BP5,Supporting,"2 or 3 tumors: CRC/Endometrial tumors with MSS and/or no loss of MMR protein expression and/or LS spectrum tumors
-f
- with loss of MMR protein(s) that is inconsistent with the gene demonstrating genetic variation.
-
-
-OR 
-
-
-1 BRAF V600E (Colon only)/
-MLH1
- methylation (in LS spectrum tumor only) with MSI-H/
-MLH1
- loss.",Disease-specific
-PMS2 (HGNC:9122),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-PMS2 (HGNC:9122),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-PMS2 (HGNC:9122),BP7,Supporting,A synonymous (silent) or intronic variant at or beyond -21/+7 (5′/3′ exonic). Variants may satisfy both BP7 and BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenLeberCongenitalAmaurosisearlyonsetRetinalDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGUCY2DVersion1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenLeberCongenitalAmaurosisearlyonsetRetinalDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGUCY2DVersion1.0.0_version=1.0.0.csv
deleted file mode 100644
index f681f26923e880af208019779cea5dc4465e69a4..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenLeberCongenitalAmaurosisearlyonsetRetinalDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGUCY2DVersion1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,481 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-GUCY2D (HGNC:4689),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-GUCY2D (HGNC:4689),PVS1,Very Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-Use as defined by ClinGen SVI working group (Abou Tayoun et al., 2018
-16
-) and as updated by the ClinGen SVI Splicing Subgroup (Walker et al., 2023
-17
-).
-
-
-Refer to GUCY2D-specific PVS1 Decision Tree, file attached.
-
-
-PVS1: Predicted splice defects at +/- 1,2 in exons 2-20
-
-
-PVS1: Single to multi-exon deletions, with or without predicted NMD. All exons are considered critical to protein function.
-
-
-PVS1: Applied to variants in the initiation codon. The second in-frame methionine is located at residue 218 and use of this as a start codon would eliminate the leader sequence which targets the protein to the endoplasmic reticulum. There is no known study indicating that this methionine in GUCY2D can be used as start codon. Variants affecting Met1 can lead to a complete absence of the protein product. Additionally, there are multiple variants located upstream of p.Met218 that have been reported as a pathogenic in HGMD and ClinVar, evidence that this entire region of the protein is functionally important.
-
-
-PVS1: Nonsense or frameshift mutations from p.Thr2 through p.Lys1068
-
-
-PVS1: Duplications of exons proven in tandem
-
-
-PVS1(RNA): RNA splicing data with evidence of alternative transcript production at complete levels, relative to normal allele.",Gene-specific
-GUCY2D (HGNC:4689),PVS1,Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-Use as defined by ClinGen SVI working group (Abou Tayoun et al., 2018
-16
-) and as updated by the ClinGen SVI Splicing Subgroup (Walker et al., 2023
-17
-).
-
-
-Refer to GUCY2D-specific PVS1 Decision Tree, file attached.
-
-
-PVS1_Strong: Nonsense or frameshift mutations from p.Pro1069 through p.Ser1103
-
-
-PVS1_Strong: Duplications of exons presumed in tandem
-
-
-PVS1(RNA)_Strong: RNA splicing data with evidence of alternative transcript production at near complete levels, relative to normal allele.",Gene-specific
-GUCY2D (HGNC:4689),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-GUCY2D (HGNC:4689),PS1,Strong,"Same amino acid change as a previously established Pathogenic variant regardless of nucleotide change.
-
-
-
-
-Must have one comparison variant that reaches a Pathogenic classification using this rule specification.
-
-
-
-
-Same predicted splicing impact as a previously classified Pathogenic variant. 
-
-
-
-
-Used in conjunction with PP3 for variants located outside the splice donor/acceptor +/-1,2 dinucleotide positions that have a splice AI score ≥0.2 and have a comparable nucleotide variant at the 
-same position
- that has been designated 
-Pathogenic
-.
-
-
-Used in conjunction with PVS1 for variants located at the splice donor/acceptor +/-1,2 dinucleotide positions and that have a comparable variant within the same splice donor/acceptor +/-1,2 dinucleotide that has been designated Pathogenic.
-
-
-
-
-Specific combinations are found in GUCY2D-specific PVS1 Decision Tree 
-part (b)
- (Table 2 from Walker 2023).",Gene-specific
-GUCY2D (HGNC:4689),PS1,Moderate,"Same amino acid change as a previously established Likely Pathogenic variant regardless of nucleotide change.
-
-
-
-
-Must have one comparison variant that reaches a Likely Pathogenic classification using this rule specification.
-
-
-
-
-Same predicted splicing impact as previously classified Likely Pathogenic variant.
-
-
-
-
-Used in conjunction with PP3 for variants located outside the splice donor/acceptor +/-1,2 dinucleotide positions that have a splice AI score ≥0.2 and have a comparable nucleotide variant at the 
-same position
- that has been designated 
-Likely Pathogenic
-.
-
-
-Used in conjunction with PVS1_(reduced strength) for variants located at the splice donor/acceptor +/-1,2 dinucleotide positions and have a comparable variant 
-within the same splice donor/acceptor motif
- (but outside the +/-1,2 dinucleotide) that has been designated 
-Pathogenic
-.
-
-
-
-
-Specific combinations are found in GUCY2D-specific PVS1 Decision Tree 
-part (b)
- (Table 2 from Walker 2023).","Gene-specific,Strength"
-GUCY2D (HGNC:4689),PS1,Supporting,"Used in conjunction with PP3 for variants located outside the splice donor/acceptor +/-1,2 dinucleotide positions that have a splice AI score ≥0.2 and have a comparable nucleotide variant within the 
-same motif
- that has been designated 
-Likely Pathogenic
-.
-
-
-Used in conjunction with PVS1 or PVS1_(reduced strength) for variants located at the splice donor/acceptor +/-1,2 dinucleotide positions and have a comparable Likely Pathogenic or Pathogenic variant either within the same splice site donor/acceptor motif, outside the +/-1,2 dinucleotide, or at the +/-1,2 dinucleotide.
-
-
-
-
- Specific combinations are found in GUCY2D-specific PVS1 Decision Tree 
-part (b)
- (Table 2 from Walker 2023).","Gene-specific,Strength"
-GUCY2D (HGNC:4689),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-GUCY2D (HGNC:4689),PS2,Very Strong,"De novo (
-both
- maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-Use ClinGen SVI's recommendation for assigning weight to the PS2/PM6 codes (See PS2-Table 1 within PS2/PM6 file). 
-
-
-Total of 4 or more points required for Very Strong level",Gene-specific
-GUCY2D (HGNC:4689),PS2,Strong,"De novo (
-both
- maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-Use ClinGen SVI's recommendation for assigning weight to the PS2/PM6 codes (See PS2-Table 1 within PS2/PM6 file). 
-
-
-Total of 2.00 - 3.75 points required for Strong level",Gene-specific
-GUCY2D (HGNC:4689),PS2,Moderate,"De novo (
-both
- maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-Use ClinGen SVI's recommendation for assigning weight to the PS2/PM6 codes (See PS2-Table 1 within PS2/PM6 file). 
-
-
-Total of 1.00 - 1.75 points required for Moderate level",Gene-specific
-GUCY2D (HGNC:4689),PS2,Supporting,"De novo (
-both
- maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-Use ClinGen SVI's recommendation for assigning weight to the PS2/PM6 codes (See Table 1 within PS2/PM6 file). 
-
-
-Total of 0.50 - 0.75 points required for Supporting level",Gene-specific
-GUCY2D (HGNC:4689),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-GUCY2D (HGNC:4689),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect. 
-
-
-See attached table for acceptable functional studies. 
-
-
-Eligible results include 
-Gucy2e−/−Gucy2f−/−
- knockout mice subretinally injected with adeno-associated virus-packaged constructs encoding a GUCY2D variant (Boye et al., 2016,
-10
-) or mice with knock-in of a 
-GUCY2D
- variant (not yet available in the published literature). Results should include flat or nearly flat scotopic and photopic electroretinogram responses in comparison to wild-type injected control, absent or near-absent guanylate cyclase activity in comparison to wild-type injected control, and/or absent or near absent GUCY2D expression at the protein level despite approximately wild-type expression at the RNA level.","Gene-specific,Strength"
-GUCY2D (HGNC:4689),PS3,Supporting,"Well-established in vitro or in vivo functional studies supportive of a damaging effect. Not applicable for splicing effects (replaced by PVS1_Strength (RNA))
-
-
-See attached table for acceptable functional studies.
-
-
-For studies reporting guanylate cyclase activity, cutoff is ≤10% of wild-type control.","Gene-specific,Strength"
-GUCY2D (HGNC:4689),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",NA
-GUCY2D (HGNC:4689),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-GUCY2D (HGNC:4689),PM1,Moderate,"Met by active site residues that bind the GTP substrate or the Mg
-2+
- ion; Phe883, Asp885, Thr890, Leu905, Glu925, Ile927, Asp929, Met932, Arg976, Arg995, Cys997, Leu998, Phe999, Gly1000, Val1003, Asn1004, Arg1008, and Glu1010 
-13
-.",Gene-specific
-GUCY2D (HGNC:4689),PM1,Supporting,"Met by variants not explicitly listed above, encoding missense substitutions between positions p.873-951. This region forms part of the guanylate cyclase catalytic domain and exhibits intolerance to missense variation 
-14
-.
-
-
-Met by variants in the 6 bp CRX binding site located at position 17:8002593-8002598 (hg38) 
-18",Gene-specific
-GUCY2D (HGNC:4689),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-GUCY2D (HGNC:4689),PM2,Supporting,"Absent/rare from controls in an ethnically-matched cohort population sample.
-
-
-
-
-Used if the gnomAD total allele frequency is ≤ 4.0 x 10
--4
-.","Disease-specific,Strength"
-GUCY2D (HGNC:4689),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-GUCY2D (HGNC:4689),PM3,Very Strong,"Points are calculated using Table 1 from 
-https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf
- (or attached file “PM3 Tables”)
-
-
-
-
-≥4 points from Table 1",Disease-specific
-GUCY2D (HGNC:4689),PM3,Strong,"Points are calculated using Table 1 from 
-https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf
- (or attached file “PM3 Tables”)
-
-
-
-
- 2 to 3.75 points from Table 1",Disease-specific
-GUCY2D (HGNC:4689),PM3,Moderate,"Points are calculated using Table 1 from 
-https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf
- (or attached file “PM3 Tables”)
-
-
-
-
- 1 to 1.75 points from Table 1",Disease-specific
-GUCY2D (HGNC:4689),PM3,Supporting,"Points are calculated using Table 1 from 
-https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf
- (or attached file “PM3 Tables”)
-
-
-
-
- 0.5 to 0.75 points from Table 1",Disease-specific
-GUCY2D (HGNC:4689),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-GUCY2D (HGNC:4689),PM4,Moderate,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
- Protein length change of ≥2 amino acids that leads to loss of at least one conserved residue (PhyloP>2.0) or insertion of new amino acids adjacent to at least one conserved residue (PhyloP>2.0).",Gene-specific
-GUCY2D (HGNC:4689),PM4,Supporting,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
- Protein length change of 1 amino acid that leads to loss of at least one conserved residue (PhyloP>2.0) or insertion of new amino acid adjacent to at least one conserved residue (PhyloP>2.0).","Gene-specific,Strength"
-GUCY2D (HGNC:4689),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-GUCY2D (HGNC:4689),PM5,Moderate,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-Must have one comparison variant that reaches a Pathogenic classification using this rule specification.
-
-
-SpliceAI scores for both variants should be in the same category (<0.1, between 0.1 and 0.2, >0.2)",None
-GUCY2D (HGNC:4689),PM5,Supporting,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-Must have one comparison variant that reaches a Likely Pathogenic classification using this rule specification.
-
-
-SpliceAI scores for both variants should be in the same category (<0.1, between 0.1 and 0.2, >0.2)",Strength
-GUCY2D (HGNC:4689),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-GUCY2D (HGNC:4689),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-GUCY2D (HGNC:4689),PP1,Strong,"Co-segregation with disease in multiple affected family members and evidence that this variant and another GUCY2D variant are 
-in trans
-.
-
-
-
-
-Requires segregation in one proband plus ≥3 similarly affected relatives","Disease-specific,Strength"
-GUCY2D (HGNC:4689),PP1,Moderate,"Co-segregation with disease in multiple affected family members and evidence that this variant and another GUCY2D variant are 
-in trans
-.
-
-
-
-
-Requires segregation in one proband plus 2 similarly affected relatives","Disease-specific,Strength"
-GUCY2D (HGNC:4689),PP1,Supporting,"Co-segregation with disease in multiple affected family members and evidence that this variant and another GUCY2D variant are 
-in trans
-.
-
-
-
-
-Requires segregation in one proband plus 1 similarly affected relative","Disease-specific,Strength"
-GUCY2D (HGNC:4689),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-GUCY2D (HGNC:4689),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-GUCY2D (HGNC:4689),PP3,Moderate,"For a missense variant use REVEL, requires a score of ≥ 0.774.
-
-
-Splice variants use PP3 only at Supporting level.","Gene-specific,Strength"
-GUCY2D (HGNC:4689),PP3,Supporting,"For a missense variant use REVEL, requires a score of 0.644 - 0.773.
-
-
-For a variant in an untranslated region use CADD, requires a score of ≥ 20.0
-
-
-For a predicted splicing variant use SpliceAI with max distance set to 500 bp. Highest delta score from SpliceAI must be ≥ 0.2 to use this code. See GUCY2D-specific PVS1 Decision Tree 
-part (a)
- for SpliceAI flowchart.",Gene-specific
-GUCY2D (HGNC:4689),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-GUCY2D (HGNC:4689),PP4,Moderate,"8 phenotype points or more are required to use this code at the moderate strength for a single proband (see points list below).
-
-
-Additionally, at least one 
-specific
- criterion must be met (see below).
-
-
-Do not include a proband with a suspected diagnosis of more than one retinal dystrophy.","Disease-specific,Strength"
-GUCY2D (HGNC:4689),PP4,Supporting,"4-7.5 phenotype points are required to use this code (see points list below).
-
-
-Do not include a proband with a suspected diagnosis of more than one retinal dystrophy.",Disease-specific
-GUCY2D (HGNC:4689),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-GUCY2D (HGNC:4689),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-GUCY2D (HGNC:4689),BA1,Stand Alone,"Use gnomAD Grpmax FAF if available, cutoff of  >0.016
-
-
-
-
-Use large population databases (i.e. gnomAD).",Disease-specific
-GUCY2D (HGNC:4689),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-GUCY2D (HGNC:4689),BS1,Strong,"Allele frequency greater than expected for disorder. Use gnomAD Grpmax FAF if available.
-
-
-
-
-Allele frequency of 0.0016 - 0.016",Disease-specific
-GUCY2D (HGNC:4689),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-GUCY2D (HGNC:4689),BS2,Strong,"Variant is present in ≥ 3 homozygotes without any features of the phenotype. This rule applies to individuals found in the literature who have been well-phenotyped and are unaffected by age 40. Alternatively, this strength can be applied if the variant is present in ≥ 6 homozygotes in gnomAD v.4.1.0 or later.","Disease-specific,Strength"
-GUCY2D (HGNC:4689),BS2,Supporting,Variant is present in ≥ 3 homozygotes in gnomAD v.4.1.0 or later.,"Disease-specific,Strength"
-GUCY2D (HGNC:4689),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-GUCY2D (HGNC:4689),BS3,Supporting,"Not applicable for splicing effects (replaced by BP7_Strong (RNA)).
-
-
-For studies reporting guanylate cyclase activity, cutoff is >50% of wild-type control. Studies included; Peshenko et al., 2020
-1
-, Feng et al., 2020, Jacobson et al., 2021
-2
-, Jacobson et al., 2020
-3
-, Tucker et al., 2004
-4
-, Jacobson et al., 2013
-5
-, and Peshenko et al., 2015
-7
-
-
-See attached table of Approved PS3 Functional Assays for a list of acceptable functional studies including those that:
-
-
-
-
-Report failure of GUCY2D to localize to the cell surface : Zulliger et al., 2015
-6
-.
-
-
-Report failure of GUCY2D to bind RD3: Zulliger et al., 2015
-6
-. 
-
-
-Report failure of GCAP1, GCAP2, or RD3 to co-localize with GUCY2D at the cell surface: Peshenko et al., 2020
-1
-, Jacobson et al., 2020
-3
-, and Peshenko et al., 2015
-7
-.","Gene-specific,Strength"
-GUCY2D (HGNC:4689),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-GUCY2D (HGNC:4689),BS4,Strong,"Lack of segregation in affected members of a family.
-
-
-
-
-One or both variants are absent in a similarly affected family member.",Clarification
-GUCY2D (HGNC:4689),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-GUCY2D (HGNC:4689),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-GUCY2D (HGNC:4689),BP2,Supporting,"Observed in cis with a Pathogenic variant.
-
-
-
-
-Use code if the variant of interest is 
-in cis
- with a Pathogenic or Likely Pathogenic variant. The other variant must meet a Likely Pathogenic or Pathogenic classification using these rule specifications.",Disease-specific
-GUCY2D (HGNC:4689),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-GUCY2D (HGNC:4689),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-GUCY2D (HGNC:4689),BP4,Moderate,"For a missense variant use REVEL, requires a score of ≤0.183. In addition, highest SpliceAI delta score should also be below cutoff of 0.1.","Gene-specific,Strength"
-GUCY2D (HGNC:4689),BP4,Supporting,"For a missense variant use REVEL, requires a score between 0.183 - 0.290. In addition, highest SpliceAI delta score should also be below cutoff of 0.1.
-
-
-For a silent / intronic variant outside the designated splice region (conservatively at or beyond positions +7/-21) and synonymous (silent) exonic variants located outside of the first and the last 3 bases of the exon, BP4 can be met if the highest of the four delta scores within SpliceAI is below the cutoff of ≤0.1. See GUCY2D-specific PVS1 Decision Tree 
-part (a)
- for SpliceAI flowchart.
-
-
-
-
-Please note that BP7 can be met as well.",Gene-specific
-GUCY2D (HGNC:4689),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-GUCY2D (HGNC:4689),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-GUCY2D (HGNC:4689),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-GUCY2D (HGNC:4689),BP7,Strong,"BP7_Strong (RNA) Used to designate capture of splicing data (not BS3). See GUCY2D-specific PVS1 Decision Tree, file attached, for weighting and combining with other codes.",Disease-specific
-GUCY2D (HGNC:4689),BP7,Supporting,"Use not only for synonymous variants but also for intronic variants located outside of the donor/acceptor +/- 1,2 dinucleotide positions. 
-
-
-If SpliceAI score ≤0.1, apply BP4 followed by assessment of BP7. See GUCY2D-specific PVS1 Decision Tree 
-part (a)
- for SpliceAI flowchart.
-
-
-
-
-Positions 
-excluded
- from BP7:
-
-
-Synonymous substitutions at the first base of an exon
-
-
-Synonymous substitutions in the last 3 bases of an exon
-
-
-+1 through +7 of donor sequence
-
-
--1 through -21 of acceptor sequence",Gene-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenLeberCongenitalAmaurosisearlyonsetRetinalDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRPE65Version1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenLeberCongenitalAmaurosisearlyonsetRetinalDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRPE65Version1.0.0_version=1.0.0.csv
deleted file mode 100644
index 316ea37c85c234ef58662694a64323571bc76674..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenLeberCongenitalAmaurosisearlyonsetRetinalDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRPE65Version1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,446 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-RPE65 (HGNC:10294),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-RPE65 (HGNC:10294),PVS1,Very Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-Use as defined by ClinGen SVI working group 
-16
- and as updated by the ClinGen SVI Splicing Subgroup 
-17
-
-
-Refer to RPE65-specific PVS1 Decision Tree, file attached.
-
-
-PVS1: Predicted splice defects at +/- 1,2 in exons 1-14
-
-
-PVS1: Single to multi-exon deletions, with or without predicted NMD. All exons are considered critical to protein function.
-
-
-PVS1: Nonsense or frameshift mutations from p.Ser2 through p.Gly528
-
-
-PVS1: Duplications of exons proven in tandem
-
-
-PVS1(RNA): RNA splicing data with evidence of alternative transcript production at complete levels, relative to normal allele.",Gene-specific
-RPE65 (HGNC:10294),PVS1,Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-Use as defined by ClinGen SVI working group 
-16
- and as updated by the ClinGen SVI Splicing Subgroup 
-17
-
-
-Refer to RPE65-specific PVS1 Decision Tree, file attached.
-
-
-PVS1_Strong:Applied to variants in the initiation codon. The second in-frame methionine is located at residue 93, and there is no known study indicating that this methionine in 
-RPE65
- can be used as start codon. Variants affecting Met1 can lead to a complete absence of the protein product. Even though we cannot exclude the possibility of a 2nd Met being used as start codon, the translation efficiency maybe significantly reduced due to lack of other important elements (Kozak sequence, etc.). Also, there are multiple variants located upstream of Met93 having been reported as a pathogenic variant in HGMD and ClinVar, evidence that this region of the protein is functionally important.
-
-
-PVS1_Strong: Nonsense or frameshift mutations from p.Leu529 through p.Ser533
-
-
-PVS1_Strong: Duplications of exons presumed in tandem
-
-
-PVS1(RNA)_Strong: RNA splicing data with evidence of alternative transcript production at near complete levels, relative to normal allele.",Gene-specific
-RPE65 (HGNC:10294),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RPE65 (HGNC:10294),PS1,Strong,"Same amino acid change as a previously established Pathogenic variant regardless of nucleotide change.
-
-
-
-
-Must have one comparison variant that reaches a Pathogenic classification using this rule specification.
-
-
-For assessing same amino acid changes, SpliceAI scores for both variants should be within 10% of each other.
-
-
-
-
-Same predicted splicing impact as a previously classified Pathogenic variant. 
-
-
-
-
-Used in conjunction with PP3 for variants located outside the splice donor/acceptor +/-1,2 dinucleotide positions that have a splice AI score ≥0.2 and have a comparable nucleotide variant at the 
-same position
- that has been designated 
-Pathogenic
-.
-
-
-Used in conjunction with PVS1 for variants located at the splice donor/acceptor +/-1,2 dinucleotide positions and that have a comparable variant within the same splice donor/acceptor +/-1,2 dinucleotide that has been designated Pathogenic.
-
-
-
-
-Specific combinations are found in RPE65-specific PVS1 Decision Tree 
-part (b)
- (Table 2 from Walker 2023).",Gene-specific
-RPE65 (HGNC:10294),PS1,Moderate,"Same amino acid change as a previously established Likely Pathogenic variant regardless of nucleotide change.
-
-
-
-
-Must have one comparison variant that reaches a Likely Pathogenic classification using this rule specification.
-
-
-For assessing same amino acid changes, SpliceAI scores for both variants should be within 10% of each other.
-
-
-
-
-Same predicted splicing impact as previously classified Likely Pathogenic variant.
-
-
-
-
-Used in conjunction with PP3 for variants located outside the splice donor/acceptor +/-1,2 dinucleotide positions that have a splice AI score ≥0.2 and have a comparable nucleotide variant at the 
-same position
- that has been designated 
-Likely Pathogenic
-.
-
-
-Used in conjunction with PVS1_(reduced strength) for variants located at the splice donor/acceptor +/-1,2 dinucleotide positions and have a comparable variant 
-within the same splice donor/acceptor motif
- (but outside the +/-1,2 dinucleotide) that has been designated 
-Pathogenic
-.
-
-
-
-
-Specific combinations are found in RPE65-specific PVS1 Decision Tree 
-part (b)
- (Table 2 from Walker 2023).","Gene-specific,Strength"
-RPE65 (HGNC:10294),PS1,Supporting,"Used in conjunction with PP3 for variants located outside the splice donor/acceptor +/-1,2 dinucleotide positions that have a splice AI score ≥0.2 and have a comparable nucleotide variant within the 
-same motif
- that has been designated 
-Likely Pathogenic
-.
-
-
-Used in conjunction with PVS1 or PVS1_(reduced strength) for variants located at the splice donor/acceptor +/-1,2 dinucleotide positions and have a comparable Likely Pathogenic or Pathogenic variant either within the same splice site donor/acceptor motif, outside the +/-1,2 dinucleotide, or at the +/-1,2 dinucleotide.
-
-
-
-
- Specific combinations are found in RPE65-specific PVS1 Decision Tree 
-part (b)
- (Table 2 from Walker 2023).","Gene-specific,Strength"
-RPE65 (HGNC:10294),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-RPE65 (HGNC:10294),PS2,Very Strong,"De novo (
-both
- maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-Use ClinGen SVI's recommendation for assigning weight to the PS2/PM6 codes (See PS2-Table 1 within PS2/PM6 file). Use option 3 “Phenotype consistent with gene but not highly specific and high genetic heterogeneity” (maximum 0.5 points/proband)
-
-
-Total of 4 or more points required for Very Strong level",Gene-specific
-RPE65 (HGNC:10294),PS2,Strong,"De novo (
-both
- maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-Use ClinGen SVI's recommendation for assigning weight to the PS2/PM6 codes (See PS2-Table 1 within PS2/PM6 file). Use option 3 “Phenotype consistent with gene but not highly specific and high genetic heterogeneity” (maximum 0.5 points/proband)
-
-
-Total of 2.00 - 3.75 points required for Strong level",Gene-specific
-RPE65 (HGNC:10294),PS2,Moderate,"De novo (
-both
- maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-Use ClinGen SVI's recommendation for assigning weight to the PS2/PM6 codes (See PS2-Table 1 within PS2/PM6 file). Use option 3 “Phenotype consistent with gene but not highly specific and high genetic heterogeneity” (maximum 0.5 points/proband)
-
-
-Total of 1.00 - 1.75 points required for Moderate level",Gene-specific
-RPE65 (HGNC:10294),PS2,Supporting,"De novo (
-both
- maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-Use ClinGen SVI's recommendation for assigning weight to the PS2/PM6 codes (See Table 1 within PS2/PM6 file). Use option 3 “Phenotype consistent with gene but not highly specific and high genetic heterogeneity” (maximum 0.5 points/proband)
-
-
-Total of 0.50 - 0.75 points required for Supporting level",Gene-specific
-RPE65 (HGNC:10294),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-RPE65 (HGNC:10294),PS3,Supporting,"Well-established in vitro or in vivo functional studies supportive of a damaging effect. Not applicable for splicing effects (replaced by PVS1_Strength (RNA))
-
-
-See attached table for acceptable functional studies.
-
-
-For studies reporting isomerhydrolase activity, cutoff is ≤10% of wild-type control.","Gene-specific,Strength"
-RPE65 (HGNC:10294),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",NA
-RPE65 (HGNC:10294),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-RPE65 (HGNC:10294),PM1,Moderate,"Located in a mutational hot spot and/or critical and well-established functional domain.
-
-
-
-
-Met by variants encoding missense substitutions at His180, His182, His241, His313, Glu417, or His527, which are required residues located within the active site
-16
-.
-
-
-Met by variants encoding missense substitutions between Ala107 and Gly125, which are known to mediate localization to the ER membrane
-15
-.",Gene-specific
-RPE65 (HGNC:10294),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-RPE65 (HGNC:10294),PM2,Supporting,"Absent/rare from controls in an ethnically-matched cohort population sample.
-
-
-
-
-Used if the gnomAD PopMax Filtering Allele Frequency (FAF) is ≤ 2.0 x 10
--4
-.","Disease-specific,Strength"
-RPE65 (HGNC:10294),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-RPE65 (HGNC:10294),PM3,Very Strong,"Points are calculated using Table 1 from 
-https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf
- (or attached file “PM3 Tables”)
-
-
-
-
-≥4 points from Table 1",Disease-specific
-RPE65 (HGNC:10294),PM3,Strong,"Points are calculated using Table 1 from 
-https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf
- (or attached file “PM3 Tables”)
-
-
-
-
- 2 to 3.75 points from Table 1",Disease-specific
-RPE65 (HGNC:10294),PM3,Moderate,"Points are calculated using Table 1 from 
-https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf
- (or attached file “PM3 Tables”)
-
-
-
-
- 1 to 1.75 points from Table 1",Disease-specific
-RPE65 (HGNC:10294),PM3,Supporting,"Points are calculated using Table 1 from 
-https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf
- (or attached file “PM3 Tables”)
-
-
-
-
- 0.5 to 0.75 points from Table 1",Disease-specific
-RPE65 (HGNC:10294),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-RPE65 (HGNC:10294),PM4,Moderate,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
- Protein length change of ≥2 amino acids that leads to loss of at least one conserved residue (PhyloP>2.0) or insertion of new amino acids adjacent to at least one conserved residue (PhyloP>2.0).",Gene-specific
-RPE65 (HGNC:10294),PM4,Supporting,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
- Protein length change of 1 amino acid that leads to loss of at least one conserved residue (PhyloP>2.0) or insertion of new amino acid adjacent to at least one conserved residue (PhyloP>2.0).","Gene-specific,Strength"
-RPE65 (HGNC:10294),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RPE65 (HGNC:10294),PM5,Moderate,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-Must have one comparison variant that reaches a Pathogenic classification using this rule specification.
-
-
-For assessing same amino acid changes, SpliceAI scores for both variants should be within 10% of each other.",None
-RPE65 (HGNC:10294),PM5,Supporting,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-Must have one comparison variant that reaches a Likely Pathogenic classification using this rule specification.
-
-
-For assessing same amino acid changes, SpliceAI scores for both variants should be within 10% of each other.",Strength
-RPE65 (HGNC:10294),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-RPE65 (HGNC:10294),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-RPE65 (HGNC:10294),PP1,Strong,"Co-segregation with disease in multiple affected family members and evidence that this variant and another RPE65 variant are 
-in trans
-.
-
-
-
-
-Requires segregation in proband plus ≥3 similarly affected relatives","Disease-specific,Strength"
-RPE65 (HGNC:10294),PP1,Moderate,"Co-segregation with disease in multiple affected family members and evidence that this variant and another RPE65 variant are 
-in trans
-.
-
-
-
-
-Requires segregation in proband plus 2 similarly affected relatives","Disease-specific,Strength"
-RPE65 (HGNC:10294),PP1,Supporting,"Co-segregation with disease in multiple affected family members and evidence that this variant and another RPE65 variant are 
-in trans
-.
-
-
-
-
-Requires segregation in proband plus 1 similarly affected relative","Disease-specific,Strength"
-RPE65 (HGNC:10294),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-RPE65 (HGNC:10294),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-RPE65 (HGNC:10294),PP3,Moderate,"For a missense variant use REVEL, requires a score of ≥ 0.774.
-
-
-Splice variants use PP3 only at Supporting level.","Gene-specific,Strength"
-RPE65 (HGNC:10294),PP3,Supporting,"For a missense variant use REVEL, requires a score of 0.644 - 0.773.
-
-
-For a predicted splicing variant use SpliceAI with max distance set to 500 bp. Highest delta score from SpliceAI must be ≥ 0.2 to use this code. See RPE65-specific PVS1 Decision Tree 
-part (a)
- for SpliceAI flowchart.",Gene-specific
-RPE65 (HGNC:10294),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-RPE65 (HGNC:10294),PP4,Moderate,"8 phenotype points or more are required to use this code at the moderate strength for a single proband (see points list below).
-
-
-Additionally, at least one 
-specific
- criterion must be met (see below).
-
-
-Do not include a proband with a suspected diagnosis of more than one retinal dystrophy.","Disease-specific,Strength"
-RPE65 (HGNC:10294),PP4,Supporting,"4-7.5 phenotype points are required to use this code (see points list below).
-
-
-Do not include a proband with a suspected diagnosis of more than one retinal dystrophy.",Disease-specific
-RPE65 (HGNC:10294),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RPE65 (HGNC:10294),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-RPE65 (HGNC:10294),BA1,Stand Alone,"Use gnomAD PopMax FAF if available, cutoff of  ≥8 x 10
--3
-
-
-
-
-Use large population databases (i.e. gnomAD).",Disease-specific
-RPE65 (HGNC:10294),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-RPE65 (HGNC:10294),BS1,Strong,"Allele frequency greater than expected for disorder. Use gnomAD PopMax FAF if available.
-
-
-
-
-Allele frequency of between 8x10
--3
- and 8x10
--4",Disease-specific
-RPE65 (HGNC:10294),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-RPE65 (HGNC:10294),BS2,Strong,"Variant is present in ≥ 3 homozygotes without any features of the phenotype. This rule only applies to individuals found in the literature who have been well-phenotyped  and are unaffected by age 40.
-
-
-Presence in databases such as gnomAD are not considered.",Disease-specific
-RPE65 (HGNC:10294),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-RPE65 (HGNC:10294),BS3,Supporting,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function. Not applicable for splicing effects (replaced by BP7_Strong (RNA)).
-
-
-See attached table for list of acceptable functional studies.
-
-
-For studies reporting isomerohydrolase activity, activity must be ≥50% of wild-type control.","Gene-specific,Strength"
-RPE65 (HGNC:10294),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-RPE65 (HGNC:10294),BS4,Strong,"Lack of segregation in affected members of a family.
-
-
-
-
-One or both variants are absent in a similarly affected family member.",Clarification
-RPE65 (HGNC:10294),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-RPE65 (HGNC:10294),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-RPE65 (HGNC:10294),BP2,Supporting,"Observed in cis with a Pathogenic variant.
-
-
-
-
-Use code if the variant of interest is 
-in cis
- with a Pathogenic or Likely Pathogenic variant. The other variant must meet a Likely Pathogenic or Pathogenic classification using these rule specifications.",Disease-specific
-RPE65 (HGNC:10294),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-RPE65 (HGNC:10294),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-RPE65 (HGNC:10294),BP4,Moderate,"For a missense variant use REVEL, requires a score of ≤0.183. In addition, highest SpliceAI delta score should also be below cutoff of 0.1.","Gene-specific,Strength"
-RPE65 (HGNC:10294),BP4,Supporting,"For a missense variant use REVEL, requires a score between 0.183 - 0.290. In addition, highest SpliceAI delta score should also be below cutoff of 0.1.
-
-
-For a silent / intronic variant outside the designated splice region (conservatively at or beyond positions +7/-21) and synonymous (silent) exonic variants located outside of the first and the last 3 bases of the exon, BP4 can be met if the highest of the four delta scores within SpliceAI is below the cutoff of ≤0.1. See RPE65-specific PVS1 Decision Tree 
-part (a)
- for SpliceAI flowchart.
-
-
-
-
-Please note that BP7 can be met as well.",Gene-specific
-RPE65 (HGNC:10294),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-RPE65 (HGNC:10294),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RPE65 (HGNC:10294),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-RPE65 (HGNC:10294),BP7,Strong,"BP7_Strong (RNA) Used to designate capture of splicing data (not BS3). See RPE65-specific PVS1 Decision Tree, file attached, for weighting and combining with other codes.",Disease-specific
-RPE65 (HGNC:10294),BP7,Supporting,"Use for variants located outside of the donor/acceptor +/- 1,2 dinucleotide positions. 
-
-
-If SpliceAI score ≤0.1, apply BP4 followed by assessment of BP7. See RPE65-specific PVS1 Decision Tree 
-part (a)
- for SpliceAI flowchart.
-
-
-
-
-Positions 
-excluded
- from BP7:
-
-
-Synonymous substitutions at the first base of an exon
-
-
-Synonymous substitutions in the last 3 bases of an exon
-
-
-+1 through +7 of donor sequence
-
-
--1 through -21 of acceptor sequence",Gene-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforANO5Version1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforANO5Version1.0.0_version=1.0.0.csv
deleted file mode 100644
index bb3126d809ca0eef9c3c67fa8995d50f7e5868f4..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforANO5Version1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,256 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-ANO5 (HGNC:27337),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-ANO5 (HGNC:27337),PVS1,Very Strong,"Please see attached 
-ANO5
- PVS1 flowchart. In addition, follow the SVI Working Group’s recommendations (Walker et al. 2023; PMID: 37352859) for any variant for which an impact on splicing has been experimentally demonstrated OR is predicted to affect splicing but occurs outside of a donor/acceptor +/-1,2 dinucleotide position.","General recommendation,Gene-specific"
-ANO5 (HGNC:27337),PVS1,Strong,"Please see attached 
-ANO5
- PVS1 flowchart. In addition, follow the SVI Working Group’s recommendations (Walker et al. 2023; PMID: 37352859) for any variant for which an impact on splicing has been experimentally demonstrated OR is predicted to affect splicing but occurs outside of a donor/acceptor +/-1,2 dinucleotide position.","General recommendation,Gene-specific,Strength"
-ANO5 (HGNC:27337),PVS1,Moderate,"Please see attached 
-ANO5
- PVS1 flowchart. In addition, follow the SVI Working Group’s recommendations (Walker et al. 2023; PMID: 37352859) for any variant for which an impact on splicing has been experimentally demonstrated OR is predicted to affect splicing but occurs outside of a donor/acceptor +/-1,2 dinucleotide position.","General recommendation,Gene-specific,Strength"
-ANO5 (HGNC:27337),PVS1,Supporting,"Please see attached 
-ANO5
- PVS1 flowchart. In addition, follow the SVI Working Group’s recommendations (Walker et al. 2023; PMID: 37352859) for any variant for which an impact on splicing has been experimentally demonstrated OR is predicted to affect splicing but occurs outside of a donor/acceptor +/-1,2 dinucleotide position.","General recommendation,Gene-specific,Strength"
-ANO5 (HGNC:27337),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-ANO5 (HGNC:27337),PS1,Strong,"For missense variants for which the amino acid change is the expected mechanism of disease, apply at Strong for 1 pathogenic or 2 likely pathogenic variants resulting in the same amino acid change. The likely pathogenic or pathogenic variant(s) must have been classified using LGMD VCEP specifications, and potential splice effects must be excluded for the missense variant under curation and the variant(s) resulting in the same amino acid change (SpliceAI score ≤0.10 or experimental evidence of normal splicing). PS1 can potentially be applied to multiple nucleotide changes at the same residue as long as the variant classification that determines the strength level does not depend on PS1 application.
-
-
-For missense variants encoded by the first or last 3 nucleotides of an exon, PS1 should be considered only in the context of altered splicing (see below), unless a splice effect has been experimentally ruled out for the variant under curation and the variant(s) resulting in the same amino acid change. 
-
-
-For variants for which the nucleotide change is the expected mechanism of disease (altered splicing), follow SVI Working Group recommendations (Walker et al. 2023; PMID: 37352859).","Disease-specific,General recommendation"
-ANO5 (HGNC:27337),PS1,Moderate,"For missense variants for which the amino acid change is the expected mechanism of disease, apply at Moderate for 1 likely pathogenic variant resulting in the same amino acid change. The likely pathogenic variant must have been classified using LGMD VCEP specifications, and potential splice effects must be excluded for the missense variant under curation and the variant resulting in the same amino acid change (SpliceAI score ≤0.10 or experimental evidence of normal splicing). PS1 can potentially be applied to multiple nucleotide changes at the same residue as long as the variant classification that determines the strength level does not depend on PS1 application.
-
-
-For missense variants encoded by the first or last 3 nucleotides of an exon, PS1 should be considered only in the context of altered splicing (see below), unless a splice effect has been experimentally ruled out for the variant under curation and the variant(s) resulting in the same amino acid change. 
-
-
-For variants for which the nucleotide change is the expected mechanism of disease (altered splicing), follow SVI Working Group recommendations (Walker et al. 2023; PMID: 37352859).","Disease-specific,General recommendation,Strength"
-ANO5 (HGNC:27337),PS1,Supporting,"For variants for which the nucleotide change is the expected mechanism of disease (altered splicing), follow SVI Working Group recommendations (Walker et al. 2023; PMID: 37352859).","General recommendation,Strength"
-ANO5 (HGNC:27337),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-ANO5 (HGNC:27337),PS2,Very Strong,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. ≥ 4 pts is required to apply PS2 at Very Strong.,"Disease-specific,General recommendation,Strength"
-ANO5 (HGNC:27337),PS2,Strong,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PS2 should be applied for ≥ 2 pts but < 4 pts.,"Disease-specific,General recommendation"
-ANO5 (HGNC:27337),PS2,Moderate,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PS2_Moderate should be applied for ≥ 1 pt but < 2 pts.,"Disease-specific,General recommendation,Strength"
-ANO5 (HGNC:27337),PS2,Supporting,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PS2_Supporting should be applied for ≥ 0.5 pts but < 1 pt.,"Disease-specific,General recommendation,Strength"
-ANO5 (HGNC:27337),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-ANO5 (HGNC:27337),PS3,Strong,"Variant-specific animal models are rare but may be assessed on a case-by-case basis and PS3 applied at a strength level that reflects how well the model recapitulates features observed in human patients. Apply PS3 at Strong for a variant-specific animal model that meets all of the following conditions, regardless of species: 
-
-
-
-
-signs of myopathy or dystrophy are present in skeletal muscle 
-
-
-an effect on gene or protein function is demonstrated (e.g., decreased protein expression, impaired membrane localization, or other functional abnormality)
-
-
-behavioral signs of muscle weakness
-
-
-progression over time
-
-
-
-
-For 
-ANO5
-, functional studies in heterologous systems are hard to conduct and rare in the literature. Therefore, PS3 is not applicable at this time for 
-in vitro
- assays for variants in 
-ANO5
-. 
-
-
-For any variant type, experimental evidence for altered splicing should be scored under PVS1 in accordance with the decision tree for RNA splicing assay results outlined in Walker et al. 2023 (PMID: 37352859).
-
-
-Apply PS3 only once, for the piece of evidence that meets the highest possible strength level.","Disease-specific,General recommendation"
-ANO5 (HGNC:27337),PS3,Moderate,"Variant-specific animal models are rare but may be assessed on a case-by-case basis and PS3 applied at a strength level that reflects how well the model recapitulates features observed in human patients. Apply PS3_Moderate for a variant-specific animal model that meets all of the following conditions, regardless of species: 
-
-
-
-
-signs of myopathy or dystrophy are present in skeletal muscle 
-
-
-an effect on gene or protein function is demonstrated (e.g., decreased protein expression, impaired membrane localization, or other functional abnormality)
-
-
-
-
-For 
-ANO5
-, functional studies in heterologous systems are hard to conduct and rare in the literature. Therefore, PS3 is not applicable at this time for 
-in vitro
- assays for variants in 
-ANO5
-. 
-
-
-For any variant type, experimental evidence for altered splicing should be scored under PVS1 in accordance with the decision tree for RNA splicing assay results outlined in Walker et al. 2023 (PMID: 37352859).
-
-
-Apply PS3 only once, for the piece of evidence that meets the highest possible strength level.","Disease-specific,General recommendation,Gene-specific,Strength"
-ANO5 (HGNC:27337),PS3,Supporting,"For 
-ANO5
-, functional studies in heterologous systems are hard to conduct and rare in the literature. Therefore, PS3 is not applicable at this time for 
-in vitro
- assays for variants in 
-ANO5
-. 
-
-
-For any variant type, experimental evidence for altered splicing should be scored under PVS1 in accordance with the decision tree for RNA splicing assay results outlined in Walker et al. 2023 (PMID: 37352859).
-
-
-Apply PS3 only once, for the piece of evidence that meets the highest possible strength level.","Disease-specific,General recommendation,Gene-specific,Strength"
-ANO5 (HGNC:27337),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-ANO5 (HGNC:27337),PS4,Strong,"Use without disease-specific modification if case-control studies are available. 
-While case-control studies could potentially be considered for a few pathogenic variants with high minor allele frequency, the VCEP is unaware of any such studies being conducted for 
-ANO5
-. Any case-control study would require careful selection of an appropriate control population given the potential for late onset and mild disease.",Clarification
-ANO5 (HGNC:27337),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-ANO5 (HGNC:27337),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-ANO5 (HGNC:27337),PM2,Supporting,"Apply if the Grpmax alternate allele frequency / upper bound of the 95% confidence interval (95% CI) of the Grpmax alternate allele frequency in gnomAD is <0.0001. 
-
-
-
-
-If only 1 or 2 alternate alleles are reported in the Grpmax population, apply if the Grpmax alternate allele frequency is <0.0001. 
-
-
-If at least 3 alternate alleles are reported in the Grpmax population, apply if the upper bound of the 95% CI of the Grpmax alternate allele frequency is <0.0001.
-
-
-
-
-Grpmax refers to the gnomAD subpopulation with the highest alternate allele frequency. Use large, non-bottlenecked genetic ancestry groups for the Grpmax; avoid using the Amish, Ashkenazi Jewish, European Finnish, Remaining, or Middle Eastern (genomes).
-
-
-The upper bound of the 95% CI must be calculated using the exome or genome allele numbers and counts from gnomAD. Confidence interval tools, such as Confit-de-MAF (
-https://www.genecalculators.net/confit-de-maf.html
-), can be used.
-
-
-When comparing different versions of gnomAD for the variant frequency, use the allele count from the version with the largest allele number. 
-
-
-For larger deletions or duplications that may not be well represented in gnomAD (e.g., single- or multi-exon events), also confirm the variant is not common in gnomAD SVs, gnomAD CNVs, or the Database of Genomic Variants (DGV) (
-https://dgv.tcag.ca/dgv/app/home
-).","Disease-specific,Strength"
-ANO5 (HGNC:27337),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-ANO5 (HGNC:27337),PM3,Very Strong,Use the SVI Working Group’s recommended point system to determine PM3 strength (see supplementary file “PM3 table”). ≥ 4 pts is required to apply PM3 at Very Strong.,"Disease-specific,General recommendation,Strength"
-ANO5 (HGNC:27337),PM3,Strong,Use the SVI Working Group’s recommended point system to determine PM3 strength (see supplementary file “PM3 table”). PM3_Strong should be applied for ≥ 2 pts but < 4 pts.,"Disease-specific,General recommendation,Strength"
-ANO5 (HGNC:27337),PM3,Moderate,Use the SVI Working Group’s recommended point system to determine PM3 strength (see supplementary file “PM3 table”). PM3 (Moderate) should be applied for ≥ 1 pt but < 2 pts.,"Disease-specific,General recommendation"
-ANO5 (HGNC:27337),PM3,Supporting,Use the SVI Working Group’s recommended point system to determine PM3 strength (see supplementary file “PM3 table”). PM3_Supporting should be applied for ≥ 0.5 pts but < 1 pt.,"Disease-specific,General recommendation,Strength"
-ANO5 (HGNC:27337),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-ANO5 (HGNC:27337),PM4,Moderate,"Use as is, regardless of the length of the in-frame insertion or deletion.",No change
-ANO5 (HGNC:27337),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-ANO5 (HGNC:27337),PM5,Strong,"Apply only for missense variants for which the amino acid change is the expected mechanism of disease. For the missense variant under curation and the variant(s) resulting in a different amino acid change, exclude potential splice effects (SpliceAI score ≤0.10 or experimental evidence of normal splicing) and confirm the applicability of PP3. Missense changes at the same residue must be classified according to LGMD VCEP specifications, and no benign missense variation should be present at the residue. Do not apply for missense variants encoded by the first or last 3 nucleotides of an exon unless a splice effect has been experimentally ruled out for the variant under curation and the variant(s) resulting in the same amino acid change. Apply at Strong for 2 pathogenic or 3 likely pathogenic variants resulting in different amino acid changes at the same residue as the variant under curation.
-
-
-PM5 can potentially be applied to multiple amino acid changes at the same residue as long as the variant classification that determines the strength level does not depend on PM5 application.","Disease-specific,Strength"
-ANO5 (HGNC:27337),PM5,Moderate,"Apply only for missense variants for which the amino acid change is the expected mechanism of disease. For the missense variant under curation and the variant(s) resulting in a different amino acid change, exclude potential splice effects (SpliceAI score ≤0.10 or experimental evidence of normal splicing) and confirm the applicability of PP3. Missense changes at the same residue must be classified according to LGMD VCEP specifications, and no benign missense variation should be present at the residue. Do not apply for missense variants encoded by the first or last 3 nucleotides of an exon unless a splice effect has been experimentally ruled out for the variant under curation and the variant(s) resulting in the same amino acid change. Apply at Moderate for 1 pathogenic or 2 likely pathogenic variants resulting in different amino acid changes at the same residue as the variant under curation.
-
-
-PM5 can potentially be applied to multiple amino acid changes at the same residue as long as the variant classification that determines the strength level does not depend on PM5 application.",Disease-specific
-ANO5 (HGNC:27337),PM5,Supporting,"Apply only for missense variants for which the amino acid change is the expected mechanism of disease. For the missense variant under curation and the variant(s) resulting in a different amino acid change, exclude potential splice effects (SpliceAI score ≤0.10 or experimental evidence of normal splicing) and confirm the applicability of PP3. Missense changes at the same residue must be classified according to LGMD VCEP specifications, and no benign missense variation should be present at the residue. Do not apply for missense variants encoded by the first or last 3 nucleotides of an exon unless a splice effect has been experimentally ruled out for the variant under curation and the variant resulting in the same amino acid change. Apply at Supporting for 1 likely pathogenic variant resulting in a different amino acid change at the same residue as the variant under curation.
-
-
-PM5 can potentially be applied to multiple amino acid changes at the same residue as long as the variant classification that determines the strength level does not depend on PM5 application.","Disease-specific,Strength"
-ANO5 (HGNC:27337),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-ANO5 (HGNC:27337),PM6,Strong,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PM6_Strong should be applied for ≥ 2 pts but < 4 pts.,"Disease-specific,General recommendation,Strength"
-ANO5 (HGNC:27337),PM6,Moderate,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PM6 should be applied for ≥ 1 pt but < 2 pts.,"Disease-specific,General recommendation"
-ANO5 (HGNC:27337),PM6,Supporting,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PM6_Supporting should be applied for ≥ 0.5 pts but < 1 pt.,"Disease-specific,General recommendation,Strength"
-ANO5 (HGNC:27337),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-ANO5 (HGNC:27337),PP1,Strong,"Segregations should be counted across families, with the total number of segregations determining the strength level. Apply PP1_Strong for 3 affected segregations (in addition to proband) across ≥2 families. When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate).","Disease-specific,Strength"
-ANO5 (HGNC:27337),PP1,Moderate,"Segregations should be counted across families, with the total number of segregations determining the strength level. Apply PP1_Moderate for 2 affected segregations (in addition to proband; may be from a single family). When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate).","Disease-specific,Strength"
-ANO5 (HGNC:27337),PP1,Supporting,"Segregations should be counted across families, with the total number of segregations determining the strength level. Apply PP1 (Supporting) for 1 affected segregation (in addition to proband). When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate).",Disease-specific
-ANO5 (HGNC:27337),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-ANO5 (HGNC:27337),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-ANO5 (HGNC:27337),PP3,Supporting,"For missense variants, use REVEL with a score ≥0.7. 
-
-
-For variants that may affect splicing, use SpliceAI with a score ≥0.5.",Disease-specific
-ANO5 (HGNC:27337),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-ANO5 (HGNC:27337),PP4,Supporting,"Apply PP4 (Supporting) for a proband meeting both of the following criteria:
-
-
-
-
-progressive limb-girdle pattern of muscle weakness observed over ≥6 mo OR clinical suspicion of LGMD
-1
-
-
-2 presumed diagnostic variants in 
-ANO5
-, 1 of which is the variant under curation
-2
-
-
-
-
-1
- May be accompanied by supporting EMG, MRI, muscle histology, elevated CK but not required.
-
-
-2
- Screening of all exons and exon/intron boundaries of 
-ANO5
- required. Screening of additional neuromuscular disease genes (e.g., through a panel) is recommended but not required. If variants have not yet been curated by the LGMD VCEP, confirm they cannot be classified as LB or B (e.g., through application of BA1, BS1, and/or BP4/BP7). If phase is unknown, do not apply if the identified variants were ever confirmed 
-in cis
- or if gnomAD co-occurrence data (
-https://gnomad.broadinstitute.org/variant-cooccurrence
-) predict the variants may be part of the same haplotype in at least one genetic ancestry group.",Disease-specific
-ANO5 (HGNC:27337),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-ANO5 (HGNC:27337),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-ANO5 (HGNC:27337),BA1,Stand Alone,"Apply if the variant Grpmax FAF (the lower bound of the 95% confidence interval of the maximum credible genetic ancestry group allele frequency) is >0.003. This value can be taken directly from gnomAD. See supplementary file “benign frequency exceptions” for a list of variants defined as exceptions to the benign frequency rules. Ongoing updates to this list will be available at the LGMD VCEP webpage: 
-https://clinicalgenome.org/affiliation/50061/.
- Variants whose frequency may not be reliable (e.g., variants that may reflect a sequencing artifact) should be critically evaluated and brought to the attention of the LGMD VCEP.",Disease-specific
-ANO5 (HGNC:27337),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-ANO5 (HGNC:27337),BS1,Strong,"Apply if the variant Grpmax FAF (the lower bound of the 95% confidence interval of the maximum credible genetic ancestry group allele frequency) is >0.001. This value can be taken directly from gnomAD. See supplementary file “benign frequency exceptions” for a list of variants defined as exceptions to the benign frequency rules. Ongoing updates to this list will be available at the LGMD VCEP webpage: 
-https://clinicalgenome.org/affiliation/50061/.
- Variants whose frequency may not be reliable (e.g., variants that may reflect a sequencing artifact) should be critically evaluated and brought to the attention of the LGMD VCEP.",Disease-specific
-ANO5 (HGNC:27337),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",NA
-ANO5 (HGNC:27337),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-ANO5 (HGNC:27337),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-ANO5 (HGNC:27337),BS4,Strong,"Use as is. One affected individual (genotype-, phenotype+) is sufficient for BS4. Do not apply for genotype+, phenotype- individuals, as LGMD is characterized by variable expressivity and late onset is not uncommon.",Clarification
-ANO5 (HGNC:27337),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-ANO5 (HGNC:27337),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-ANO5 (HGNC:27337),BP2,Supporting,"Use when variant is found 
-in cis
- with a variant classified as pathogenic or likely pathogenic using the LGMD VCEP specifications.",Disease-specific
-ANO5 (HGNC:27337),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-ANO5 (HGNC:27337),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-ANO5 (HGNC:27337),BP4,Supporting,"For missense variants, use REVEL with a score ≤0.1 AND SpliceAI with a score ≤0.05.
-
-
-For variants that may affect splicing, use SpliceAI with a score ≤0.05.
-
-
-Splice AI scores can be calculated here: 
-https://spliceailookup.broadinstitute.org/",Disease-specific
-ANO5 (HGNC:27337),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-ANO5 (HGNC:27337),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-ANO5 (HGNC:27337),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-ANO5 (HGNC:27337),BP7,Supporting,"For splice predictions, use SpliceAI with a score ≤0.05. BP7 may be co-applied with BP4 for synonymous, UTR, and intronic variants located outside the splice donor/acceptor regions designated in Walker et al. 2023 (+7/-21).",Disease-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCAPN3Version1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCAPN3Version1.0.0_version=1.0.0.csv
deleted file mode 100644
index 0436c678aecef4c6e9643c2a5bf532341c237380..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCAPN3Version1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,226 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-CAPN3 (HGNC:1480),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-CAPN3 (HGNC:1480),PVS1,Very Strong,"Please see attached 
-CAPN3
- PVS1 flowchart. In addition, follow the SVI Working Group’s recommendations (Walker et al. 2023; PMID: 37352859) for any variant for which an impact on splicing has been experimentally demonstrated OR is predicted to affect splicing but occurs outside of a donor/acceptor +/-1,2 dinucleotide position.","General recommendation,Gene-specific"
-CAPN3 (HGNC:1480),PVS1,Strong,"Please see attached 
-CAPN3
- PVS1 flowchart. In addition, follow the SVI Working Group’s recommendations (Walker et al. 2023; PMID: 37352859) for any variant for which an impact on splicing has been experimentally demonstrated OR is predicted to affect splicing but occurs outside of a donor/acceptor +/-1,2 dinucleotide position.","General recommendation,Gene-specific,Strength"
-CAPN3 (HGNC:1480),PVS1,Moderate,"Please see attached 
-CAPN3
- PVS1 flowchart. In addition, follow the SVI Working Group’s recommendations (Walker et al. 2023; PMID: 37352859) for any variant for which an impact on splicing has been experimentally demonstrated OR is predicted to affect splicing but occurs outside of a donor/acceptor +/-1,2 dinucleotide position.","General recommendation,Gene-specific,Strength"
-CAPN3 (HGNC:1480),PVS1,Supporting,"Please see attached 
-CAPN3
- PVS1 flowchart. In addition, follow the SVI Working Group’s recommendations (Walker et al. 2023; PMID: 37352859) for any variant for which an impact on splicing has been experimentally demonstrated OR is predicted to affect splicing but occurs outside of a donor/acceptor +/-1,2 dinucleotide position.","General recommendation,Gene-specific,Strength"
-CAPN3 (HGNC:1480),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-CAPN3 (HGNC:1480),PS1,Strong,"For missense variants for which the amino acid change is the expected mechanism of disease, apply at Strong for 1 pathogenic or 2 likely pathogenic variants resulting in the same amino acid change. The likely pathogenic or pathogenic variant(s) must have been classified using LGMD VCEP specifications, and potential splice effects must be excluded for the missense variant under curation and the variant(s) resulting in the same amino acid change (SpliceAI score ≤0.10 or experimental evidence of normal splicing). PS1 can potentially be applied to multiple nucleotide changes at the same residue as long as the variant classification that determines the strength level does not depend on PS1 application.
-
-
-For missense variants encoded by the first or last 3 nucleotides of an exon, PS1 should be considered only in the context of altered splicing (see below), unless a splice effect has been experimentally ruled out for the variant under curation and the variant(s) resulting in the same amino acid change. 
-
-
-For variants for which the nucleotide change is the expected mechanism of disease (altered splicing), follow SVI Working Group recommendations (Walker et al. 2023; PMID: 37352859).","Disease-specific,General recommendation"
-CAPN3 (HGNC:1480),PS1,Moderate,"For missense variants for which the amino acid change is the expected mechanism of disease, apply at Moderate for 1 likely pathogenic variant resulting in the same amino acid change. The likely pathogenic variant must have been classified using LGMD VCEP specifications, and potential splice effects must be excluded for the missense variant under curation and the variant resulting in the same amino acid change (SpliceAI score ≤0.10 or experimental evidence of normal splicing). PS1 can potentially be applied to multiple nucleotide changes at the same residue as long as the variant classification that determines the strength level does not depend on PS1 application.
-
-
-For missense variants encoded by the first or last 3 nucleotides of an exon, PS1 should be considered only in the context of altered splicing (see below), unless a splice effect has been experimentally ruled out for the variant under curation and the variant(s) resulting in the same amino acid change. 
-
-
-For variants for which the nucleotide change is the expected mechanism of disease (altered splicing), follow SVI Working Group recommendations (Walker et al. 2023; PMID: 37352859).","Disease-specific,General recommendation,Strength"
-CAPN3 (HGNC:1480),PS1,Supporting,"For variants for which the nucleotide change is the expected mechanism of disease (altered splicing), follow SVI Working Group recommendations (Walker et al. 2023; PMID: 37352859).","General recommendation,Strength"
-CAPN3 (HGNC:1480),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-CAPN3 (HGNC:1480),PS2,Very Strong,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for at least PP4_Moderate or PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. ≥ 4 pts is required to apply PS2 at Very Strong.,"Disease-specific,General recommendation,Strength"
-CAPN3 (HGNC:1480),PS2,Strong,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for at least PP4_Moderate or PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PS2 should be applied for ≥ 2 pts but < 4 pts.,"Disease-specific,General recommendation"
-CAPN3 (HGNC:1480),PS2,Moderate,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for at least PP4_Moderate or PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PS2_Moderate should be applied for ≥ 1 pt but < 2 pts.,"Disease-specific,General recommendation,Strength"
-CAPN3 (HGNC:1480),PS2,Supporting,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for at least PP4_Moderate or PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PS2_Supporting should be applied for ≥ 0.5 pts but < 1 pt.,"Disease-specific,General recommendation,Strength"
-CAPN3 (HGNC:1480),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-CAPN3 (HGNC:1480),PS3,Strong,"Variant-specific animal models are rare but may be assessed on a case-by-case basis and PS3 applied at a strength level that reflects how well the model recapitulates features observed in human patients. Apply PS3 at Strong for a variant-specific animal model that meets all of the following conditions, regardless of species: 
-
-
-
-
-signs of myopathy or dystrophy are present in skeletal muscle 
-
-
-an effect on gene or protein function is demonstrated (e.g., decreased protein expression, impaired membrane localization, or other functional abnormality)
-
-
-behavioral signs of muscle weakness
-
-
-progression over time
-
-
-
-
-For 
-CAPN3
-, functional studies in heterologous systems are hard to conduct and rare in the literature. Therefore, PS3 is not applicable at this time for 
-in vitro
- assays for variants in 
-CAPN3
-. Assays that may be considered in the future include titin ectopic expression, titin degradation assay, baculovirus-based titin cleavage assay, and assays of autolytic activity.
-
-
-For any variant type, experimental evidence for altered splicing should be scored under PVS1 in accordance with the decision tree for RNA splicing assay results outlined in Walker et al. 2023 (PMID: 37352859).
-
-
-Apply PS3 only once, for the piece of evidence that meets the highest possible strength level.","Disease-specific,General recommendation"
-CAPN3 (HGNC:1480),PS3,Moderate,"Variant-specific animal models are rare but may be assessed on a case-by-case basis and PS3 applied at a strength level that reflects how well the model recapitulates features observed in human patients. Apply PS3_Moderate for a variant-specific animal model that meets all of the following conditions, regardless of species: 
-
-
-
-
-signs of myopathy or dystrophy are present in skeletal muscle 
-
-
-an effect on gene or protein function is demonstrated (e.g., decreased protein expression, impaired membrane localization, or other functional abnormality)
-
-
-
-
-For 
-CAPN3
-, functional studies in heterologous systems are hard to conduct and rare in the literature. Therefore, PS3 is not applicable at this time for 
-in vitro
- assays for variants in 
-CAPN3
-. Assays that may be considered in the future include titin ectopic expression, titin degradation assay, baculovirus-based titin cleavage assay, and assays of autolytic activity.
-
-
-For any variant type, experimental evidence for altered splicing should be scored under PVS1 in accordance with the decision tree for RNA splicing assay results outlined in Walker et al. 2023 (PMID: 37352859).
-
-
-Apply PS3 only once, for the piece of evidence that meets the highest possible strength level.","Disease-specific,General recommendation,Gene-specific,Strength"
-CAPN3 (HGNC:1480),PS3,Supporting,"For 
-CAPN3
-, functional studies in heterologous systems are hard to conduct and rare in the literature. Therefore, PS3 is not applicable at this time for 
-in vitro
- assays for variants in 
-CAPN3
-. Assays that may be considered in the future include titin ectopic expression, titin degradation assay, baculovirus-based titin cleavage assay, and assays of autolytic activity.
-
-
-For any variant type, experimental evidence for altered splicing should be scored under PVS1 in accordance with the decision tree for RNA splicing assay results outlined in Walker et al. 2023 (PMID: 37352859).
-
-
-Apply PS3 only once, for the piece of evidence that meets the highest possible strength level.","Disease-specific,General recommendation,Gene-specific,Strength"
-CAPN3 (HGNC:1480),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-CAPN3 (HGNC:1480),PS4,Strong,"Use without disease-specific modification if case-control studies are available. 
-While case-control studies could potentially be considered for a few pathogenic variants with high minor allele frequency, the VCEP is unaware of any such studies being conducted for 
-CAPN3
-. Any case-control study would require careful selection of an appropriate control population given the potential for late onset and mild disease.",Clarification
-CAPN3 (HGNC:1480),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-CAPN3 (HGNC:1480),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-CAPN3 (HGNC:1480),PM2,Supporting,"Apply if the Grpmax alternate allele frequency / upper bound of the 95% confidence interval (95% CI) of the Grpmax alternate allele frequency in gnomAD is <0.0001. 
-
-
-
-
-If only 1 or 2 alternate alleles are reported in the Grpmax population, apply if the Grpmax alternate allele frequency is <0.0001. 
-
-
-If at least 3 alternate alleles are reported in the Grpmax population, apply if the upper bound of the 95% CI of the Grpmax alternate allele frequency is <0.0001.
-
-
-
-
-Grpmax refers to the gnomAD subpopulation with the highest alternate allele frequency. Use large, non-bottlenecked genetic ancestry groups for the Grpmax; avoid using the Amish, Ashkenazi Jewish, European Finnish, Remaining, or Middle Eastern (genome).
-
-
-The upper bound of the 95% CI must be calculated using the exome or genome allele numbers and counts from gnomAD. Confidence interval tools, such as Confit-de-MAF (
-https://www.genecalculators.net/confit-de-maf.html
-), can be used.
-
-
-When comparing different versions of gnomAD for the variant frequency, use the allele count from the version with the largest allele number. 
-
-
-For larger deletions or duplications that may not be well represented in gnomAD (e.g., single- or multi-exon events), also confirm the variant is not common in gnomAD SVs, gnomAD CNVs, or the Database of Genomic Variants (DGV) (
-https://dgv.tcag.ca/dgv/app/home
-).","Disease-specific,Strength"
-CAPN3 (HGNC:1480),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-CAPN3 (HGNC:1480),PM3,Very Strong,Use the SVI Working Group’s recommended point system to determine PM3 strength (see supplementary file “PM3 table”). ≥ 4 pts is required to apply PM3 at Very Strong.,"Disease-specific,General recommendation,Strength"
-CAPN3 (HGNC:1480),PM3,Strong,Use the SVI Working Group’s recommended point system to determine PM3 strength (see supplementary file “PM3 table”). PM3_Strong should be applied for ≥ 2 pts but < 4 pts.,"Disease-specific,General recommendation,Strength"
-CAPN3 (HGNC:1480),PM3,Moderate,Use the SVI Working Group’s recommended point system to determine PM3 strength (see supplementary file “PM3 table”). PM3 (Moderate) should be applied for ≥ 1 pt but < 2 pts.,"Disease-specific,General recommendation"
-CAPN3 (HGNC:1480),PM3,Supporting,Use the SVI Working Group’s recommended point system to determine PM3 strength (see supplementary file “PM3 table”). PM3_Supporting should be applied for ≥ 0.5 pts but < 1 pt.,"Disease-specific,General recommendation,Strength"
-CAPN3 (HGNC:1480),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-CAPN3 (HGNC:1480),PM4,Moderate,"Use as is, regardless of the length of the in-frame insertion or deletion.",No change
-CAPN3 (HGNC:1480),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-CAPN3 (HGNC:1480),PM5,Strong,"Apply only for missense variants for which the amino acid change is the expected mechanism of disease. For the missense variant under curation and the variant(s) resulting in a different amino acid change, exclude potential splice effects (SpliceAI score ≤0.10 or experimental evidence of normal splicing) and confirm the applicability of PP3. Missense changes at the same residue must be classified according to LGMD VCEP specifications, and no benign missense variation should be present at the residue. Do not apply for missense variants encoded by the first or last 3 nucleotides of an exon unless a splice effect has been experimentally ruled out for the variant under curation and the variant(s) resulting in the same amino acid change. Apply at Strong for 2 pathogenic or 3 likely pathogenic variants resulting in different amino acid changes at the same residue as the variant under curation.
-
-
-PM5 can potentially be applied to multiple amino acid changes at the same residue as long as the variant classification that determines the strength level does not depend on PM5 application.","Disease-specific,Strength"
-CAPN3 (HGNC:1480),PM5,Moderate,"Apply only for missense variants for which the amino acid change is the expected mechanism of disease. For the missense variant under curation and the variant(s) resulting in a different amino acid change, exclude potential splice effects (SpliceAI score ≤0.10 or experimental evidence of normal splicing) and confirm the applicability of PP3. Missense changes at the same residue must be classified according to LGMD VCEP specifications, and no benign missense variation should be present at the residue. Do not apply for missense variants encoded by the first or last 3 nucleotides of an exon unless a splice effect has been experimentally ruled out for the variant under curation and the variant(s) resulting in the same amino acid change. Apply at Moderate for 1 pathogenic or 2 likely pathogenic variants resulting in different amino acid changes at the same residue as the variant under curation.
-
-
-PM5 can potentially be applied to multiple amino acid changes at the same residue as long as the variant classification that determines the strength level does not depend on PM5 application.",Disease-specific
-CAPN3 (HGNC:1480),PM5,Supporting,"Apply only for missense variants for which the amino acid change is the expected mechanism of disease. For the missense variant under curation and the variant(s) resulting in a different amino acid change, exclude potential splice effects (SpliceAI score ≤0.10 or experimental evidence of normal splicing) and confirm the applicability of PP3. Missense changes at the same residue must be classified according to LGMD VCEP specifications, and no benign missense variation should be present at the residue. Do not apply for missense variants encoded by the first or last 3 nucleotides of an exon unless a splice effect has been experimentally ruled out for the variant under curation and the variant resulting in the same amino acid change. Apply at Supporting for 1 likely pathogenic variant resulting in a different amino acid change at the same residue as the variant under curation.
-
-
-PM5 can potentially be applied to multiple amino acid changes at the same residue as long as the variant classification that determines the strength level does not depend on PM5 application.","Disease-specific,Strength"
-CAPN3 (HGNC:1480),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-CAPN3 (HGNC:1480),PM6,Strong,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for at least PP4_Moderate or PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PM6_Strong should be applied for ≥ 2 pts but < 4 pts.,"Disease-specific,General recommendation,Strength"
-CAPN3 (HGNC:1480),PM6,Moderate,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for at least PP4_Moderate or PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PM6 should be applied for ≥ 1 pt but < 2 pts.,"Disease-specific,General recommendation"
-CAPN3 (HGNC:1480),PM6,Supporting,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for at least PP4_Moderate or PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PM6_Supporting should be applied for ≥ 0.5 pts but < 1 pt.,"Disease-specific,General recommendation,Strength"
-CAPN3 (HGNC:1480),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-CAPN3 (HGNC:1480),PP1,Strong,"Segregations should be counted across families, with the total number of segregations determining the strength level. Apply PP1_Strong for 3 affected segregations (in addition to proband) across ≥2 families. When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate).","Disease-specific,Strength"
-CAPN3 (HGNC:1480),PP1,Moderate,"Segregations should be counted across families, with the total number of segregations determining the strength level. Apply PP1_Moderate for 2 affected segregations (in addition to proband; may be from a single family). When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate).","Disease-specific,Strength"
-CAPN3 (HGNC:1480),PP1,Supporting,"Segregations should be counted across families, with the total number of segregations determining the strength level. Apply PP1 (Supporting) for 1 affected segregation (in addition to proband). When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate).",Disease-specific
-CAPN3 (HGNC:1480),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-CAPN3 (HGNC:1480),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-CAPN3 (HGNC:1480),PP3,Supporting,"For missense variants, use REVEL with a score ≥0.7. 
-
-
-For variants that may affect splicing, use SpliceAI with a score ≥0.5.",Disease-specific
-CAPN3 (HGNC:1480),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-CAPN3 (HGNC:1480),PP4,Strong,"Use the PP4 table (see supplementary file “PP4 table CAPN3”) to determine the appropriate PP4 strength level. Apply PP4 only once, for a patient meeting the highest possible strength level. When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate).","Disease-specific,Gene-specific,Strength"
-CAPN3 (HGNC:1480),PP4,Moderate,"Use the PP4 table (see supplementary file “PP4 table CAPN3”) to determine the appropriate PP4 strength level. Apply PP4 only once, for a patient meeting the highest possible strength level. When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate). If PP1_Moderate is applied and the criteria for PP4_Strong are also met, a downgraded PP4_Moderate can be applied.","Disease-specific,Gene-specific,Strength"
-CAPN3 (HGNC:1480),PP4,Supporting,"Use the PP4 table (see supplementary file “PP4 table CAPN3”) to determine the appropriate PP4 strength level. Apply PP4 only once, for a patient meeting the highest possible strength level. When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate).",Disease-specific
-CAPN3 (HGNC:1480),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-CAPN3 (HGNC:1480),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-CAPN3 (HGNC:1480),BA1,Stand Alone,"Apply if the variant Grpmax FAF (the lower bound of the 95% confidence interval of the maximum credible genetic ancestry group allele frequency) is >0.003. This value can be taken directly from gnomAD. See supplementary file “benign frequency exceptions” for a list of variants defined as exceptions to the benign frequency rules. Ongoing updates to this list will be available at the LGMD VCEP webpage: 
-https://clinicalgenome.org/affiliation/50061/.
- Variants whose frequency may not be reliable (e.g., variants that may reflect a sequencing artifact) should be critically evaluated and brought to the attention of the LGMD VCEP.",Disease-specific
-CAPN3 (HGNC:1480),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-CAPN3 (HGNC:1480),BS1,Strong,"Apply if the variant Grpmax FAF (the lower bound of the 95% confidence interval of the maximum credible genetic ancestry group allele frequency) is >0.001. This value can be taken directly from gnomAD. See supplementary file “benign frequency exceptions” for a list of variants defined as exceptions to the benign frequency rules. Ongoing updates to this list will be available at the LGMD VCEP webpage: 
-https://clinicalgenome.org/affiliation/50061/.
- Variants whose frequency may not be reliable (e.g., variants that may reflect a sequencing artifact) should be critically evaluated and brought to the attention of the LGMD VCEP.",Disease-specific
-CAPN3 (HGNC:1480),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",NA
-CAPN3 (HGNC:1480),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-CAPN3 (HGNC:1480),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-CAPN3 (HGNC:1480),BS4,Strong,"Use as is. One affected individual (genotype-, phenotype+) is sufficient for BS4. Do not apply for genotype+, phenotype- individuals, as LGMD is characterized by variable expressivity and late onset is not uncommon.",Clarification
-CAPN3 (HGNC:1480),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-CAPN3 (HGNC:1480),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-CAPN3 (HGNC:1480),BP2,Supporting,"Use when variant is found 
-in cis
- with a variant classified as pathogenic or likely pathogenic using the LGMD VCEP specifications.",Disease-specific
-CAPN3 (HGNC:1480),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-CAPN3 (HGNC:1480),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-CAPN3 (HGNC:1480),BP4,Supporting,"For missense variants, use REVEL with a score ≤0.1 AND SpliceAI with a score ≤0.05.
-
-
-For variants that may affect splicing, use SpliceAI with a score ≤0.05.",Disease-specific
-CAPN3 (HGNC:1480),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-CAPN3 (HGNC:1480),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-CAPN3 (HGNC:1480),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-CAPN3 (HGNC:1480),BP7,Supporting,"For splice predictions, use SpliceAI with a score ≤0.05. BP7 may be co-applied with BP4 for synonymous, UTR, and intronic variants located outside the splice donor/acceptor regions designated in Walker et al. 2023 (+7/-21).",Disease-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDYSFVersion1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDYSFVersion1.0.0_version=1.0.0.csv
deleted file mode 100644
index 43527e731d4c61c7cc7db6786008d1d24963a286..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDYSFVersion1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,219 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-DYSF (HGNC:3097),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-DYSF (HGNC:3097),PVS1,Very Strong,"Please see attached 
-DYSF
- PVS1 flowchart. In addition, follow the SVI Working Group’s recommendations (Walker et al. 2023; PMID: 37352859) for any variant for which an impact on splicing has been experimentally demonstrated OR is predicted to affect splicing but occurs outside of a donor/acceptor +/-1,2 dinucleotide position.","General recommendation,Gene-specific"
-DYSF (HGNC:3097),PVS1,Strong,"Please see attached 
-DYSF
- PVS1 flowchart. In addition, follow the SVI Working Group’s recommendations (Walker et al. 2023; PMID: 37352859) for any variant for which an impact on splicing has been experimentally demonstrated OR is predicted to affect splicing but occurs outside of a donor/acceptor +/-1,2 dinucleotide position.","General recommendation,Gene-specific,Strength"
-DYSF (HGNC:3097),PVS1,Moderate,"Please see attached 
-DYSF
- PVS1 flowchart. In addition, follow the SVI Working Group’s recommendations (Walker et al. 2023; PMID: 37352859) for any variant for which an impact on splicing has been experimentally demonstrated OR is predicted to affect splicing but occurs outside of a donor/acceptor +/-1,2 dinucleotide position.","General recommendation,Gene-specific,Strength"
-DYSF (HGNC:3097),PVS1,Supporting,"Please see attached 
-DYSF
- PVS1 flowchart. In addition, follow the SVI Working Group’s recommendations (Walker et al. 2023; PMID: 37352859) for any variant for which an impact on splicing has been experimentally demonstrated OR is predicted to affect splicing but occurs outside of a donor/acceptor +/-1,2 dinucleotide position.","General recommendation,Gene-specific,Strength"
-DYSF (HGNC:3097),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-DYSF (HGNC:3097),PS1,Strong,"For missense variants for which the amino acid change is the expected mechanism of disease, apply at Strong for 1 pathogenic or 2 likely pathogenic variants resulting in the same amino acid change. The likely pathogenic or pathogenic variant(s) must have been classified using LGMD VCEP specifications, and potential splice effects must be excluded for the missense variant under curation and the variant(s) resulting in the same amino acid change (SpliceAI score ≤0.10 or experimental evidence of normal splicing). PS1 can potentially be applied to multiple nucleotide changes at the same residue as long as the variant classification that determines the strength level does not depend on PS1 application.
-
-
-For missense variants encoded by the first or last 3 nucleotides of an exon, PS1 should be considered only in the context of altered splicing (see below), unless a splice effect has been experimentally ruled out for the variant under curation and the variant(s) resulting in the same amino acid change. 
-
-
-For variants for which the nucleotide change is the expected mechanism of disease (altered splicing), follow SVI Working Group recommendations (Walker et al. 2023; PMID: 37352859).","Disease-specific,General recommendation"
-DYSF (HGNC:3097),PS1,Moderate,"For missense variants for which the amino acid change is the expected mechanism of disease, apply at Moderate for 1 likely pathogenic variant resulting in the same amino acid change. The likely pathogenic variant must have been classified using LGMD VCEP specifications, and potential splice effects must be excluded for the missense variant under curation and the variant resulting in the same amino acid change (SpliceAI score ≤0.10 or experimental evidence of normal splicing). PS1 can potentially be applied to multiple nucleotide changes at the same residue as long as the variant classification that determines the strength level does not depend on PS1 application.
-
-
-For missense variants encoded by the first or last 3 nucleotides of an exon, PS1 should be considered only in the context of altered splicing (see below), unless a splice effect has been experimentally ruled out for the variant under curation and the variant(s) resulting in the same amino acid change. 
-
-
-For variants for which the nucleotide change is the expected mechanism of disease (altered splicing), follow SVI Working Group recommendations (Walker et al. 2023; PMID: 37352859).","Disease-specific,General recommendation,Strength"
-DYSF (HGNC:3097),PS1,Supporting,"For variants for which the nucleotide change is the expected mechanism of disease (altered splicing), follow SVI Working Group recommendations (Walker et al. 2023; PMID: 37352859).","General recommendation,Strength"
-DYSF (HGNC:3097),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-DYSF (HGNC:3097),PS2,Very Strong,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. ≥ 4 pts is required to apply PS2 at Very Strong.,"Disease-specific,General recommendation,Strength"
-DYSF (HGNC:3097),PS2,Strong,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PS2 should be applied for ≥ 2 pts but < 4 pts.,"Disease-specific,General recommendation"
-DYSF (HGNC:3097),PS2,Moderate,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PS2_Moderate should be applied for ≥ 1 pt but < 2 pts.,"Disease-specific,General recommendation,Strength"
-DYSF (HGNC:3097),PS2,Supporting,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PS2_Supporting should be applied for ≥ 0.5 pts but < 1 pt.,"Disease-specific,General recommendation,Strength"
-DYSF (HGNC:3097),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-DYSF (HGNC:3097),PS3,Strong,"Variant-specific animal models are rare but may be assessed on a case-by-case basis and PS3 applied at a strength level that reflects how well the model recapitulates features observed in human patients. Apply PS3 at Strong for a variant-specific animal model that meets all of the following conditions, regardless of species: 
-
-
-
-
-signs of myopathy or dystrophy are present in skeletal muscle 
-
-
-an effect on gene or protein function is demonstrated (e.g., decreased protein expression, impaired membrane localization, or other functional abnormality)
-
-
-behavioral signs of muscle weakness
-
-
-progression over time
-
-
-
-
-For any variant type, experimental evidence for altered splicing should be scored under PVS1 in accordance with the decision tree for RNA splicing assay results outlined in Walker et al. 2023 (PMID: 37352859).
-
-
-Apply PS3 only once, for the piece of evidence that meets the highest possible strength level.","Disease-specific,General recommendation"
-DYSF (HGNC:3097),PS3,Moderate,"Variant-specific animal models are rare but may be assessed on a case-by-case basis and PS3 applied at a strength level that reflects how well the model recapitulates features observed in human patients. Apply PS3_Moderate for a variant-specific animal model that meets all of the following conditions, regardless of species: 
-
-
-
-
-signs of myopathy or dystrophy are present in skeletal muscle 
-
-
-an effect on gene or protein function is demonstrated (e.g., decreased protein expression, impaired membrane localization, or other functional abnormality)
-
-
-
-
-PS3_Moderate may also be applied for dysferlin membrane localization assays that have been clinically validated with ≥11 control variants that meet criteria specified in Brnich et al. 2020 (PMID: 31892348) for the number of pathogenic and benign control variants. 
-
-
-
-
-Dysferlin membrane localization functional score <0.25 AND concordant immunocytochemistry assay result in Tominaga et al. 2022 (concordant readout of “non-functional” for both assays) (PMID: 35028538). See supplementary file “PS3 assays_DYSF”.
-
-
-
-
-For any variant type, experimental evidence for altered splicing should be scored under PVS1 in accordance with the decision tree for RNA splicing assay results outlined in Walker et al. 2023 (PMID: 37352859).
-
-
-Apply PS3 only once, for the piece of evidence that meets the highest possible strength level.","General recommendation,Gene-specific,Strength"
-DYSF (HGNC:3097),PS3,Supporting,"PS3_Supporting may be applied if the variant is expressed in heterologous cell lines/model organisms and shows absent membrane localization of the dysferlin protein but fewer than 11 control variants were used, in accordance with Brnich et al. 2020 (PMID: 31892348). See supplementary file “PS3 assays_DYSF”.
-
-
-For any variant type, experimental evidence for altered splicing should be scored under PVS1 in accordance with the decision tree for RNA splicing assay results outlined in Walker et al. 2023 (PMID: 37352859).
-
-
-Apply PS3 only once, for the piece of evidence that meets the highest possible strength level.
-
-
-Assays that may be considered in the future include membrane resealing activity assays and calcium signaling assays.","Disease-specific,General recommendation,Gene-specific,Strength"
-DYSF (HGNC:3097),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-DYSF (HGNC:3097),PS4,Strong,"Use without disease-specific modification if case-control studies are available. 
-While case-control studies could potentially be considered for a few pathogenic variants with high minor allele frequency, the VCEP is unaware of any such studies being conducted for 
-DYSF
-. Any case-control study would require careful selection of an appropriate control population given the potential for late onset and mild disease.",Clarification
-DYSF (HGNC:3097),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-DYSF (HGNC:3097),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-DYSF (HGNC:3097),PM2,Supporting,"Apply if the Grpmax alternate allele frequency / upper bound of the 95% confidence interval (95% CI) of the Grpmax alternate allele frequency in gnomAD is <0.0001. 
-
-
-
-
-If only 1 or 2 alternate alleles are reported in the Grpmax population, apply if the Grpmax alternate allele frequency is <0.0001. 
-
-
-If at least 3 alternate alleles are reported in the Grpmax population, apply if the upper bound of the 95% CI of the Grpmax alternate allele frequency is <0.0001.
-
-
-
-
-Grpmax refers to the gnomAD subpopulation with the highest alternate allele frequency. Use large, non-bottlenecked genetic ancestry groups for the Grpmax; avoid using the Amish, Ashkenazi Jewish, European Finnish, Remaining, or Middle Eastern (genome).
-
-
-The upper bound of the 95% CI must be calculated using the exome or genome allele numbers and counts from gnomAD. Confidence interval tools, such as Confit-de-MAF (
-https://www.genecalculators.net/confit-de-maf.html
-), can be used.
-
-
-When comparing different versions of gnomAD for the variant frequency, use the allele count from the version with the largest allele number. 
-
-
-For larger deletions or duplications that may not be well represented in gnomAD (e.g., single- or multi-exon events), also confirm the variant is not common in gnomAD SVs, gnomAD CNVs, or the Database of Genomic Variants (DGV) (
-https://dgv.tcag.ca/dgv/app/home
-).","Disease-specific,Strength"
-DYSF (HGNC:3097),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-DYSF (HGNC:3097),PM3,Very Strong,Use the SVI Working Group’s recommended point system to determine PM3 strength (see supplementary file “PM3 table”). ≥ 4 pts is required to apply PM3 at Very Strong.,"Disease-specific,General recommendation,Strength"
-DYSF (HGNC:3097),PM3,Strong,Use the SVI Working Group’s recommended point system to determine PM3 strength (see supplementary file “PM3 table”). PM3_Strong should be applied for ≥ 2 pts but < 4 pts.,"Disease-specific,General recommendation,Strength"
-DYSF (HGNC:3097),PM3,Moderate,Use the SVI Working Group’s recommended point system to determine PM3 strength (see supplementary file “PM3 table”). PM3 (Moderate) should be applied for ≥ 1 pt but < 2 pts.,"Disease-specific,General recommendation"
-DYSF (HGNC:3097),PM3,Supporting,Use the SVI Working Group’s recommended point system to determine PM3 strength (see supplementary file “PM3 table”). PM3_Supporting should be applied for ≥ 0.5 pts but < 1 pt.,"Disease-specific,General recommendation,Strength"
-DYSF (HGNC:3097),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-DYSF (HGNC:3097),PM4,Moderate,"Use as is, regardless of the length of the in-frame insertion or deletion.",No change
-DYSF (HGNC:3097),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-DYSF (HGNC:3097),PM5,Strong,"Apply only for missense variants for which the amino acid change is the expected mechanism of disease. For the missense variant under curation and the variant(s) resulting in a different amino acid change, exclude potential splice effects (SpliceAI score ≤0.10 or experimental evidence of normal splicing) and confirm the applicability of PP3. Missense changes at the same residue must be classified according to LGMD VCEP specifications, and no benign missense variation should be present at the residue. Do not apply for missense variants encoded by the first or last 3 nucleotides of an exon unless a splice effect has been experimentally ruled out for the variant under curation and the variant(s) resulting in the same amino acid change. Apply at Strong for 2 pathogenic or 3 likely pathogenic variants resulting in different amino acid changes at the same residue as the variant under curation.
-
-
-PM5 can potentially be applied to multiple amino acid changes at the same residue as long as the variant classification that determines the strength level does not depend on PM5 application.","Disease-specific,Strength"
-DYSF (HGNC:3097),PM5,Moderate,"Apply only for missense variants for which the amino acid change is the expected mechanism of disease. For the missense variant under curation and the variant(s) resulting in a different amino acid change, exclude potential splice effects (SpliceAI score ≤0.10 or experimental evidence of normal splicing) and confirm the applicability of PP3. Missense changes at the same residue must be classified according to LGMD VCEP specifications, and no benign missense variation should be present at the residue. Do not apply for missense variants encoded by the first or last 3 nucleotides of an exon unless a splice effect has been experimentally ruled out for the variant under curation and the variant(s) resulting in the same amino acid change. Apply at Moderate for 1 pathogenic or 2 likely pathogenic variants resulting in different amino acid changes at the same residue as the variant under curation.
-
-
-PM5 can potentially be applied to multiple amino acid changes at the same residue as long as the variant classification that determines the strength level does not depend on PM5 application.",Disease-specific
-DYSF (HGNC:3097),PM5,Supporting,"Apply only for missense variants for which the amino acid change is the expected mechanism of disease. For the missense variant under curation and the variant(s) resulting in a different amino acid change, exclude potential splice effects (SpliceAI score ≤0.10 or experimental evidence of normal splicing) and confirm the applicability of PP3. Missense changes at the same residue must be classified according to LGMD VCEP specifications, and no benign missense variation should be present at the residue. Do not apply for missense variants encoded by the first or last 3 nucleotides of an exon unless a splice effect has been experimentally ruled out for the variant under curation and the variant resulting in the same amino acid change. Apply at Supporting for 1 likely pathogenic variant resulting in a different amino acid change at the same residue as the variant under curation.
-
-
-PM5 can potentially be applied to multiple amino acid changes at the same residue as long as the variant classification that determines the strength level does not depend on PM5 application.","Disease-specific,Strength"
-DYSF (HGNC:3097),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-DYSF (HGNC:3097),PM6,Strong,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PM6_Strong should be applied for ≥ 2 pts but < 4 pts.,"Disease-specific,General recommendation,Strength"
-DYSF (HGNC:3097),PM6,Moderate,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PM6 should be applied for ≥ 1 pt but < 2 pts.,"Disease-specific,General recommendation"
-DYSF (HGNC:3097),PM6,Supporting,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PM6_Supporting should be applied for ≥ 0.5 pts but < 1 pt.,"Disease-specific,General recommendation,Strength"
-DYSF (HGNC:3097),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-DYSF (HGNC:3097),PP1,Strong,"Segregations should be counted across families, with the total number of segregations determining the strength level. Apply PP1_Strong for 3 affected segregations (in addition to proband) across ≥2 families. When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate).","Disease-specific,Strength"
-DYSF (HGNC:3097),PP1,Moderate,"Segregations should be counted across families, with the total number of segregations determining the strength level. Apply PP1_Moderate for 2 affected segregations (in addition to proband; may be from a single family). When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate).","Disease-specific,Strength"
-DYSF (HGNC:3097),PP1,Supporting,"Segregations should be counted across families, with the total number of segregations determining the strength level. Apply PP1 (Supporting) for 1 affected segregation (in addition to proband). When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate).",Disease-specific
-DYSF (HGNC:3097),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-DYSF (HGNC:3097),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-DYSF (HGNC:3097),PP3,Supporting,"For missense variants, use REVEL with a score ≥0.7. 
-
-
-For variants that may affect splicing, use SpliceAI with a score ≥0.5.",Disease-specific
-DYSF (HGNC:3097),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-DYSF (HGNC:3097),PP4,Strong,"Use the PP4 table (see supplementary file “PP4 table DYSF”) to determine the appropriate PP4 strength level. Apply PP4 only once, for a patient meeting the highest possible strength level. When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate).","Disease-specific,Gene-specific,Strength"
-DYSF (HGNC:3097),PP4,Moderate,"Use the PP4 table (see supplementary file “PP4 table DYSF”) to determine the appropriate PP4 strength level. Apply PP4 only once, for a patient meeting the highest possible strength level. When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate). If PP1_Moderate is applied and the criteria for PP4_Strong are also met, a downgraded PP4_Moderate can be applied.","Disease-specific,Gene-specific,Strength"
-DYSF (HGNC:3097),PP4,Supporting,"Use the PP4 table (see supplementary file “PP4 table DYSF”) to determine the appropriate PP4 strength level. Apply PP4 only once, for a patient meeting the highest possible strength level. When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate). Apply PP4 only once, for a patient meeting the highest possible strength level.",Disease-specific
-DYSF (HGNC:3097),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-DYSF (HGNC:3097),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-DYSF (HGNC:3097),BA1,Stand Alone,"Apply if the variant Grpmax FAF (the lower bound of the 95% confidence interval of the maximum credible genetic ancestry group allele frequency) is >0.003. This value can be taken directly from gnomAD. See supplementary file “benign frequency exceptions” for a list of variants defined as exceptions to the benign frequency rules. Ongoing updates to this list will be available at the LGMD VCEP webpage: 
-https://clinicalgenome.org/affiliation/50061/.
- Variants whose frequency may not be reliable (e.g., variants that may reflect a sequencing artifact) should be critically evaluated and brought to the attention of the LGMD VCEP.",Disease-specific
-DYSF (HGNC:3097),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-DYSF (HGNC:3097),BS1,Strong,"Apply if the variant Grpmax FAF (the lower bound of the 95% confidence interval of the maximum credible genetic ancestry group allele frequency) is >0.001. This value can be taken directly from gnomAD. See supplementary file “benign frequency exceptions” for a list of variants defined as exceptions to the benign frequency rules. Ongoing updates to this list will be available at the LGMD VCEP webpage: 
-https://clinicalgenome.org/affiliation/50061/.
- Variants whose frequency may not be reliable (e.g., variants that may reflect a sequencing artifact) should be critically evaluated and brought to the attention of the LGMD VCEP.",Disease-specific
-DYSF (HGNC:3097),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",NA
-DYSF (HGNC:3097),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-DYSF (HGNC:3097),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-DYSF (HGNC:3097),BS4,Strong,"Use as is. One affected individual (genotype-, phenotype+) is sufficient for BS4. Do not apply for genotype+, phenotype- individuals, as LGMD is characterized by variable expressivity and late onset is not uncommon.",Clarification
-DYSF (HGNC:3097),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-DYSF (HGNC:3097),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-DYSF (HGNC:3097),BP2,Supporting,"Use when variant is found 
-in cis
- with a variant classified as pathogenic or likely pathogenic using the LGMD VCEP specifications.",Disease-specific
-DYSF (HGNC:3097),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-DYSF (HGNC:3097),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-DYSF (HGNC:3097),BP4,Supporting,"For missense variants, use REVEL with a score ≤0.1 AND SpliceAI with a score ≤0.05.
-
-
-For variants that may affect splicing, use SpliceAI with a score ≤0.05.
-
-
-Splice AI scores can be calculated here: 
-https://spliceailookup.broadinstitute.org/",Disease-specific
-DYSF (HGNC:3097),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-DYSF (HGNC:3097),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-DYSF (HGNC:3097),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-DYSF (HGNC:3097),BP7,Supporting,"For splice predictions, use SpliceAI with a score ≤0.05. BP7 may be co-applied with BP4 for synonymous, UTR, and intronic variants located outside the splice donor/acceptor regions designated in Walker et al. 2023 (+7/-21).",Disease-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSGCAVersion1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSGCAVersion1.0.0_version=1.0.0.csv
deleted file mode 100644
index 1669f6e02198ff73d39cd0d9b5867ab7493a279e..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSGCAVersion1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,209 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-SGCA (HGNC:10805),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-SGCA (HGNC:10805),PVS1,Very Strong,"Please see attached 
-SGCA
- PVS1 flowchart. In addition, follow the SVI Working Group’s recommendations (Walker et al. 2023; PMID: 37352859) for any variant for which an impact on splicing has been experimentally demonstrated OR is predicted to affect splicing but occurs outside of a donor/acceptor +/-1,2 dinucleotide position.","General recommendation,Gene-specific"
-SGCA (HGNC:10805),PVS1,Strong,"Please see attached 
-SGCA
- PVS1 flowchart. In addition, follow the SVI Working Group’s recommendations (Walker et al. 2023; PMID: 37352859) for any variant for which an impact on splicing has been experimentally demonstrated OR is predicted to affect splicing but occurs outside of a donor/acceptor +/-1,2 dinucleotide position.","General recommendation,Gene-specific,Strength"
-SGCA (HGNC:10805),PVS1,Moderate,"Please see attached 
-SGCA
- PVS1 flowchart. In addition, follow the SVI Working Group’s recommendations (Walker et al. 2023; PMID: 37352859) for any variant for which an impact on splicing has been experimentally demonstrated OR is predicted to affect splicing but occurs outside of a donor/acceptor +/-1,2 dinucleotide position.","General recommendation,Gene-specific,Strength"
-SGCA (HGNC:10805),PVS1,Supporting,"Please see attached 
-SGCA
- PVS1 flowchart. In addition, follow the SVI Working Group’s recommendations (Walker et al. 2023; PMID: 37352859) for any variant for which an impact on splicing has been experimentally demonstrated OR is predicted to affect splicing but occurs outside of a donor/acceptor +/-1,2 dinucleotide position.","General recommendation,Gene-specific,Strength"
-SGCA (HGNC:10805),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SGCA (HGNC:10805),PS1,Strong,"For missense variants for which the amino acid change is the expected mechanism of disease, apply at Strong for 1 pathogenic or 2 likely pathogenic variants resulting in the same amino acid change. The likely pathogenic or pathogenic variant(s) must have been classified using LGMD VCEP specifications, and potential splice effects must be excluded for the missense variant under curation and the variant(s) resulting in the same amino acid change (SpliceAI score ≤0.10 or experimental evidence of normal splicing). PS1 can potentially be applied to multiple nucleotide changes at the same residue as long as the variant classification that determines the strength level does not depend on PS1 application.
-
-
-For missense variants encoded by the first or last 3 nucleotides of an exon, PS1 should be considered only in the context of altered splicing (see below), unless a splice effect has been experimentally ruled out for the variant under curation and the variant(s) resulting in the same amino acid change. 
-
-
-For variants for which the nucleotide change is the expected mechanism of disease (altered splicing), follow SVI Working Group recommendations (Walker et al. 2023; PMID: 37352859).","Disease-specific,General recommendation"
-SGCA (HGNC:10805),PS1,Moderate,"For missense variants for which the amino acid change is the expected mechanism of disease, apply at Moderate for 1 likely pathogenic variant resulting in the same amino acid change. The likely pathogenic variant must have been classified using LGMD VCEP specifications, and potential splice effects must be excluded for the missense variant under curation and the variant resulting in the same amino acid change (SpliceAI score ≤0.10 or experimental evidence of normal splicing). PS1 can potentially be applied to multiple nucleotide changes at the same residue as long as the variant classification that determines the strength level does not depend on PS1 application.
-
-
-For missense variants encoded by the first or last 3 nucleotides of an exon, PS1 should be considered only in the context of altered splicing (see below), unless a splice effect has been experimentally ruled out for the variant under curation and the variant(s) resulting in the same amino acid change. 
-
-
-For variants for which the nucleotide change is the expected mechanism of disease (altered splicing), follow SVI Working Group recommendations (Walker et al. 2023; PMID: 37352859).","Disease-specific,General recommendation,Strength"
-SGCA (HGNC:10805),PS1,Supporting,"For variants for which the nucleotide change is the expected mechanism of disease (altered splicing), follow SVI Working Group recommendations (Walker et al. 2023; PMID: 37352859).","General recommendation,Strength"
-SGCA (HGNC:10805),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-SGCA (HGNC:10805),PS2,Very Strong,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. ≥ 4 pts is required to apply PS2 at Very Strong.,"Disease-specific,General recommendation,Strength"
-SGCA (HGNC:10805),PS2,Strong,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PS2 should be applied for ≥ 2 pts but < 4 pts.,"Disease-specific,General recommendation"
-SGCA (HGNC:10805),PS2,Moderate,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PS2_Moderate should be applied for ≥ 1 pt but < 2 pts.,"Disease-specific,General recommendation,Strength"
-SGCA (HGNC:10805),PS2,Supporting,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PS2_Supporting should be applied for ≥ 0.5 pts but < 1 pt.,"Disease-specific,General recommendation,Strength"
-SGCA (HGNC:10805),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-SGCA (HGNC:10805),PS3,Strong,"Variant-specific animal models are rare but may be assessed on a case-by-case basis and PS3 applied at a strength level that reflects how well the model recapitulates features observed in human patients. Apply PS3 at Strong for a variant-specific animal model that meets all of the following conditions, regardless of species: 
-
-
-
-
-signs of myopathy or dystrophy are present in skeletal muscle 
-
-
-an effect on gene or protein function is demonstrated (e.g., decreased protein expression, impaired membrane localization, or other functional abnormality)
-
-
-behavioral signs of muscle weakness
-
-
-progression over time
-
-
-
-
-For any variant type, experimental evidence for altered splicing should be scored under PVS1 in accordance with the decision tree for RNA splicing assay results outlined in Walker et al. 2023 (PMID: 37352859).
-
-
-Apply PS3 only once, for the piece of evidence that meets the highest possible strength level.","Disease-specific,General recommendation"
-SGCA (HGNC:10805),PS3,Moderate,"Variant-specific animal models are rare but may be assessed on a case-by-case basis and PS3 applied at a strength level that reflects how well the model recapitulates features observed in human patients. Apply PS3_Moderate for a variant-specific animal model that meets all of the following conditions, regardless of species: 
-
-
-
-
-signs of myopathy or dystrophy are present in skeletal muscle 
-
-
-an effect on gene or protein function is demonstrated (e.g., decreased protein expression, impaired membrane localization, or other functional abnormality)
-
-
-
-
-PS3_Moderate may be applied for sarcoglycan complex membrane localization assays that have been clinically validated with ≥11 control variants that meet criteria specified in Brnich et al. 2020 (PMID: 31892348) for the number of pathogenic and benign control variants. See supplementary file “PS3 assays_SGCA”.
-
-
-For any variant type, experimental evidence for altered splicing should be scored under PVS1 in accordance with the decision tree for RNA splicing assay results outlined in Walker et al. 2023 (PMID: 37352859).
-
-
-Apply PS3 only once, for the piece of evidence that meets the highest possible strength level.","Disease-specific,General recommendation,Strength"
-SGCA (HGNC:10805),PS3,Supporting,"PS3_Supporting may be applied if the variant is expressed in heterologous cell lines/model organisms and shows absent membrane localization of the sarcoglycan protein complex and fewer than 11 control variants were used, in accordance with Brnich et al. 2020 (PMID: 31892348). See supplementary file “PS3 assays_SGCA”.
-
-
-For any variant type, experimental evidence for altered splicing should be scored under PVS1 in accordance with the decision tree for RNA splicing assay results outlined in Walker et al. 2023 (PMID: 37352859).
-
-
-Apply PS3 only once, for the piece of evidence that meets the highest possible strength level.","Disease-specific,General recommendation,Gene-specific,Strength"
-SGCA (HGNC:10805),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-SGCA (HGNC:10805),PS4,Strong,"Use without disease-specific modification if case-control studies are available. 
-While case-control studies could potentially be considered for a few pathogenic variants with high minor allele frequency, the VCEP is unaware of any such studies being conducted for 
-SGCA
-. Any case-control study would require careful selection of an appropriate control population given the potential for late onset and mild disease.",Clarification
-SGCA (HGNC:10805),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-SGCA (HGNC:10805),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-SGCA (HGNC:10805),PM2,Supporting,"Apply if the Grpmax alternate allele frequency / upper bound of the 95% confidence interval (95% CI) of the Grpmax alternate allele frequency in gnomAD is <0.00009. 
-
-
-
-
-If only 1 or 2 alternate alleles are reported in the Grpmax population, apply if the Grpmax alternate allele frequency is <0.00009. 
-
-
-If at least 3 alternate alleles are reported in the Grpmax population, apply if the upper bound of the 95% CI of the Grpmax alternate allele frequency is <0.00009.
-
-
-
-
-Grpmax refers to the gnomAD subpopulation with the highest alternate allele frequency. Use large, non-bottlenecked genetic ancestry groups for the Grpmax; avoid using the Amish, Ashkenazi Jewish, European Finnish, Remaining, or Middle Eastern (genome).
-
-
-The upper bound of the 95% CI must be calculated using the exome or genome allele numbers and counts from gnomAD. Confidence interval tools, such as Confit-de-MAF (
-https://www.genecalculators.net/confit-de-maf.html
-), can be used.
-
-
-When comparing different versions of gnomAD for the variant frequency, use the allele count from the version with the largest allele number. 
-
-
-For larger deletions or duplications that may not be well represented in gnomAD (e.g., single- or multi-exon events), also confirm the variant is not common in gnomAD SVs, gnomAD CNVs, or the Database of Genomic Variants (DGV) (
-https://dgv.tcag.ca/dgv/app/home
-).","Disease-specific,Strength"
-SGCA (HGNC:10805),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-SGCA (HGNC:10805),PM3,Very Strong,Use the SVI Working Group’s recommended point system to determine PM3 strength (see supplementary file “PM3 table”). ≥ 4 pts is required to apply PM3 at Very Strong.,"Disease-specific,General recommendation,Strength"
-SGCA (HGNC:10805),PM3,Strong,Use the SVI Working Group’s recommended point system to determine PM3 strength (see supplementary file “PM3 table”). PM3_Strong should be applied for ≥ 2 pts but < 4 pts.,"Disease-specific,General recommendation,Strength"
-SGCA (HGNC:10805),PM3,Moderate,Use the SVI Working Group’s recommended point system to determine PM3 strength (see supplementary file “PM3 table”). PM3 (Moderate) should be applied for ≥ 1 pt but < 2 pts.,"Disease-specific,General recommendation"
-SGCA (HGNC:10805),PM3,Supporting,Use the SVI Working Group’s recommended point system to determine PM3 strength (see supplementary file “PM3 table”). PM3_Supporting should be applied for ≥ 0.5 pts but < 1 pt.,"Disease-specific,General recommendation,Strength"
-SGCA (HGNC:10805),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-SGCA (HGNC:10805),PM4,Moderate,"Use as is, regardless of the length of the in-frame insertion or deletion.",No change
-SGCA (HGNC:10805),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SGCA (HGNC:10805),PM5,Strong,"Apply only for missense variants for which the amino acid change is the expected mechanism of disease. For the missense variant under curation and the variant(s) resulting in a different amino acid change, exclude potential splice effects (SpliceAI score ≤0.10 or experimental evidence of normal splicing) and confirm the applicability of PP3. Missense changes at the same residue must be classified according to LGMD VCEP specifications, and no benign missense variation should be present at the residue. Do not apply for missense variants encoded by the first or last 3 nucleotides of an exon unless a splice effect has been experimentally ruled out for the variant under curation and the variant(s) resulting in the same amino acid change. Apply at Strong for 2 pathogenic or 3 likely pathogenic variants resulting in different amino acid changes at the same residue as the variant under curation.
-
-
-PM5 can potentially be applied to multiple amino acid changes at the same residue as long as the variant classification that determines the strength level does not depend on PM5 application.","Disease-specific,Strength"
-SGCA (HGNC:10805),PM5,Moderate,"Apply only for missense variants for which the amino acid change is the expected mechanism of disease. For the missense variant under curation and the variant(s) resulting in a different amino acid change, exclude potential splice effects (SpliceAI score ≤0.10 or experimental evidence of normal splicing) and confirm the applicability of PP3. Missense changes at the same residue must be classified according to LGMD VCEP specifications, and no benign missense variation should be present at the residue. Do not apply for missense variants encoded by the first or last 3 nucleotides of an exon unless a splice effect has been experimentally ruled out for the variant under curation and the variant(s) resulting in the same amino acid change. Apply at Moderate for 1 pathogenic or 2 likely pathogenic variants resulting in different amino acid changes at the same residue as the variant under curation.
-
-
-PM5 can potentially be applied to multiple amino acid changes at the same residue as long as the variant classification that determines the strength level does not depend on PM5 application.",Disease-specific
-SGCA (HGNC:10805),PM5,Supporting,"Apply only for missense variants for which the amino acid change is the expected mechanism of disease. For the missense variant under curation and the variant(s) resulting in a different amino acid change, exclude potential splice effects (SpliceAI score ≤0.10 or experimental evidence of normal splicing) and confirm the applicability of PP3. Missense changes at the same residue must be classified according to LGMD VCEP specifications, and no benign missense variation should be present at the residue. Do not apply for missense variants encoded by the first or last 3 nucleotides of an exon unless a splice effect has been experimentally ruled out for the variant under curation and the variant resulting in the same amino acid change. Apply at Supporting for 1 likely pathogenic variant resulting in a different amino acid change at the same residue as the variant under curation.
-
-
-PM5 can potentially be applied to multiple amino acid changes at the same residue as long as the variant classification that determines the strength level does not depend on PM5 application.","Disease-specific,Strength"
-SGCA (HGNC:10805),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-SGCA (HGNC:10805),PM6,Strong,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PM6_Strong should be applied for ≥ 2 pts but < 4 pts.,"Disease-specific,General recommendation,Strength"
-SGCA (HGNC:10805),PM6,Moderate,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PM6 should be applied for ≥ 1 pt but < 2 pts.,"Disease-specific,General recommendation"
-SGCA (HGNC:10805),PM6,Supporting,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PM6_Supporting should be applied for ≥ 0.5 pts but < 1 pt.,"Disease-specific,General recommendation,Strength"
-SGCA (HGNC:10805),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-SGCA (HGNC:10805),PP1,Strong,"Segregations should be counted across families, with the total number of segregations determining the strength level. Apply PP1_Strong for 3 affected segregations (in addition to proband) across ≥2 families. When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate).","Disease-specific,Strength"
-SGCA (HGNC:10805),PP1,Moderate,"Segregations should be counted across families, with the total number of segregations determining the strength level. Apply PP1_Moderate for 2 affected segregations (in addition to proband; may be from a single family). When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate).","Disease-specific,Strength"
-SGCA (HGNC:10805),PP1,Supporting,"Segregations should be counted across families, with the total number of segregations determining the strength level. Apply PP1 (Supporting) for 1 affected segregation (in addition to proband). When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate).",Disease-specific
-SGCA (HGNC:10805),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-SGCA (HGNC:10805),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-SGCA (HGNC:10805),PP3,Supporting,"For missense variants, use REVEL with a score ≥0.7. 
-
-
-For variants that may affect splicing, use SpliceAI with a score ≥0.5.",Disease-specific
-SGCA (HGNC:10805),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-SGCA (HGNC:10805),PP4,Strong,"Use the PP4 table (see supplementary file “PP4 table SGCA”) to determine the appropriate PP4 strength level. Apply PP4 only once, for a patient meeting the highest possible strength level. When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate).","Disease-specific,Gene-specific,Strength"
-SGCA (HGNC:10805),PP4,Moderate,"Use the PP4 table (see supplementary file “PP4 table SGCA”) to determine the appropriate PP4 strength level. Apply PP4 only once, for a patient meeting the highest possible strength level. When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate). If PP1_Moderate is applied and the criteria for PP4_Strong are also met, a downgraded PP4_Moderate can be applied.","Disease-specific,Gene-specific,Strength"
-SGCA (HGNC:10805),PP4,Supporting,"Use the PP4 table (see supplementary file “PP4 table SGCA”) to determine the appropriate PP4 strength level.  Apply PP4 only once, for a patient meeting the highest possible strength level. When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate).",Disease-specific
-SGCA (HGNC:10805),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SGCA (HGNC:10805),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-SGCA (HGNC:10805),BA1,Stand Alone,"Apply if the variant Grpmax FAF (the lower bound of the 95% confidence interval of the maximum credible genetic ancestry group allele frequency) is >0.002. This value can be taken directly from gnomAD. See supplementary file “benign frequency exceptions” for a list of variants defined as exceptions to the benign frequency rules. Ongoing updates to this list will be available at the LGMD VCEP webpage: 
-https://clinicalgenome.org/affiliation/50061/.
- Variants whose frequency may not be reliable (e.g., variants that may reflect a sequencing artifact) should be critically evaluated and brought to the attention of the LGMD VCEP.",Disease-specific
-SGCA (HGNC:10805),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-SGCA (HGNC:10805),BS1,Strong,"Apply if the variant Grpmax FAF (the lower bound of the 95% confidence interval of the maximum credible genetic ancestry group allele frequency) is >0.0009. This value can be taken directly from gnomAD. See supplementary file “benign frequency exceptions” for a list of variants defined as exceptions to the benign frequency rules. Ongoing updates to this list will be available at the LGMD VCEP webpage: 
-https://clinicalgenome.org/affiliation/50061/.
- Variants whose frequency may not be reliable (e.g., variants that may reflect a sequencing artifact) should be critically evaluated and brought to the attention of the LGMD VCEP.",Disease-specific
-SGCA (HGNC:10805),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",NA
-SGCA (HGNC:10805),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-SGCA (HGNC:10805),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-SGCA (HGNC:10805),BS4,Strong,"Use as is. One affected individual (genotype-, phenotype+) is sufficient for BS4. Do not apply for genotype+, phenotype- individuals, as LGMD is characterized by variable expressivity and late onset is not uncommon.",Clarification
-SGCA (HGNC:10805),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-SGCA (HGNC:10805),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-SGCA (HGNC:10805),BP2,Supporting,"Use when variant is found 
-in cis
- with a variant classified as pathogenic or likely pathogenic using the LGMD VCEP specifications.",Disease-specific
-SGCA (HGNC:10805),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-SGCA (HGNC:10805),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SGCA (HGNC:10805),BP4,Supporting,"For missense variants, use REVEL with a score ≤0.1 AND SpliceAI with a score ≤0.05.
-
-
-For variants that may affect splicing, use SpliceAI with a score ≤0.05.
-
-
-Splice AI scores can be calculated here: 
-https://spliceailookup.broadinstitute.org/",Disease-specific
-SGCA (HGNC:10805),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-SGCA (HGNC:10805),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SGCA (HGNC:10805),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-SGCA (HGNC:10805),BP7,Supporting,"For splice predictions, use SpliceAI with a score ≤0.05. BP7 may be co-applied with BP4 for synonymous, UTR, and intronic variants located outside the splice donor/acceptor regions designated in Walker et al. 2023 (+7/-21).",Disease-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSGCBVersion1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSGCBVersion1.0.0_version=1.0.0.csv
deleted file mode 100644
index 34bf6d67d7bea5c8149d0c26830317aa84dc8f40..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSGCBVersion1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,216 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-SGCB (HGNC:10806),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-SGCB (HGNC:10806),PVS1,Very Strong,"Please see attached 
-SGCB
- PVS1 flowchart. In addition, follow the SVI Working Group’s recommendations (Walker et al. 2023; PMID: 37352859) for any variant for which an impact on splicing has been experimentally demonstrated OR is predicted to affect splicing but occurs outside of a donor/acceptor +/-1,2 dinucleotide position.","General recommendation,Gene-specific"
-SGCB (HGNC:10806),PVS1,Strong,"Please see attached 
-SGCB
- PVS1 flowchart. In addition, follow the SVI Working Group’s recommendations (Walker et al. 2023; PMID: 37352859) for any variant for which an impact on splicing has been experimentally demonstrated OR is predicted to affect splicing but occurs outside of a donor/acceptor +/-1,2 dinucleotide position.","General recommendation,Gene-specific,Strength"
-SGCB (HGNC:10806),PVS1,Moderate,"Please see attached 
-SGCB
- PVS1 flowchart. In addition, follow the SVI Working Group’s recommendations (Walker et al. 2023; PMID: 37352859) for any variant for which an impact on splicing has been experimentally demonstrated OR is predicted to affect splicing but occurs outside of a donor/acceptor +/-1,2 dinucleotide position.","General recommendation,Gene-specific,Strength"
-SGCB (HGNC:10806),PVS1,Supporting,"Please see attached 
-SGCB
- PVS1 flowchart. In addition, follow the SVI Working Group’s recommendations (Walker et al. 2023; PMID: 37352859) for any variant for which an impact on splicing has been experimentally demonstrated OR is predicted to affect splicing but occurs outside of a donor/acceptor +/-1,2 dinucleotide position.","General recommendation,Gene-specific,Strength"
-SGCB (HGNC:10806),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SGCB (HGNC:10806),PS1,Strong,"For missense variants for which the amino acid change is the expected mechanism of disease, apply at Strong for 1 pathogenic or 2 likely pathogenic variants resulting in the same amino acid change. The likely pathogenic or pathogenic variant(s) must have been classified using LGMD VCEP specifications, and potential splice effects must be excluded for the missense variant under curation and the variant(s) resulting in the same amino acid change (SpliceAI score ≤0.10 or experimental evidence of normal splicing). PS1 can potentially be applied to multiple nucleotide changes at the same residue as long as the variant classification that determines the strength level does not depend on PS1 application.
-
-
-For missense variants encoded by the first or last 3 nucleotides of an exon, PS1 should be considered only in the context of altered splicing (see below), unless a splice effect has been experimentally ruled out for the variant under curation and the variant(s) resulting in the same amino acid change. 
-
-
-For variants for which the nucleotide change is the expected mechanism of disease (altered splicing), follow SVI Working Group recommendations (Walker et al. 2023; PMID: 37352859).","Disease-specific,General recommendation"
-SGCB (HGNC:10806),PS1,Moderate,"For missense variants for which the amino acid change is the expected mechanism of disease, apply at Moderate for 1 likely pathogenic variant resulting in the same amino acid change. The likely pathogenic variant must have been classified using LGMD VCEP specifications, and potential splice effects must be excluded for the missense variant under curation and the variant resulting in the same amino acid change (SpliceAI score ≤0.10 or experimental evidence of normal splicing). PS1 can potentially be applied to multiple nucleotide changes at the same residue as long as the variant classification that determines the strength level does not depend on PS1 application.
-
-
-For missense variants encoded by the first or last 3 nucleotides of an exon, PS1 should be considered only in the context of altered splicing (see below), unless a splice effect has been experimentally ruled out for the variant under curation and the variant(s) resulting in the same amino acid change. 
-
-
-For variants for which the nucleotide change is the expected mechanism of disease (altered splicing), follow SVI Working Group recommendations (Walker et al. 2023; PMID: 37352859).","Disease-specific,General recommendation,Strength"
-SGCB (HGNC:10806),PS1,Supporting,"For variants for which the nucleotide change is the expected mechanism of disease (altered splicing), follow SVI Working Group recommendations (Walker et al. 2023; PMID: 37352859).","General recommendation,Strength"
-SGCB (HGNC:10806),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-SGCB (HGNC:10806),PS2,Very Strong,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. ≥ 4 pts is required to apply PS2 at Very Strong.,"Disease-specific,General recommendation,Strength"
-SGCB (HGNC:10806),PS2,Strong,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PS2 should be applied for ≥ 2 pts but < 4 pts.,"Disease-specific,General recommendation"
-SGCB (HGNC:10806),PS2,Moderate,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PS2_Moderate should be applied for ≥ 1 pt but < 2 pts.,"Disease-specific,General recommendation,Strength"
-SGCB (HGNC:10806),PS2,Supporting,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PS2_Supporting should be applied for ≥ 0.5 pts but < 1 pt.,"Disease-specific,General recommendation,Strength"
-SGCB (HGNC:10806),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-SGCB (HGNC:10806),PS3,Strong,"Variant-specific animal models are rare but may be assessed on a case-by-case basis and PS3 applied at a strength level that reflects how well the model recapitulates features observed in human patients. Apply PS3 at Strong for a variant-specific animal model that meets all of the following conditions, regardless of species: 
-
-
-
-
-signs of myopathy or dystrophy are present in skeletal muscle 
-
-
-an effect on gene or protein function is demonstrated (e.g., decreased protein expression, impaired membrane localization, or other functional abnormality)
-
-
-behavioral signs of muscle weakness
-
-
-progression over time
-
-
-
-
-For any variant type, experimental evidence for altered splicing should be scored under PVS1 in accordance with the decision tree for RNA splicing assay results outlined in Walker et al. 2023 (PMID: 37352859).
-
-
-Apply PS3 only once, for the piece of evidence that meets the highest possible strength level.","Disease-specific,General recommendation"
-SGCB (HGNC:10806),PS3,Moderate,"Variant-specific animal models are rare but may be assessed on a case-by-case basis and PS3 applied at a strength level that reflects how well the model recapitulates features observed in human patients. Apply PS3_Moderate for a variant-specific animal model that meets all of the following conditions, regardless of species: 
-
-
-
-
-signs of myopathy or dystrophy are present in skeletal muscle 
-
-
-an effect on gene or protein function is demonstrated (e.g., decreased protein expression, impaired membrane localization, or other functional abnormality)
-
-
-
-
-PS3_Moderate may be applicable for sarcoglycan complex membrane localization assays that have been clinically validated with ≥11 control variants that meet criteria specified in Brnich et al. 2020 (PMID: 31892348) for the number of pathogenic and benign control variants. 
-
-
-
-
-Sarcoglycan complex cell surface localization functional score <-0.5 in Li et al. 2023 (PMID: 37317968). See supplementary file “PS3 assays_SGCB”.
-
-
-
-
-For any variant type, experimental evidence for altered splicing should be scored under PVS1 in accordance with the decision tree for RNA splicing assay results outlined in Walker et al. 2023 (PMID: 37352859).
-
-
-Apply PS3 only once, for the piece of evidence that meets the highest possible strength level.","Disease-specific,General recommendation,Gene-specific,Strength"
-SGCB (HGNC:10806),PS3,Supporting,"PS3_Supporting may be applied if the variant is expressed in heterologous cell lines/model organisms and shows absent membrane localization of the sarcoglycan protein complex and fewer than 11 control variants were used, in accordance with Brnich et al. 2020 (PMID: 31892348). See supplementary file “PS3 assays_SGCB”.
-
-
-For any variant type, experimental evidence for altered splicing should be scored under PVS1 in accordance with the decision tree for RNA splicing assay results outlined in Walker et al. 2023 (PMID: 37352859).
-
-
-Apply PS3 only once, for the piece of evidence that meets the highest possible strength level.","Disease-specific,General recommendation,Gene-specific,Strength"
-SGCB (HGNC:10806),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-SGCB (HGNC:10806),PS4,Strong,"Use without disease-specific modification if case-control studies are available. 
-While case-control studies could potentially be considered for a few pathogenic variants with high minor allele frequency, the VCEP is unaware of any such studies being conducted for 
-SGCB
-. Any case-control study would require careful selection of an appropriate control population given the potential for late onset and mild disease.",Clarification
-SGCB (HGNC:10806),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-SGCB (HGNC:10806),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-SGCB (HGNC:10806),PM2,Supporting,"Apply if the Grpmax alternate allele frequency / upper bound of the 95% confidence interval (95% CI) of the Grpmax alternate allele frequency in gnomAD is <0.00009. 
-
-
-
-
-If only 1 or 2 alternate alleles are reported in the Grpmax population, apply if the Grpmax alternate allele frequency is <0.00009. 
-
-
-If at least 3 alternate alleles are reported in the Grpmax population, apply if the upper bound of the 95% CI of the Grpmax alternate allele frequency is <0.00009.
-
-
-
-
-Grpmax refers to the gnomAD subpopulation with the highest alternate allele frequency. Use large, non-bottlenecked genetic ancestry groups for the Grpmax; avoid using the Amish, Ashkenazi Jewish, European Finnish, Remaining, or Middle Eastern (genome).
-
-
-The upper bound of the 95% CI must be calculated using the exome or genome allele numbers and counts from gnomAD. Confidence interval tools, such as Confit-de-MAF (
-https://www.genecalculators.net/confit-de-maf.html
-), can be used.
-
-
-When comparing different versions of gnomAD for the variant frequency, use the allele count from the version with the largest allele number. 
-
-
-For larger deletions or duplications that may not be well represented in gnomAD (e.g., single- or multi-exon events), also confirm the variant is not common in gnomAD SVs, gnomAD CNVs, or the Database of Genomic Variants (DGV) (
-https://dgv.tcag.ca/dgv/app/home
-).","Disease-specific,Strength"
-SGCB (HGNC:10806),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-SGCB (HGNC:10806),PM3,Very Strong,Use the SVI Working Group’s recommended point system to determine PM3 strength (see supplementary file “PM3 table”). ≥ 4 pts is required to apply PM3 at Very Strong.,"Disease-specific,General recommendation,Strength"
-SGCB (HGNC:10806),PM3,Strong,Use the SVI Working Group’s recommended point system to determine PM3 strength (see supplementary file “PM3 table”). PM3_Strong should be applied for ≥ 2 pts but < 4 pts.,"Disease-specific,General recommendation,Strength"
-SGCB (HGNC:10806),PM3,Moderate,Use the SVI Working Group’s recommended point system to determine PM3 strength (see supplementary file “PM3 table”). PM3 (Moderate) should be applied for ≥ 1 pt but < 2 pts.,"Disease-specific,General recommendation"
-SGCB (HGNC:10806),PM3,Supporting,Use the SVI Working Group’s recommended point system to determine PM3 strength (see supplementary file “PM3 table”). PM3_Supporting should be applied for ≥ 0.5 pts but < 1 pt.,"Disease-specific,General recommendation,Strength"
-SGCB (HGNC:10806),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-SGCB (HGNC:10806),PM4,Moderate,"Use as is, regardless of the length of the in-frame insertion or deletion.",No change
-SGCB (HGNC:10806),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SGCB (HGNC:10806),PM5,Strong,"Apply only for missense variants for which the amino acid change is the expected mechanism of disease. For the missense variant under curation and the variant(s) resulting in a different amino acid change, exclude potential splice effects (SpliceAI score ≤0.10 or experimental evidence of normal splicing) and confirm the applicability of PP3. Missense changes at the same residue must be classified according to LGMD VCEP specifications, and no benign missense variation should be present at the residue. Do not apply for missense variants encoded by the first or last 3 nucleotides of an exon unless a splice effect has been experimentally ruled out for the variant under curation and the variant(s) resulting in the same amino acid change. Apply at Strong for 2 pathogenic or 3 likely pathogenic variants resulting in different amino acid changes at the same residue as the variant under curation.
-
-
-PM5 can potentially be applied to multiple amino acid changes at the same residue as long as the variant classification that determines the strength level does not depend on PM5 application.","Disease-specific,Strength"
-SGCB (HGNC:10806),PM5,Moderate,"Apply only for missense variants for which the amino acid change is the expected mechanism of disease. For the missense variant under curation and the variant(s) resulting in a different amino acid change, exclude potential splice effects (SpliceAI score ≤0.10 or experimental evidence of normal splicing) and confirm the applicability of PP3. Missense changes at the same residue must be classified according to LGMD VCEP specifications, and no benign missense variation should be present at the residue. Do not apply for missense variants encoded by the first or last 3 nucleotides of an exon unless a splice effect has been experimentally ruled out for the variant under curation and the variant(s) resulting in the same amino acid change. Apply at Moderate for 1 pathogenic or 2 likely pathogenic variants resulting in different amino acid changes at the same residue as the variant under curation.
-
-
-PM5 can potentially be applied to multiple amino acid changes at the same residue as long as the variant classification that determines the strength level does not depend on PM5 application.",Disease-specific
-SGCB (HGNC:10806),PM5,Supporting,"Apply only for missense variants for which the amino acid change is the expected mechanism of disease. For the missense variant under curation and the variant(s) resulting in a different amino acid change, exclude potential splice effects (SpliceAI score ≤0.10 or experimental evidence of normal splicing) and confirm the applicability of PP3. Missense changes at the same residue must be classified according to LGMD VCEP specifications, and no benign missense variation should be present at the residue. Do not apply for missense variants encoded by the first or last 3 nucleotides of an exon unless a splice effect has been experimentally ruled out for the variant under curation and the variant resulting in the same amino acid change. Apply at Supporting for 1 likely pathogenic variant resulting in a different amino acid change at the same residue as the variant under curation.
-
-
-PM5 can potentially be applied to multiple amino acid changes at the same residue as long as the variant classification that determines the strength level does not depend on PM5 application.","Disease-specific,Strength"
-SGCB (HGNC:10806),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-SGCB (HGNC:10806),PM6,Strong,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PM6_Strong should be applied for ≥ 2 pts but < 4 pts.,"Disease-specific,General recommendation,Strength"
-SGCB (HGNC:10806),PM6,Moderate,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PM6 should be applied for ≥ 1 pt but < 2 pts.,"Disease-specific,General recommendation"
-SGCB (HGNC:10806),PM6,Supporting,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PM6_Supporting should be applied for ≥ 0.5 pts but < 1 pt.,"Disease-specific,General recommendation,Strength"
-SGCB (HGNC:10806),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-SGCB (HGNC:10806),PP1,Strong,"Segregations should be counted across families, with the total number of segregations determining the strength level. Apply PP1_Strong for 3 affected segregations (in addition to proband) across ≥2 families. When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate).","Disease-specific,Strength"
-SGCB (HGNC:10806),PP1,Moderate,"Segregations should be counted across families, with the total number of segregations determining the strength level. Apply PP1_Moderate for 2 affected segregations (in addition to proband; may be from a single family). When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate).","Disease-specific,Strength"
-SGCB (HGNC:10806),PP1,Supporting,"Segregations should be counted across families, with the total number of segregations determining the strength level. Apply PP1 (Supporting) for 1 affected segregation (in addition to proband). When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate).",Disease-specific
-SGCB (HGNC:10806),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-SGCB (HGNC:10806),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-SGCB (HGNC:10806),PP3,Supporting,"For missense variants, use REVEL with a score ≥0.7. 
-
-
-For variants that may affect splicing, use SpliceAI with a score ≥0.5.",Disease-specific
-SGCB (HGNC:10806),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-SGCB (HGNC:10806),PP4,Strong,"Use the PP4 table (see supplementary file “PP4 table SGCB”) to determine the appropriate PP4 strength level. Apply PP4 only once, for a patient meeting the highest possible strength level. When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate).","Disease-specific,Gene-specific,Strength"
-SGCB (HGNC:10806),PP4,Moderate,"Use the PP4 table (see supplementary file “PP4 table SGCB”) to determine the appropriate PP4 strength level. Apply PP4 only once, for a patient meeting the highest possible strength level. When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate). If PP1_Moderate is applied and the criteria for PP4_Strong are also met, a downgraded PP4_Moderate can be applied.","Disease-specific,Gene-specific,Strength"
-SGCB (HGNC:10806),PP4,Supporting,"Use the PP4 table (see supplementary file “PP4 table SGCB”) to determine the appropriate PP4 strength level. Apply PP4 only once, for a patient meeting the highest possible strength level. When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate).",Disease-specific
-SGCB (HGNC:10806),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SGCB (HGNC:10806),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-SGCB (HGNC:10806),BA1,Stand Alone,"Apply if the variant Grpmax FAF (the lower bound of the 95% confidence interval of the maximum credible genetic ancestry group allele frequency) is >0.002. This value can be taken directly from gnomAD. See supplementary file “benign frequency exceptions” for a list of variants defined as exceptions to the benign frequency rules. Ongoing updates to this list will be available at the LGMD VCEP webpage: 
-https://clinicalgenome.org/affiliation/50061/.
- Variants whose frequency may not be reliable (e.g., variants that may reflect a sequencing artifact) should be critically evaluated and brought to the attention of the LGMD VCEP.",Disease-specific
-SGCB (HGNC:10806),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-SGCB (HGNC:10806),BS1,Strong,"Apply if the variant Grpmax FAF (the lower bound of the 95% confidence interval of the maximum credible genetic ancestry group allele frequency) is >0.0009. This value can be taken directly from gnomAD. See supplementary file “benign frequency exceptions” for a list of variants defined as exceptions to the benign frequency rules. Ongoing updates to this list will be available at the LGMD VCEP webpage: 
-https://clinicalgenome.org/affiliation/50061/.
- Variants whose frequency may not be reliable (e.g., variants that may reflect a sequencing artifact) should be critically evaluated and brought to the attention of the LGMD VCEP.",Disease-specific
-SGCB (HGNC:10806),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",NA
-SGCB (HGNC:10806),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-SGCB (HGNC:10806),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-SGCB (HGNC:10806),BS4,Strong,"Use as is. One affected individual (genotype-, phenotype+) is sufficient for BS4. Do not apply for genotype+, phenotype- individuals, as LGMD is characterized by variable expressivity and late onset is not uncommon.",Clarification
-SGCB (HGNC:10806),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-SGCB (HGNC:10806),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-SGCB (HGNC:10806),BP2,Supporting,"Use when variant is found 
-in cis
- with a variant classified as pathogenic or likely pathogenic using the LGMD VCEP specifications.",Disease-specific
-SGCB (HGNC:10806),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-SGCB (HGNC:10806),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SGCB (HGNC:10806),BP4,Supporting,"For missense variants, use REVEL with a score ≤0.1 AND SpliceAI with a score ≤0.05.
-
-
-For variants that may affect splicing, use SpliceAI with a score ≤0.05.
-
-
-Splice AI scores can be calculated here: 
-https://spliceailookup.broadinstitute.org/",Disease-specific
-SGCB (HGNC:10806),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-SGCB (HGNC:10806),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SGCB (HGNC:10806),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-SGCB (HGNC:10806),BP7,Supporting,"For splice predictions, use SpliceAI with a score ≤0.05. BP7 may be co-applied with BP4 for synonymous, UTR, and intronic variants located outside the splice donor/acceptor regions designated in Walker et al. 2023 (+7/-21).",Disease-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSGCDVersion1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSGCDVersion1.0.0_version=1.0.0.csv
deleted file mode 100644
index dcc225631f716bbba0e0a263fa98821affc7d01e..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSGCDVersion1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,209 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-SGCD (HGNC:10807),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-SGCD (HGNC:10807),PVS1,Very Strong,"Please see attached 
-SGCD
- PVS1 flowchart. In addition, follow the SVI Working Group’s recommendations (Walker et al. 2023; PMID: 37352859) for any variant for which an impact on splicing has been experimentally demonstrated OR is predicted to affect splicing but occurs outside of a donor/acceptor +/-1,2 dinucleotide position.","General recommendation,Gene-specific"
-SGCD (HGNC:10807),PVS1,Strong,"Please see attached 
-SGCD
- PVS1 flowchart. In addition, follow the SVI Working Group’s recommendations (Walker et al. 2023; PMID: 37352859) for any variant for which an impact on splicing has been experimentally demonstrated OR is predicted to affect splicing but occurs outside of a donor/acceptor +/-1,2 dinucleotide position.","General recommendation,Gene-specific,Strength"
-SGCD (HGNC:10807),PVS1,Moderate,"Please see attached 
-SGCD
- PVS1 flowchart. In addition, follow the SVI Working Group’s recommendations (Walker et al. 2023; PMID: 37352859) for any variant for which an impact on splicing has been experimentally demonstrated OR is predicted to affect splicing but occurs outside of a donor/acceptor +/-1,2 dinucleotide position.","General recommendation,Gene-specific,Strength"
-SGCD (HGNC:10807),PVS1,Supporting,"Please see attached 
-SGCD
- PVS1 flowchart. In addition, follow the SVI Working Group’s recommendations (Walker et al. 2023; PMID: 37352859) for any variant for which an impact on splicing has been experimentally demonstrated OR is predicted to affect splicing but occurs outside of a donor/acceptor +/-1,2 dinucleotide position.","General recommendation,Gene-specific,Strength"
-SGCD (HGNC:10807),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SGCD (HGNC:10807),PS1,Strong,"For missense variants for which the amino acid change is the expected mechanism of disease, apply at Strong for 1 pathogenic or 2 likely pathogenic variants resulting in the same amino acid change. The likely pathogenic or pathogenic variant(s) must have been classified using LGMD VCEP specifications, and potential splice effects must be excluded for the missense variant under curation and the variant(s) resulting in the same amino acid change (SpliceAI score ≤0.10 or experimental evidence of normal splicing). PS1 can potentially be applied to multiple nucleotide changes at the same residue as long as the variant classification that determines the strength level does not depend on PS1 application.
-
-
-For missense variants encoded by the first or last 3 nucleotides of an exon, PS1 should be considered only in the context of altered splicing (see below), unless a splice effect has been experimentally ruled out for the variant under curation and the variant(s) resulting in the same amino acid change. 
-
-
-For variants for which the nucleotide change is the expected mechanism of disease (altered splicing), follow SVI Working Group recommendations (Walker et al. 2023; PMID: 37352859).","Disease-specific,General recommendation"
-SGCD (HGNC:10807),PS1,Moderate,"For missense variants for which the amino acid change is the expected mechanism of disease, apply at Moderate for 1 likely pathogenic variant resulting in the same amino acid change. The likely pathogenic variant must have been classified using LGMD VCEP specifications, and potential splice effects must be excluded for the missense variant under curation and the variant resulting in the same amino acid change (SpliceAI score ≤0.10 or experimental evidence of normal splicing). PS1 can potentially be applied to multiple nucleotide changes at the same residue as long as the variant classification that determines the strength level does not depend on PS1 application.
-
-
-For missense variants encoded by the first or last 3 nucleotides of an exon, PS1 should be considered only in the context of altered splicing (see below), unless a splice effect has been experimentally ruled out for the variant under curation and the variant(s) resulting in the same amino acid change. 
-
-
-For variants for which the nucleotide change is the expected mechanism of disease (altered splicing), follow SVI Working Group recommendations (Walker et al. 2023; PMID: 37352859).","Disease-specific,General recommendation,Strength"
-SGCD (HGNC:10807),PS1,Supporting,"For variants for which the nucleotide change is the expected mechanism of disease (altered splicing), follow SVI Working Group recommendations (Walker et al. 2023; PMID: 37352859).","General recommendation,Strength"
-SGCD (HGNC:10807),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-SGCD (HGNC:10807),PS2,Very Strong,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for at least PP4_Moderate or PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. ≥ 4 pts is required to apply PS2 at Very Strong.,"Disease-specific,General recommendation,Strength"
-SGCD (HGNC:10807),PS2,Strong,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for at least PP4_Moderate or PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PS2 should be applied for ≥ 2 pts but < 4 pts.,"Disease-specific,General recommendation"
-SGCD (HGNC:10807),PS2,Moderate,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for at least PP4_Moderate or PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PS2_Moderate should be applied for ≥ 1 pt but < 2 pts.,"Disease-specific,General recommendation,Strength"
-SGCD (HGNC:10807),PS2,Supporting,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for at least PP4_Moderate or PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PS2_Supporting should be applied for ≥ 0.5 pts but < 1 pt.,"Disease-specific,General recommendation,Strength"
-SGCD (HGNC:10807),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-SGCD (HGNC:10807),PS3,Strong,"Variant-specific animal models are rare but may be assessed on a case-by-case basis and PS3 applied at a strength level that reflects how well the model recapitulates features observed in human patients. Apply PS3 at Strong for a variant-specific animal model that meets all of the following conditions, regardless of species: 
-
-
-
-
-signs of myopathy or dystrophy are present in skeletal muscle 
-
-
-an effect on gene or protein function is demonstrated (e.g., decreased protein expression, impaired membrane localization, or other functional abnormality)
-
-
-behavioral signs of muscle weakness
-
-
-progression over time
-
-
-
-
-For any variant type, experimental evidence for altered splicing should be scored under PVS1 in accordance with the decision tree for RNA splicing assay results outlined in Walker et al. 2023 (PMID: 37352859).
-
-
-Apply PS3 only once, for the piece of evidence that meets the highest possible strength level.","Disease-specific,General recommendation"
-SGCD (HGNC:10807),PS3,Moderate,"Variant-specific animal models are rare but may be assessed on a case-by-case basis and PS3 applied at a strength level that reflects how well the model recapitulates features observed in human patients. Apply PS3_Moderate for a variant-specific animal model that meets all of the following conditions, regardless of species: 
-
-
-
-
-signs of myopathy or dystrophy are present in skeletal muscle 
-
-
-an effect on gene or protein function is demonstrated (e.g., decreased protein expression, impaired membrane localization, or other functional abnormality)
-
-
-
-
-PS3_Moderate may be applied for sarcoglycan complex membrane localization assays that have been clinically validated with ≥11 control variants that meet criteria specified in Brnich et al. 2020 (PMID: 31892348) for the number of pathogenic and benign control variants. See supplementary file “PS3 assays_SGCD”.
-
-
-For any variant type, experimental evidence for altered splicing should be scored under PVS1 in accordance with the decision tree for RNA splicing assay results outlined in Walker et al. 2023 (PMID: 37352859).
-
-
-Apply PS3 only once, for the piece of evidence that meets the highest possible strength level.","Disease-specific,General recommendation,Strength"
-SGCD (HGNC:10807),PS3,Supporting,"PS3_Supporting may be applied if the variant is expressed in heterologous cell lines/model organisms and shows absent membrane localization of the sarcoglycan protein complex and fewer than 11 control variants were used, in accordance with Brnich et al. 2020 (PMID: 31892348). See supplementary file “PS3 assays_SGCD”.
-
-
-For any variant type, experimental evidence for altered splicing should be scored under PVS1 in accordance with the decision tree for RNA splicing assay results outlined in Walker et al. 2023 (PMID: 37352859).
-
-
-Apply PS3 only once, for the piece of evidence that meets the highest possible strength level.","Disease-specific,General recommendation,Gene-specific,Strength"
-SGCD (HGNC:10807),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-SGCD (HGNC:10807),PS4,Strong,"Use without disease-specific modification if case-control studies are available. 
-While case-control studies could potentially be considered for a few pathogenic variants with high minor allele frequency, the VCEP is unaware of any such studies being conducted for 
-SGCD
-. Any case-control study would require careful selection of an appropriate control population given the potential for late onset and mild disease.",Clarification
-SGCD (HGNC:10807),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-SGCD (HGNC:10807),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-SGCD (HGNC:10807),PM2,Supporting,"Apply if the Grpmax alternate allele frequency / upper bound of the 95% confidence interval (95% CI) of the Grpmax alternate allele frequency in gnomAD is <0.00009. 
-
-
-
-
-If only 1 or 2 alternate alleles are reported in the Grpmax population, apply if the Grpmax alternate allele frequency is <0.00009. 
-
-
-If at least 3 alternate alleles are reported in the Grpmax population, apply if the upper bound of the 95% CI of the Grpmax alternate allele frequency is <0.00009.
-
-
-
-
-Grpmax refers to the gnomAD subpopulation with the highest alternate allele frequency. Use large, non-bottlenecked genetic ancestry groups for the Grpmax; avoid using the Amish, Ashkenazi Jewish, European Finnish, Remaining, or Middle Eastern (genome).
-
-
-The upper bound of the 95% CI must be calculated using the exome or genome allele numbers and counts from gnomAD. Confidence interval tools, such as Confit-de-MAF (
-https://www.genecalculators.net/confit-de-maf.html
-), can be used.
-
-
-When comparing different versions of gnomAD for the variant frequency, use the allele count from the version with the largest allele number. 
-
-
-For larger deletions or duplications that may not be well represented in gnomAD (e.g., single- or multi-exon events), also confirm the variant is not common in gnomAD SVs, gnomAD CNVs, or the Database of Genomic Variants (DGV) (
-https://dgv.tcag.ca/dgv/app/home
-).","Disease-specific,Strength"
-SGCD (HGNC:10807),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-SGCD (HGNC:10807),PM3,Very Strong,Use the SVI Working Group’s recommended point system to determine PM3 strength (see supplementary file “PM3 table”). ≥ 4 pts is required to apply PM3 at Very Strong.,"Disease-specific,General recommendation,Strength"
-SGCD (HGNC:10807),PM3,Strong,Use the SVI Working Group’s recommended point system to determine PM3 strength (see supplementary file “PM3 table”). PM3_Strong should be applied for ≥ 2 pts but < 4 pts.,"Disease-specific,General recommendation,Strength"
-SGCD (HGNC:10807),PM3,Moderate,Use the SVI Working Group’s recommended point system to determine PM3 strength (see supplementary file “PM3 table”). PM3 (Moderate) should be applied for ≥ 1 pt but < 2 pts.,"Disease-specific,General recommendation"
-SGCD (HGNC:10807),PM3,Supporting,Use the SVI Working Group’s recommended point system to determine PM3 strength (see supplementary file “PM3 table”). PM3_Supporting should be applied for ≥ 0.5 pts but < 1 pt.,"Disease-specific,General recommendation,Strength"
-SGCD (HGNC:10807),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-SGCD (HGNC:10807),PM4,Moderate,"Use as is, regardless of the length of the in-frame insertion or deletion.",No change
-SGCD (HGNC:10807),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SGCD (HGNC:10807),PM5,Strong,"Apply only for missense variants for which the amino acid change is the expected mechanism of disease. For the missense variant under curation and the variant(s) resulting in a different amino acid change, exclude potential splice effects (SpliceAI score ≤0.10 or experimental evidence of normal splicing) and confirm the applicability of PP3. Missense changes at the same residue must be classified according to LGMD VCEP specifications, and no benign missense variation should be present at the residue. Do not apply for missense variants encoded by the first or last 3 nucleotides of an exon unless a splice effect has been experimentally ruled out for the variant under curation and the variant(s) resulting in the same amino acid change. Apply at Strong for 2 pathogenic or 3 likely pathogenic variants resulting in different amino acid changes at the same residue as the variant under curation.
-
-
-PM5 can potentially be applied to multiple amino acid changes at the same residue as long as the variant classification that determines the strength level does not depend on PM5 application.","Disease-specific,Strength"
-SGCD (HGNC:10807),PM5,Moderate,"Apply only for missense variants for which the amino acid change is the expected mechanism of disease. For the missense variant under curation and the variant(s) resulting in a different amino acid change, exclude potential splice effects (SpliceAI score ≤0.10 or experimental evidence of normal splicing) and confirm the applicability of PP3. Missense changes at the same residue must be classified according to LGMD VCEP specifications, and no benign missense variation should be present at the residue. Do not apply for missense variants encoded by the first or last 3 nucleotides of an exon unless a splice effect has been experimentally ruled out for the variant under curation and the variant(s) resulting in the same amino acid change. Apply at Moderate for 1 pathogenic or 2 likely pathogenic variants resulting in different amino acid changes at the same residue as the variant under curation.
-
-
-PM5 can potentially be applied to multiple amino acid changes at the same residue as long as the variant classification that determines the strength level does not depend on PM5 application.",Disease-specific
-SGCD (HGNC:10807),PM5,Supporting,"Apply only for missense variants for which the amino acid change is the expected mechanism of disease. For the missense variant under curation and the variant(s) resulting in a different amino acid change, exclude potential splice effects (SpliceAI score ≤0.10 or experimental evidence of normal splicing) and confirm the applicability of PP3. Missense changes at the same residue must be classified according to LGMD VCEP specifications, and no benign missense variation should be present at the residue. Do not apply for missense variants encoded by the first or last 3 nucleotides of an exon unless a splice effect has been experimentally ruled out for the variant under curation and the variant resulting in the same amino acid change. Apply at Supporting for 1 likely pathogenic variant resulting in a different amino acid change at the same residue as the variant under curation.
-
-
-PM5 can potentially be applied to multiple amino acid changes at the same residue as long as the variant classification that determines the strength level does not depend on PM5 application.","Disease-specific,Strength"
-SGCD (HGNC:10807),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-SGCD (HGNC:10807),PM6,Strong,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for at least PP4_Moderate or PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PM6_Strong should be applied for ≥ 2 pts but < 4 pts.,"Disease-specific,General recommendation,Strength"
-SGCD (HGNC:10807),PM6,Moderate,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for at least PP4_Moderate or PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PM6 should be applied for ≥ 1 pt but < 2 pts.,"Disease-specific,General recommendation"
-SGCD (HGNC:10807),PM6,Supporting,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for at least PP4_Moderate or PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PM6_Supporting should be applied for ≥ 0.5 pts but < 1 pt.,"Disease-specific,General recommendation,Strength"
-SGCD (HGNC:10807),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-SGCD (HGNC:10807),PP1,Strong,"Segregations should be counted across families, with the total number of segregations determining the strength level. Apply PP1_Strong for 3 affected segregations (in addition to proband) across ≥2 families. When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate).","Disease-specific,Strength"
-SGCD (HGNC:10807),PP1,Moderate,"Segregations should be counted across families, with the total number of segregations determining the strength level. Apply PP1_Moderate for 2 affected segregations (in addition to proband; may be from a single family). When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate).","Disease-specific,Strength"
-SGCD (HGNC:10807),PP1,Supporting,"Segregations should be counted across families, with the total number of segregations determining the strength level. Apply PP1 (Supporting) for 1 affected segregation (in addition to proband). When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate).",Disease-specific
-SGCD (HGNC:10807),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-SGCD (HGNC:10807),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-SGCD (HGNC:10807),PP3,Supporting,"For missense variants, use REVEL with a score ≥0.7. 
-
-
-For variants that may affect splicing, use SpliceAI with a score ≥0.5.",Disease-specific
-SGCD (HGNC:10807),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-SGCD (HGNC:10807),PP4,Strong,"Use the PP4 table (see supplementary file “PP4 table SGCD”) to determine the appropriate PP4 strength level. Apply PP4 only once, for a patient meeting the highest possible strength level. When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate).","Disease-specific,Gene-specific,Strength"
-SGCD (HGNC:10807),PP4,Moderate,"Use the PP4 table (see supplementary file “PP4 table SGCD”) to determine the appropriate PP4 strength level. Apply PP4 only once, for a patient meeting the highest possible strength level. When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate). If PP1_Moderate is applied and the criteria for PP4_Strong are also met, a downgraded PP4_Moderate can be applied.","Disease-specific,Gene-specific,Strength"
-SGCD (HGNC:10807),PP4,Supporting,"Use the PP4 table (see supplementary file “PP4 table SGCD”) to determine the appropriate PP4 strength level. Apply PP4 only once, for a patient meeting the highest possible strength level. When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate).",Disease-specific
-SGCD (HGNC:10807),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SGCD (HGNC:10807),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-SGCD (HGNC:10807),BA1,Stand Alone,"Apply if the variant Grpmax FAF (the lower bound of the 95% confidence interval of the maximum credible genetic ancestry group allele frequency) is >0.002. This value can be taken directly from gnomAD. See supplementary file “benign frequency exceptions” for a list of variants defined as exceptions to the benign frequency rules. Ongoing updates to this list will be available at the LGMD VCEP webpage: 
-https://clinicalgenome.org/affiliation/50061/.
- Variants whose frequency may not be reliable (e.g., variants that may reflect a sequencing artifact) should be critically evaluated and brought to the attention of the LGMD VCEP.",Disease-specific
-SGCD (HGNC:10807),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-SGCD (HGNC:10807),BS1,Strong,"Apply if the variant Grpmax FAF (the lower bound of the 95% confidence interval of the maximum credible genetic ancestry group allele frequency) is >0.0009. This value can be taken directly from gnomAD. See supplementary file “benign frequency exceptions” for a list of variants defined as exceptions to the benign frequency rules. Ongoing updates to this list will be available at the LGMD VCEP webpage: 
-https://clinicalgenome.org/affiliation/50061/.
- Variants whose frequency may not be reliable (e.g., variants that may reflect a sequencing artifact) should be critically evaluated and brought to the attention of the LGMD VCEP.",Disease-specific
-SGCD (HGNC:10807),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",NA
-SGCD (HGNC:10807),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-SGCD (HGNC:10807),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-SGCD (HGNC:10807),BS4,Strong,"Use as is. One affected individual (genotype-, phenotype+) is sufficient for BS4. Do not apply for genotype+, phenotype- individuals, as LGMD is characterized by variable expressivity and late onset is not uncommon.",Clarification
-SGCD (HGNC:10807),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-SGCD (HGNC:10807),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-SGCD (HGNC:10807),BP2,Supporting,"Use when variant is found 
-in cis
- with a variant classified as pathogenic or likely pathogenic using the LGMD VCEP specifications.",Disease-specific
-SGCD (HGNC:10807),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-SGCD (HGNC:10807),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SGCD (HGNC:10807),BP4,Supporting,"For missense variants, use REVEL with a score ≤0.1 AND SpliceAI with a score ≤0.05.
-
-
-For variants that may affect splicing, use SpliceAI with a score ≤0.05.
-
-
-Splice AI scores can be calculated here: 
-https://spliceailookup.broadinstitute.org/",Disease-specific
-SGCD (HGNC:10807),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-SGCD (HGNC:10807),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SGCD (HGNC:10807),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-SGCD (HGNC:10807),BP7,Supporting,"For splice predictions, use SpliceAI with a score ≤0.05. BP7 may be co-applied with BP4 for synonymous, UTR, and intronic variants located outside the splice donor/acceptor regions designated in Walker et al. 2023 (+7/-21).",Disease-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSGCGVersion1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSGCGVersion1.0.0_version=1.0.0.csv
deleted file mode 100644
index df4774ef8407abfec752df09b1f1fb7789cc9f02..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSGCGVersion1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,209 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-SGCG (HGNC:10809),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-SGCG (HGNC:10809),PVS1,Very Strong,"Please see attached 
-SGCG
- PVS1 flowchart. In addition, follow the SVI Working Group’s recommendations (Walker et al. 2023; PMID: 37352859) for any variant for which an impact on splicing has been experimentally demonstrated OR is predicted to affect splicing but occurs outside of a donor/acceptor +/-1,2 dinucleotide position.","General recommendation,Gene-specific"
-SGCG (HGNC:10809),PVS1,Strong,"Please see attached 
-SGCG
- PVS1 flowchart. In addition, follow the SVI Working Group’s recommendations (Walker et al. 2023; PMID: 37352859) for any variant for which an impact on splicing has been experimentally demonstrated OR is predicted to affect splicing but occurs outside of a donor/acceptor +/-1,2 dinucleotide position.","General recommendation,Gene-specific,Strength"
-SGCG (HGNC:10809),PVS1,Moderate,"Please see attached 
-SGCG
- PVS1 flowchart. In addition, follow the SVI Working Group’s recommendations (Walker et al. 2023; PMID: 37352859) for any variant for which an impact on splicing has been experimentally demonstrated OR is predicted to affect splicing but occurs outside of a donor/acceptor +/-1,2 dinucleotide position.","General recommendation,Gene-specific,Strength"
-SGCG (HGNC:10809),PVS1,Supporting,"Please see attached 
-SGCG
- PVS1 flowchart. In addition, follow the SVI Working Group’s recommendations (Walker et al. 2023; PMID: 37352859) for any variant for which an impact on splicing has been experimentally demonstrated OR is predicted to affect splicing but occurs outside of a donor/acceptor +/-1,2 dinucleotide position.","General recommendation,Gene-specific,Strength"
-SGCG (HGNC:10809),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SGCG (HGNC:10809),PS1,Strong,"For missense variants for which the amino acid change is the expected mechanism of disease, apply at Strong for 1 pathogenic or 2 likely pathogenic variants resulting in the same amino acid change. The likely pathogenic or pathogenic variant(s) must have been classified using LGMD VCEP specifications, and potential splice effects must be excluded for the missense variant under curation and the variant(s) resulting in the same amino acid change (SpliceAI score ≤0.10 or experimental evidence of normal splicing). PS1 can potentially be applied to multiple nucleotide changes at the same residue as long as the variant classification that determines the strength level does not depend on PS1 application.
-
-
-For missense variants encoded by the first or last 3 nucleotides of an exon, PS1 should be considered only in the context of altered splicing (see below), unless a splice effect has been experimentally ruled out for the variant under curation and the variant(s) resulting in the same amino acid change. 
-
-
-For variants for which the nucleotide change is the expected mechanism of disease (altered splicing), follow SVI Working Group recommendations (Walker et al. 2023; PMID: 37352859).","Disease-specific,General recommendation"
-SGCG (HGNC:10809),PS1,Moderate,"For missense variants for which the amino acid change is the expected mechanism of disease, apply at Moderate for 1 likely pathogenic variant resulting in the same amino acid change. The likely pathogenic variant must have been classified using LGMD VCEP specifications, and potential splice effects must be excluded for the missense variant under curation and the variant resulting in the same amino acid change (SpliceAI score ≤0.10 or experimental evidence of normal splicing). PS1 can potentially be applied to multiple nucleotide changes at the same residue as long as the variant classification that determines the strength level does not depend on PS1 application.
-
-
-For missense variants encoded by the first or last 3 nucleotides of an exon, PS1 should be considered only in the context of altered splicing (see below), unless a splice effect has been experimentally ruled out for the variant under curation and the variant(s) resulting in the same amino acid change. 
-
-
-For variants for which the nucleotide change is the expected mechanism of disease (altered splicing), follow SVI Working Group recommendations (Walker et al. 2023; PMID: 37352859).","Disease-specific,General recommendation,Strength"
-SGCG (HGNC:10809),PS1,Supporting,"For variants for which the nucleotide change is the expected mechanism of disease (altered splicing), follow SVI Working Group recommendations (Walker et al. 2023; PMID: 37352859).","General recommendation,Strength"
-SGCG (HGNC:10809),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-SGCG (HGNC:10809),PS2,Very Strong,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. ≥ 4 pts is required to apply PS2 at Very Strong.,"Disease-specific,General recommendation,Strength"
-SGCG (HGNC:10809),PS2,Strong,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PS2 should be applied for ≥ 2 pts but < 4 pts.,"Disease-specific,General recommendation"
-SGCG (HGNC:10809),PS2,Moderate,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PS2_Moderate should be applied for ≥ 1 pt but < 2 pts.,"Disease-specific,General recommendation,Strength"
-SGCG (HGNC:10809),PS2,Supporting,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PS2_Supporting should be applied for ≥ 0.5 pts but < 1 pt.,"Disease-specific,General recommendation,Strength"
-SGCG (HGNC:10809),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-SGCG (HGNC:10809),PS3,Strong,"Variant-specific animal models are rare but may be assessed on a case-by-case basis and PS3 applied at a strength level that reflects how well the model recapitulates features observed in human patients. Apply PS3 at Strong for a variant-specific animal model that meets all of the following conditions, regardless of species: 
-
-
-
-
-signs of myopathy or dystrophy are present in skeletal muscle 
-
-
-an effect on gene or protein function is demonstrated (e.g., decreased protein expression, impaired membrane localization, or other functional abnormality)
-
-
-behavioral signs of muscle weakness
-
-
-progression over time
-
-
-
-
-For any variant type, experimental evidence for altered splicing should be scored under PVS1 in accordance with the decision tree for RNA splicing assay results outlined in Walker et al. 2023 (PMID: 37352859).
-
-
-Apply PS3 only once, for the piece of evidence that meets the highest possible strength level.","Disease-specific,General recommendation"
-SGCG (HGNC:10809),PS3,Moderate,"Variant-specific animal models are rare but may be assessed on a case-by-case basis and PS3 applied at a strength level that reflects how well the model recapitulates features observed in human patients. Apply PS3_Moderate for a variant-specific animal model that meets all of the following conditions, regardless of species: 
-
-
-
-
-signs of myopathy or dystrophy are present in skeletal muscle 
-
-
-an effect on gene or protein function is demonstrated (e.g., decreased protein expression, impaired membrane localization, or other functional abnormality)
-
-
-
-
-PS3_Moderate may be applied for sarcoglycan complex membrane localization assays that have been clinically validated with ≥11 control variants that meet criteria specified in Brnich et al. 2020 (PMID: 31892348) for the number of pathogenic and benign control variants. See supplementary file “PS3 assays_SGCG”.
-
-
-For any variant type, experimental evidence for altered splicing should be scored under PVS1 in accordance with the decision tree for RNA splicing assay results outlined in Walker et al. 2023 (PMID: 37352859).
-
-
-Apply PS3 only once, for the piece of evidence that meets the highest possible strength level.","Disease-specific,General recommendation,Strength"
-SGCG (HGNC:10809),PS3,Supporting,"PS3_Supporting may be applied if the variant is expressed in heterologous cell lines/model organisms and shows absent membrane localization of the sarcoglycan protein complex and fewer than 11 control variants were used, in accordance with Brnich et al. 2020 (PMID: 31892348). See supplementary file “PS3 assays_SGCG”.
-
-
-For any variant type, experimental evidence for altered splicing should be scored under PVS1 in accordance with the decision tree for RNA splicing assay results outlined in Walker et al. 2023 (PMID: 37352859).
-
-
-Apply PS3 only once, for the piece of evidence that meets the highest possible strength level.","Disease-specific,General recommendation,Gene-specific,Strength"
-SGCG (HGNC:10809),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-SGCG (HGNC:10809),PS4,Strong,"Use without disease-specific modification if case-control studies are available. 
-While case-control studies could potentially be considered for a few pathogenic variants with high minor allele frequency, the VCEP is unaware of any such studies being conducted for 
-SGCG
-. Any case-control study would require careful selection of an appropriate control population given the potential for late onset and mild disease.",Clarification
-SGCG (HGNC:10809),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-SGCG (HGNC:10809),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-SGCG (HGNC:10809),PM2,Supporting,"Apply if the Grpmax alternate allele frequency / upper bound of the 95% confidence interval (95% CI) of the Grpmax alternate allele frequency in gnomAD is <0.00009. 
-
-
-
-
-If only 1 or 2 alternate alleles are reported in the Grpmax population, apply if the Grpmax alternate allele frequency is <0.00009.
-
-
-If at least 3 alternate alleles are reported in the Grpmax population, apply if the upper bound of the 95% CI of the Grpmax alternate allele frequency is <0.00009.
-
-
-
-
-Grpmax refers to the gnomAD subpopulation with the highest alternate allele frequency. Use large, non-bottlenecked genetic ancestry groups for the Grpmax; avoid using the Amish, Ashkenazi Jewish, European Finnish, Remaining, or Middle Eastern (genome).
-
-
-The upper bound of the 95% CI must be calculated using the exome or genome allele numbers and counts from gnomAD. Confidence interval tools, such as Confit-de-MAF (
-https://www.genecalculators.net/confit-de-maf.html
-), can be used.
-
-
-When comparing different versions of gnomAD for the variant frequency, use the allele count from the version with the largest allele number. 
-
-
-For larger deletions or duplications that may not be well represented in gnomAD (e.g., single- or multi-exon events), also confirm the variant is not common in gnomAD SVs, gnomAD CNVs, or the Database of Genomic Variants (DGV) (
-https://dgv.tcag.ca/dgv/app/home
-).","Disease-specific,Strength"
-SGCG (HGNC:10809),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-SGCG (HGNC:10809),PM3,Very Strong,Use the SVI Working Group’s recommended point system to determine PM3 strength (see supplementary file “PM3 table”). ≥ 4 pts is required to apply PM3 at Very Strong.,"Disease-specific,General recommendation,Strength"
-SGCG (HGNC:10809),PM3,Strong,Use the SVI Working Group’s recommended point system to determine PM3 strength (see supplementary file “PM3 table”). PM3_Strong should be applied for ≥ 2 pts but < 4 pts.,"Disease-specific,General recommendation,Strength"
-SGCG (HGNC:10809),PM3,Moderate,Use the SVI Working Group’s recommended point system to determine PM3 strength (see supplementary file “PM3 table”). PM3 (Moderate) should be applied for ≥ 1 pt but < 2 pts.,"Disease-specific,General recommendation"
-SGCG (HGNC:10809),PM3,Supporting,Use the SVI Working Group’s recommended point system to determine PM3 strength (see supplementary file “PM3 table”). PM3_Supporting should be applied for ≥ 0.5 pts but < 1 pt.,"Disease-specific,General recommendation,Strength"
-SGCG (HGNC:10809),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-SGCG (HGNC:10809),PM4,Moderate,"Use as is, regardless of the length of the in-frame insertion or deletion.",No change
-SGCG (HGNC:10809),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SGCG (HGNC:10809),PM5,Strong,"Apply only for missense variants for which the amino acid change is the expected mechanism of disease. For the missense variant under curation and the variant(s) resulting in a different amino acid change, exclude potential splice effects (SpliceAI score ≤0.10 or experimental evidence of normal splicing) and confirm the applicability of PP3. Missense changes at the same residue must be classified according to LGMD VCEP specifications, and no benign missense variation should be present at the residue. Do not apply for missense variants encoded by the first or last 3 nucleotides of an exon unless a splice effect has been experimentally ruled out for the variant under curation and the variant(s) resulting in the same amino acid change. Apply at Strong for 2 pathogenic or 3 likely pathogenic variants resulting in different amino acid changes at the same residue as the variant under curation.
-
-
-PM5 can potentially be applied to multiple amino acid changes at the same residue as long as the variant classification that determines the strength level does not depend on PM5 application.","Disease-specific,Strength"
-SGCG (HGNC:10809),PM5,Moderate,"Apply only for missense variants for which the amino acid change is the expected mechanism of disease. For the missense variant under curation and the variant(s) resulting in a different amino acid change, exclude potential splice effects (SpliceAI score ≤0.10 or experimental evidence of normal splicing) and confirm the applicability of PP3. Missense changes at the same residue must be classified according to LGMD VCEP specifications, and no benign missense variation should be present at the residue. Do not apply for missense variants encoded by the first or last 3 nucleotides of an exon unless a splice effect has been experimentally ruled out for the variant under curation and the variant(s) resulting in the same amino acid change. Apply at Moderate for 1 pathogenic or 2 likely pathogenic variants resulting in different amino acid changes at the same residue as the variant under curation.
-
-
-PM5 can potentially be applied to multiple amino acid changes at the same residue as long as the variant classification that determines the strength level does not depend on PM5 application.",Disease-specific
-SGCG (HGNC:10809),PM5,Supporting,"Apply only for missense variants for which the amino acid change is the expected mechanism of disease. For the missense variant under curation and the variant(s) resulting in a different amino acid change, exclude potential splice effects (SpliceAI score ≤0.10 or experimental evidence of normal splicing) and confirm the applicability of PP3. Missense changes at the same residue must be classified according to LGMD VCEP specifications, and no benign missense variation should be present at the residue. Do not apply for missense variants encoded by the first or last 3 nucleotides of an exon unless a splice effect has been experimentally ruled out for the variant under curation and the variant resulting in the same amino acid change. Apply at Supporting for 1 likely pathogenic variant resulting in a different amino acid change at the same residue as the variant under curation.
-
-
-PM5 can potentially be applied to multiple amino acid changes at the same residue as long as the variant classification that determines the strength level does not depend on PM5 application.","Disease-specific,Strength"
-SGCG (HGNC:10809),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-SGCG (HGNC:10809),PM6,Strong,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PM6_Strong should be applied for ≥ 2 pts but < 4 pts.,"Disease-specific,General recommendation,Strength"
-SGCG (HGNC:10809),PM6,Moderate,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PM6 should be applied for ≥ 1 pt but < 2 pts.,"Disease-specific,General recommendation"
-SGCG (HGNC:10809),PM6,Supporting,Use the SVI Working Group’s recommended point system (see supplementary file “de novo table”). Probands meeting the criteria for PP4_Strong can be counted as “Phenotype highly specific for gene”. Probands meeting the criteria for PP4 (Supporting) can be counted as “Phenotype consistent with gene but not highly specific”. Probands who do not meet the criteria for PP4 (Supporting) should not be counted. Maternity and paternity should be confirmed by trio WES or other testing. PM6_Supporting should be applied for ≥ 0.5 pts but < 1 pt.,"Disease-specific,General recommendation,Strength"
-SGCG (HGNC:10809),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-SGCG (HGNC:10809),PP1,Strong,"Segregations should be counted across families, with the total number of segregations determining the strength level. Apply PP1_Strong for 3 affected segregations (in addition to proband) across ≥2 families. When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate).","Disease-specific,Strength"
-SGCG (HGNC:10809),PP1,Moderate,"Segregations should be counted across families, with the total number of segregations determining the strength level. Apply PP1_Moderate for 2 affected segregations (in addition to proband; may be from a single family). When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate). If PP1_Moderate is applied and the criteria for PP4_Strong are also met, a downgraded PP4_Moderate can be applied.","Disease-specific,Strength"
-SGCG (HGNC:10809),PP1,Supporting,"Segregations should be counted across families, with the total number of segregations determining the strength level. Apply PP1 (Supporting) for 1 affected segregation (in addition to proband). When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate).",Disease-specific
-SGCG (HGNC:10809),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-SGCG (HGNC:10809),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-SGCG (HGNC:10809),PP3,Supporting,"For missense variants, use REVEL with a score ≥0.7. 
-
-
-For variants that may affect splicing, use SpliceAI with a score ≥0.5.",Disease-specific
-SGCG (HGNC:10809),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-SGCG (HGNC:10809),PP4,Strong,"Use the PP4 table (see supplementary file “PP4 table SGCG”) to determine the appropriate PP4 strength level. Apply PP4 only once, for a patient meeting the highest possible strength level. When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate).","Disease-specific,Gene-specific,Strength"
-SGCG (HGNC:10809),PP4,Moderate,"Use the PP4 table (see supplementary file “PP4 table SGCG”) to determine the appropriate PP4 strength level. Apply PP4 only once, for a patient meeting the highest possible strength level. When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate). If PP1_Moderate is applied and the criteria for PP4_Strong are also met, a downgraded PP4_Moderate can be applied.","Disease-specific,Gene-specific,Strength"
-SGCG (HGNC:10809),PP4,Supporting,"Use the PP4 table (see supplementary file “PP4 table SGCG”) to determine the appropriate PP4 strength level. Apply PP4 only once, for a patient meeting the highest possible strength level. When applied together, PP1 and PP4 cannot exceed 5 Bayesian pts (Supporting + Strong or Moderate + Moderate).",Disease-specific
-SGCG (HGNC:10809),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SGCG (HGNC:10809),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-SGCG (HGNC:10809),BA1,Stand Alone,"Apply if the variant Grpmax FAF (the lower bound of the 95% confidence interval of the maximum credible genetic ancestry group allele frequency) is >0.002. This value can be taken directly from gnomAD. See supplementary file “benign frequency exceptions” for a list of variants defined as exceptions to the benign frequency rules. Ongoing updates to this list will be available at the LGMD VCEP webpage: 
-https://clinicalgenome.org/affiliation/50061/.
- Variants whose frequency may not be reliable (e.g., variants that may reflect a sequencing artifact) should be critically evaluated and brought to the attention of the LGMD VCEP.",Disease-specific
-SGCG (HGNC:10809),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-SGCG (HGNC:10809),BS1,Strong,"Apply if the variant Grpmax FAF (the lower bound of the 95% confidence interval of the maximum credible genetic ancestry group allele frequency) is >0.0009. This value can be taken directly from gnomAD. See supplementary file “benign frequency exceptions” for a list of variants defined as exceptions to the benign frequency rules. Ongoing updates to this list will be available at the LGMD VCEP webpage: 
-https://clinicalgenome.org/affiliation/50061/.
- Variants whose frequency may not be reliable (e.g., variants that may reflect a sequencing artifact) should be critically evaluated and brought to the attention of the LGMD VCEP.",Disease-specific
-SGCG (HGNC:10809),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",NA
-SGCG (HGNC:10809),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-SGCG (HGNC:10809),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-SGCG (HGNC:10809),BS4,Strong,"Use as is. One affected individual (genotype-, phenotype+) is sufficient for BS4. Do not apply for genotype+, phenotype- individuals, as LGMD is characterized by variable expressivity and late onset is not uncommon.",Clarification
-SGCG (HGNC:10809),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-SGCG (HGNC:10809),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-SGCG (HGNC:10809),BP2,Supporting,"Use when variant is found 
-in cis
- with a variant classified as pathogenic or likely pathogenic using the LGMD VCEP specifications.",Disease-specific
-SGCG (HGNC:10809),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-SGCG (HGNC:10809),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SGCG (HGNC:10809),BP4,Supporting,"For missense variants, use REVEL with a score ≤0.1 AND SpliceAI with a score ≤0.05.
-
-
-For variants that may affect splicing, use SpliceAI with a score ≤0.05.
-
-
-Splice AI scores can be calculated here: 
-https://spliceailookup.broadinstitute.org/",Disease-specific
-SGCG (HGNC:10809),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-SGCG (HGNC:10809),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SGCG (HGNC:10809),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-SGCG (HGNC:10809),BP7,Supporting,"For splice predictions, use SpliceAI with a score ≤0.05. BP7 may be co-applied with BP4 for synonymous, UTR, and intronic variants located outside the splice donor/acceptor regions designated in Walker et al. 2023 (+7/-21).",Disease-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenLysosomalDiseasesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforIDUAVersion1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenLysosomalDiseasesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforIDUAVersion1.0.0_version=1.0.0.csv
deleted file mode 100644
index abee6507dd5e23e57d770dec4cf52dad4cf1b1e0..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenLysosomalDiseasesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforIDUAVersion1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,307 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-IDUA (HGNC:5391),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-IDUA (HGNC:5391),PVS1,Very Strong,"All nonsense and frameshift variants will meet PVS1 (Very Strong), unless the variant is predicted to be undetected by nonsense-mediated decay (NMD) i.e. if the resulting premature termination codon is in the last exon (exon 14) or in the last 50 nucleotides of the penultimate exon (exon 13; after c.1778, codon 592). In this case, PVS1_Moderate will be applied because <10% of the primary amino acid sequence is predicted to be lost (in this case, ~9.3%).
-
-
-For all variants involving either the +1 or +2 position of GT donor splice sites, the exon immediately 5’ of the variant is predicted to be skipped, and for all variants involving either the -1 or -2 position of AG acceptor splice sites, the exon immediately 3’ of the variant is predicted to be skipped, unless indicated otherwise by RT-PCR or in silico prediction. For the predicted in frame/out of frame consequences for skipping any exon in IDUA, and recommended weight for PVS1, see Appendix 1.
-
-
-Follow the recommendations of Walker et al (PMID: 37352859) for all variants occurring in splice motifs (the donor site motif = last 3 nucleotides of an exon and first 6 nucleotides of an intron; acceptor site motif = first nucleotide of an exon and 20 nucleotides upstream from the exon boundary).
-
-
-If a single or multi-exon deletion results in an out-of-frame consequence, use PVS1 (Very Strong) if NMD is predicted to occur.
-
-
-Initiation codon variants will meet PVS1.
-
-
-The next in-frame methionine is at position 133. If used as a start signal, the signal sequence (amino acids 1-27) would be lost (
-https://www.uniprot.org/uniprotkb/P35475/entry
-)
-
-
-There are 6 variants, upstream of Met133, that are classified as pathogenic in ClinVar (data accessed July 20, 2022) (Table 1).
-
-
-
-
-
-
-If a deletion results in an in-frame consequence, the deletion must encompass one or more exons for PVS1 to apply. Consult Appendix 1 and use professional judgment regarding the strength of evidence to apply.
-
-
-For duplications, consult the PVS1 decision tree and Appendix 1 to assess the impact of single and multi-exon duplications and apply PVS1 at the appropriate strength.",None
-IDUA (HGNC:5391),PVS1,Strong,"For frameshift variants at the 3’ end of IDUA that are not predicted to undergo NMD i.e. PTC downstream of c.1778, consider the length of abnormal amino acid sequence that is added due to the frameshift. If >10% of the length of the normal sequence is altered, PVS1 can be applied at strong.
-
-
-For all variants involving either the +1 or +2 position of GT donor splice sites, the exon immediately 5’ of the variant is predicted to be skipped, and for all variants involving either the -1 or -2 position of AG acceptor splice sites, the exon immediately 3’ of the variant is predicted to be skipped, unless indicated otherwise by RT-PCR or in silico prediction. For the predicted in frame/out of frame consequences for skipping any exon in IDUA, and recommended weight for PVS1, see Appendix 1.
-
-
-Follow the recommendations of Walker et al (PMID: 37352859) for all variants occurring in splice motifs (the donor site motif = last 3 nucleotides of an exon and first 6 nucleotides of an intron; acceptor site motif = first nucleotide of an exon and 20 nucleotides upstream from the exon boundary).
-
-
-If a deletion results in an in-frame consequence, the deletion must encompass one or more exons for PVS1 to apply. Consult Appendix 1 and use professional judgment regarding the strength of evidence to apply.
-
-
-For duplications, consult the PVS1 decision tree and Appendix 1 to assess the impact of single and multi-exon duplications and apply PVS1 at the appropriate strength.","Disease-specific,Strength"
-IDUA (HGNC:5391),PVS1,Moderate,"Any nonsense or frameshift variant that is predicted to be undetected by nonsense-mediated decay (NMD) i.e. if the resulting premature termination codon is in the last exon (exon 14) or in the last 50 nucleotides of the penultimate exon (exon 13; after c.1778, codon 592). In this case, PVS1_Moderate will be applied because <10% of the primary amino acid sequence is predicted to be lost ( ~9.3%).
-
-
-For frameshift variants at the 3’ end of IDUA that are not predicted to undergo NMD i.e. PTC downstream of c.1778, consider the length of abnormal amino acid sequence that is added due to the frameshift. If <10% of the length of the normal sequence is altered, PVS1 can be applied at moderate.
-
-
-For all variants involving either the +1 or +2 position of GT donor splice sites, the exon immediately 5’ of the variant is predicted to be skipped, and for all variants involving either the -1 or -2 position of AG acceptor splice sites, the exon immediately 3’ of the variant is predicted to be skipped, unless indicated otherwise by RT-PCR or in silico prediction. For the predicted in frame/out of frame consequences for skipping any exon in IDUA, and recommended weight for PVS1, see Appendix 1.
-
-
-Follow the recommendations of Walker et al (PMID: 37352859) for all variants occurring in splice motifs (the donor site motif = last 3 nucleotides of an exon and first 6 nucleotides of an intron; acceptor site motif = first nucleotide of an exon and 20 nucleotides upstream from the exon boundary).
-
-
-If a deletion results in an in-frame consequence, the deletion must encompass one or more exons for PVS1 to apply. Consult Appendix 1 and use professional judgment regarding the strength of evidence to apply.
-
-
-For duplications, see the PVS1 decision tree and Appendix 1 to assess the impact of single and multi-exon duplications and apply PVS1 at the appropriate strength.","Disease-specific,Strength"
-IDUA (HGNC:5391),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-IDUA (HGNC:5391),PS1,Strong,Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.Splice region variants following Table 3 in Walker et al (PMID: 37352859).,None
-IDUA (HGNC:5391),PS1,Moderate,Same amino acid change as a previously established likely pathogenic variant regardless of nucleotide change. Splice region variants following Table 3 in Walker et al (PMID: 37352859).,Strength
-IDUA (HGNC:5391),PS1,Supporting,Splice region variants following Table 3 in Walker et al (PMID: 37352859).,Strength
-IDUA (HGNC:5391),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-IDUA (HGNC:5391),PS2,Strong,"Variant occurs de novo in an affected individual, and the biological relationship of the parent without the variant is confirmed e.g. if the father is not heterozygous for an IDUA variant that has been detected in the patient, paternity must be confirmed.",Disease-specific
-IDUA (HGNC:5391),PS2,Moderate,"Variant occurs de novo in an affected individual, and the biological relationship of the parent without the variant is not confirmed.",Disease-specific
-IDUA (HGNC:5391),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-IDUA (HGNC:5391),PS3,Moderate,"When PS3_Supporting is met for enzyme activity AND there is expression data (Western blot, pulse chase) showing a clear difference in synthesis and/or processing of alpha-iduronidase, PS3 will be applied at moderate (e.g. Matte et al, 2003, PMID:  12559846; see Appendix 3).","Disease-specific,Strength"
-IDUA (HGNC:5391),PS3,Supporting,"In vitro
- expression studies: After assessment of the parameters listed below, results from such studies can be used at PS3_Supporting (see Appendix 3 for thresholds for specific studies; <2% activity (Beesley et al, 2001, PMID: 11735025; Yogalingam et al, 2004, PMID: 15300847; Matte et al, 2003); <1% activity / enzyme abundance (Yu et al, 2020. PMID: 33198351).
-
-
-
-
-Were clones sequenced to verify that the variant is present and that no artifacts have been introduced during the site-directed mutagenesis process? 
-
-
-Were appropriate controls included? Examples 
-
-
-Negative controls: Empty vector, antisense (at least one appropriate negative control is required); 
-
-
-Positive control: Wild type IDUA, normal cells (at least one appropriate positive control is required)
-
-
-
-
-
-
-Was the experiment replicated?
-
-
-If cells have intrinsic IDUA activity e.g., COS cells, the level of activity should be stated so that this can be taken into account.","Disease-specific,Strength"
-IDUA (HGNC:5391),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",NA
-IDUA (HGNC:5391),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-IDUA (HGNC:5391),PM1,Moderate,"Studies on functional domains (Bie et al, 2013, PMID: 24036510; Maita et al, 2013, PMID: 23959878; Saito et al, 2014, PMID: 24480078; Figueiredo et al, 2014, PMID: 25459762) have shown that the following residues are important to the function of IDUA:
-
-
-Active site nucleophiles: Glu182 and Glu299
-
-
-Active site pocket and substrate binding: Arg89, His91, Asn181, His262, Lys264, Asp301, Gly305, Trp306, Asp349, Arg363, Asn372.
-
-
-PM1 will be applied to any missense substitutions or inframe deletions of the above residues.
-
-
-There are no benign or likely benign missense or infame deletions of these residues in ClinVar, or common missense or inframe deletions of these residues in gnomAD v4.1.0 (ClinVar and gnomAD v4.1.0 data accessed on October 30, 2024).",Disease-specific
-IDUA (HGNC:5391),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-IDUA (HGNC:5391),PM2,Supporting,"This criterion will be applied at the supporting level based on 
-guidance
- from the ClinGen Sequence Variant Interpretation Working Group.
-
-
-Minor allele frequency <0.025% (0.00025) in any continental population with >2000 alleles in the most recent version of gnomAD (version # will be stated in the written summary).
-
-
-Variants may be observed in the homozygous state because MPS1 can present in adulthood, and some variants may be hypomorphic. However, the presence and number of homozygotes should be noted.","General recommendation,Strength"
-IDUA (HGNC:5391),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-IDUA (HGNC:5391),PM3,Very Strong,"Detected in trans with a pathogenic variant. Points system based on 
-guidance
- from the ClinGen Sequence Variant Interpretation Working Group. See Appendix 4 for the Lysosomal Diseases VCEP's specification of PM3. Note that points will NOT be applied for any variants of uncertain significance confirmed in trans, due to the high number of pseudodeficiency variants in IDUA. 
-
-
-These variant interpretation guidelines should be used to determine the classification of the “other variant” in order to determine the appropriate number of points to assign.","General recommendation,Strength"
-IDUA (HGNC:5391),PM3,Strong,"Detected in trans with a pathogenic variant. Points system based on 
-guidance
- from the ClinGen Sequence Variant Interpretation Working Group. See Appendix 4 for the Lysosomal Diseases VCEP's specification of PM3. Note that points will NOT be applied for any variants of uncertain significance confirmed in trans, due to the high number of pseudodeficiency variants in IDUA. 
-
-
-These variant interpretation guidelines should be used to determine the classification of the “other variant” in order to determine the appropriate number of points to assign.","General recommendation,Strength"
-IDUA (HGNC:5391),PM3,Moderate,"Detected in trans with a pathogenic variant. Points system based on 
-guidance
- from the ClinGen Sequence Variant Interpretation Working Group. See Appendix 4 for the Lysosomal Diseases VCEP's specification of PM3. Note that points will NOT be applied for any variants of uncertain significance confirmed in trans, due to the high number of pseudodeficiency variants in IDUA. 
-
-
-These variant interpretation guidelines should be used to determine the classification of the “other variant” in order to determine the appropriate number of points to assign.",None
-IDUA (HGNC:5391),PM3,Supporting,"Detected in trans with a pathogenic variant. Points system based on 
-guidance
- from the ClinGen Sequence Variant Interpretation Working Group. See Appendix 4 for the Lysosomal Diseases VCEP's specification of PM3. Note that points will NOT be applied for any variants of uncertain significance confirmed in trans, due to the high number of pseudodeficiency variants in IDUA. 
-
-
-These variant interpretation guidelines should be used to determine the classification of the “other variant” in order to determine the appropriate number of points to assign.","General recommendation,Strength"
-IDUA (HGNC:5391),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-IDUA (HGNC:5391),PM4,Moderate,"Stop loss variants, and in frame deletion/insertions of two or more amino acids but less than one exon.",None
-IDUA (HGNC:5391),PM4,Supporting,In frame deletion/insertion of one amino acid.,Strength
-IDUA (HGNC:5391),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-IDUA (HGNC:5391),PM5,Moderate,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-Stop loss variant if another stop loss variant has been determined to be pathogenic.",None
-IDUA (HGNC:5391),PM5,Supporting,"Missense change at an amino acid residue where a different missense change determined to be likely pathogenic has been seen before.
-
-
-Stop loss variant if another stop loss variant has been determined to be likely pathogenic.",Strength
-IDUA (HGNC:5391),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-IDUA (HGNC:5391),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-IDUA (HGNC:5391),PP1,Moderate,See Appendix 5 for points system and guidance (based on PMID: 38103548).,General recommendation
-IDUA (HGNC:5391),PP1,Supporting,See Appendix 5 for points system and guidance (based on PMID: 38103548).,General recommendation
-IDUA (HGNC:5391),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-IDUA (HGNC:5391),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-IDUA (HGNC:5391),PP3,Moderate,"Any missense changes with a REVEL score >0.773 will meet PP3_Moderate (Based on Pejaver et al, PMID: 3641399; Note that the VCEP has chosen not to apply PP3 at strong).",Disease-specific
-IDUA (HGNC:5391),PP3,Supporting,"Any missense changes with a REVEL score between 0.644 - 0.773 will meet PP3 (Pejaver et al., PMID: 3641399)
-
-
-For in frame insertions and deletions, use Mutation Taster (
-http://www.mutationtaster.org/
- ; count if “disease-causing”), and MutPred-Indel (
-http://mutpredindel.cs.indiana.edu/
- ; score >0.5 for “pathogenic”). Apply PP3 if both predictors indicate that the variant is deleterious.
-
-
-For non-canonical splice site variants (e.g., +3, -3), use SpliceAI (
-https://spliceailookup.broadinstitute.org/
- ). A score of >0.2 is taken to indicate disruption of the splice site allowing PP3 to be applied (based on Walker et al, PMID: 37352859). Evidence for use of a cryptic splice site and the impact on the gene product should also be assessed. PP3 for splicing variants will be applied only in the absence of functional (RNA analysis) data.",Disease-specific
-IDUA (HGNC:5391),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-IDUA (HGNC:5391),PP4,Moderate,"3 or more of the following criteria are met:
-
-
-
-
-Deficient IDUA activity, within the affected range (usually non-detectable or expressed affected range by lab) in fibroblasts, leukocytes, or plasma.
-
-
-Do not count if one or more pseudodeficiency variants are present, or if result was obtained on newborn screen without confirmatory enzyme testing.
-
-
-
-
-
-
-Enzyme replacement therapy results in a significant reduction in urine GAGs (either total or heparan sulfate).
-
-
-Urinary and/or dried blood spot GAGs expressed as either total GAGs, specific GAG (heparan sulfate, dermatan sulfate, or endogenous biomarker elevation) above normal range.
-
-
-Patient reported to have clinical features specific to MPS; At minimum at least 2 of the following: dysostosis multiplex, hepatosplenomegaly, arthropathy, corneal involvement, valvular thickening.
-
-
-Bone marrow transplant results in a significant reduction in urine GAGs (either total or heparan sulfate).","Disease-specific,Strength"
-IDUA (HGNC:5391),PP4,Supporting,"2 of the following criteria are met:
-
-
-
-
-Deficient IDUA activity, within the affected range (usually non-detectable or expressed affected range by lab) in fibroblasts, leukocytes, or plasma.
-
-
-Do not count if one or more pseudodeficiency variants are present, or if result was obtained on newborn screen without confirmatory enzyme testing.
-
-
-
-
-
-
-Enzyme replacement therapy results in a significant reduction in urine GAGs (either total or heparan sulfate).
-
-
-Urinary and/or dried blood spot GAGs expressed as either total GAGs, specific GAG (heparan sulfate, dermatan sulfate, or endogenous biomarker elevation) above normal range.
-
-
-Patient reported to have clinical features specific to MPS; At minimum at least 2 of the following: dysostosis multiplex, hepatosplenomegaly, arthropathy, corneal involvement, valvular thickening.
-
-
-Bone marrow transplant results in a significant reduction in urine GAGs (either total or heparan sulfate).",Disease-specific
-IDUA (HGNC:5391),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-IDUA (HGNC:5391),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-IDUA (HGNC:5391),BA1,Stand Alone,"Any variant with Grpmax >0.005 in the most recent version of gnomAD (95% confidence interval, lower bound) (version # will be stated in the written summary)
-
-
-BA1 minor allele frequency cut-off calculated using 
-http://cardiodb.org/allelefrequencyapp
- with prevalence = 1 in 40,000 (PMID: 33208168), genetic heterogeneity = 1.0 (IDUA is the only gene known to cause MPS1), allelic heterogeneity = 1.0, and penetrance = 1.0.",Disease-specific
-IDUA (HGNC:5391),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-IDUA (HGNC:5391),BS1,Strong,"Any variant with Grpmax >0.0025 in the most recent version of gnomAD (95% confidence interval, lower bound) (version # will be stated in the written summary).
-
-
-BS1 minor allele frequency cut-off calculated using 
-http://cardiodb.org/allelefrequencyapp
- with prevalence = 1 in 40,000 (PMID: 33208168), genetic heterogeneity = 1.0 (IDUA is the only gene known to cause MPS1), allelic heterogeneity = ~0.5 (frequency of the most common known pathogenic variants in patients with MPS1 (PMID: 28595941, 29393969), and penetrance = 1.0.",Disease-specific
-IDUA (HGNC:5391),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-IDUA (HGNC:5391),BS2,Strong,"BS2 can be applied if there is clear documentation that an individual of any age is either homozygous for the variant, or has the variant confirmed in trans with a pathogenic or likely pathogenic variant, and has normal IDUA activity. Values for IDUA activity and the reference range for the laboratory must be provided.
-
-
-Note: Patients with late onset MPS1 can present late in life (5
-th
--6
-th
- decade), can have mild symptoms, and may remain undiagnosed. Therefore, it is possible that individuals who are homozygous for hypomorphic IDUA variants could be present in population databases.",None
-IDUA (HGNC:5391),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-IDUA (HGNC:5391),BS3,Supporting,"The same assays outlined for PS3 will be used for BS3. Please see PS3 guidance for additional information on these assays. 
-
-
-BS3_Supporting can be applied for expression of IDUA sequence variants in cultured cells and subsequent measurement of enzyme activity provided that there is no other evidence to suggest that the variant could be disease-causing e.g. mislocalization (see Appendix 3 for thresholds for specific studies: >10% activity (Beesley et al, 2001, PMID: 11735025; Yogalingam et al, 2004, PMID: 15300847; Matte et al, 2003); >~10% activity / enzyme abundance (Yu et al, 2020. PMID: 33198351).","Disease-specific,Strength"
-IDUA (HGNC:5391),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-IDUA (HGNC:5391),BS4,Strong,Non-segregation with disease in a family i.e. variant is absent in an affected individual.,None
-IDUA (HGNC:5391),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-IDUA (HGNC:5391),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-IDUA (HGNC:5391),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-IDUA (HGNC:5391),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-IDUA (HGNC:5391),BP4,Supporting,"Missense changes with a REVEL score < 0.290 (threshold based on Pejaver et al; however, BP4 will only be applied at the supporting level). 
-
-
-For in frame insertions and deletions, use PROVEAN (
-http://provean.jcvi.org/seq_submit.php
- ; score >-2.5), Mutation Taster (
-http://www.mutationtaster.org/
- ; count if “polymorphism”, and MutPred-Indel (
-http://mutpredindel.cs.indiana.edu/
- ; score <0.5. Apply BP4 if all predictors indicate that the variant is benign.
-
-
-For non-canonical splice site variants, use SpliceAI (
-https://spliceailookup.broadinstitute.org/
- ) to assess the impact of variants that are not +/-1 or 2 canonical splice site variants. This criterion can be applied as PP3 (Splicing) for SpliceAI scores ≤0.1 (based on Walker et al, PMID: 37352859). 
-
-
-If there is any evidence for possible creation of a cryptic splice site, this criterion should not be applied.",Disease-specific
-IDUA (HGNC:5391),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-IDUA (HGNC:5391),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-IDUA (HGNC:5391),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-IDUA (HGNC:5391),BP7,Strong,"Experimental evidence (RT-PCR, RNA Seq, minigene) shows that the variant does not impact splicing. BP7_Strong (RNA) will be used only under strict circumstances in which it is clear that the allele with the variant is expressed at the normal level to avoid counting a “normal” result because the allele with the variant is absent due to nonsense-mediated decay (Walker et al, PMID: 37352859).",Strength
-IDUA (HGNC:5391),BP7,Supporting,"BP7 can be applied if the variant is synonymous, unless the variant is in the first nucleotide or last three nucleotides of an exon, AND BP4 is met i.e. SpliceAI predicts no impact on splicing (score ≤ 0.10)",None
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
deleted file mode 100644
index 8083dfcfb0a8feb94cadd136e6df23ec0eefcd4f..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
+++ /dev/null
@@ -1,194 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-GAA (HGNC:4065),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-GAA (HGNC:4065),PVS1,Very Strong,"Null variant in a gene where loss of function is a known mechanism of disease or in frame loss of an exon that contains residues involved in the active site of GAA.
-
-
-
-
-Any nonsense, frameshift, or splice variant creating a premature stop codon before codon 916.
-
-
-In frame deletions of an entire exon containing critical active site/substrate binding residues (exons 8 and 10), or for which another variant removing the exon is known to be pathogenic (exons 2 and 18).",None
-GAA (HGNC:4065),PVS1,Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-In frame loss of an exon which is part of the catalytic barrel domain and contains pathogenic/likely pathogenic nontruncating variants (exons 6 and 9).
-
-
-Initiator codon variant.","Strength,Disease-specific"
-GAA (HGNC:4065),PVS1,Moderate,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-Premature termination codon in the 3’ end of GAA (3’ to codon 916), not predicted to be detected by nonsense-mediated decay.
-
-
-Predicted exon-skipping due to canonical splice variant or exon deletion resulting in an in frame deletion of <10% of the gene product (exons 17, 19, and 20).","Strength,Disease-specific"
-GAA (HGNC:4065),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-GAA (HGNC:4065),PS1,Strong,Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.,None
-GAA (HGNC:4065),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",NA
-GAA (HGNC:4065),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-GAA (HGNC:4065),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RT-PCR evidence of mis-splicing for non-canonical intronic variants with no evidence of normal splice products.",None
-GAA (HGNC:4065),PS3,Moderate,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-<5% wild type GAA activity when the variant is expressed in a heterologous cell type and evidence of abnormal GAA synthesis and/or processing.
-
-
-RT-PCR evidence of mis-splicing for non-canonical intronic variants with evidence of normal splice products.","Strength,Disease-specific"
-GAA (HGNC:4065),PS3,Supporting,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-<30% wild type GAA activity when the variant is expressed in a heterologous cell type.
-
-
-RT-PCR evidence of mis-splicing for non-canonical intronic variants with evidence of normal splice products.","Strength,Disease-specific"
-GAA (HGNC:4065),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",NA
-GAA (HGNC:4065),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-GAA (HGNC:4065),PM1,Moderate,"Located in a mutational hot spot and/or critical and well-established functional domain without benign variation.
-
-
-
-
-Missense substitution or in frame deletion of residues important in the active site architecture and substrate binding of GAA:- D282, W376, D404, L405, I441, W481, W516, D518, M519, R600, W613, D616, W618, F649, L650, H674.",Disease-specific
-GAA (HGNC:4065),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-GAA (HGNC:4065),PM2,Moderate,"Low frequency in population databases.
-
-
-
-
-Minor allele frequency <0.1% (0.001) in all continental populations with >2000 alleles in gnomAD.",Disease-specific
-GAA (HGNC:4065),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-GAA (HGNC:4065),PM3,Very Strong,Detected in trans with a pathogenic variant. Points-based system. See main specifications document.,
-GAA (HGNC:4065),PM3,Strong,Detected in trans with a pathogenic variant. Points-based system. See main specifications document.,
-GAA (HGNC:4065),PM3,Moderate,Detected in trans with a pathogenic variant. Points-based system. See main specifications document.,None
-GAA (HGNC:4065),PM3,Supporting,Detected in trans with a pathogenic variant. Points-based system. See main specifications document.,Strength
-GAA (HGNC:4065),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-GAA (HGNC:4065),PM4,Moderate,"Protein length changes due to in-frame deletions/insertions in a nonrepeat region or stop-loss variants.
-
-
-
-
-In frame deletion/insertions of two or more amino acids but less than one exon.",None
-GAA (HGNC:4065),PM4,Supporting,"Protein length changes due to in-frame deletions/insertions in a nonrepeat region or stop-loss variants.
-
-
-
-
-In frame deletion/insertions of one amino acid.",Strength
-GAA (HGNC:4065),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-GAA (HGNC:4065),PM5,Moderate,Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.,None
-GAA (HGNC:4065),PM5,Supporting,Missense change at an amino acid residue where a different missense change determined to be 'likely pathogenic' has been seen before.,Strength
-GAA (HGNC:4065),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-GAA (HGNC:4065),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",NA
-GAA (HGNC:4065),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-GAA (HGNC:4065),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-GAA (HGNC:4065),PP3,Supporting,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product.
-
-
-
-
-REVEL score >0.7 for missense variants.
-
-
-In frame deletion or insertion predicted deleterious by 2 out of 3 tools (PROVEAN, MutationTaster, MutPred-InDel).
-
-
-Predicted impact on splicing by SpliceAI (score >0.5).",Disease-specific
-GAA (HGNC:4065),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-GAA (HGNC:4065),PP4,Moderate,"Phenotype specific for disease with single genetic etiology.
-
-
-
-
-Points-based system. See main specifications document","Strength,Disease-specific"
-GAA (HGNC:4065),PP4,Supporting,"Phenotype specific for disease with single genetic etiology.
-
-
-
-
-Points-based system. See main specifications document",Disease-specific
-GAA (HGNC:4065),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-GAA (HGNC:4065),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-GAA (HGNC:4065),BA1,Stand Alone,"Common in population databases.
-
-
-
-
-Highest minor allele frequency >0.01 (>1%) in any continental population in gnomAD with >2000 alleles.",Disease-specific
-GAA (HGNC:4065),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-GAA (HGNC:4065),BS1,Strong,"Allele frequency greater than expected for disease.
-
-
-
-
-Highest minor allele frequency >0.005 (>0.5%) in any continental population in gnomAD with >2000 alleles.",Disease-specific
-GAA (HGNC:4065),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-GAA (HGNC:4065),BS2,Strong,"Observed in the homozygous state in a healthy adult.
-
-
-
-
-Homozygous individual of any age with normal GAA activity.",None
-GAA (HGNC:4065),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-GAA (HGNC:4065),BS3,Supporting,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.
-
-
-
-
-
-
-50% activity when the variant is expressed in a heterologous cell type, or >30% activity if there is also evidence of normal synthesis and processing.","Strength,Disease-specific"
-GAA (HGNC:4065),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",NA
-GAA (HGNC:4065),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-GAA (HGNC:4065),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-GAA (HGNC:4065),BP2,Supporting,Observed in cis with a pathogenic variant.,None
-GAA (HGNC:4065),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-GAA (HGNC:4065),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-GAA (HGNC:4065),BP4,Supporting,"Multiple lines of computational evidence suggest no impact on gene or gene product.
-
-
-
-
-REVEL score <0.5 for missense variants.
-
-
-In frame deletion or insertion predicted benign by PROVEAN, MutationTaster, and MutPred-InDel.
-
-
-No predicted impact on splicing by SpliceAI (score <0.2)",Disease-specific
-GAA (HGNC:4065),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-GAA (HGNC:4065),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-GAA (HGNC:4065),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-GAA (HGNC:4065),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,None
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMalignantHyperthermiaSusceptibilityExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMalignantHyperthermiaSusceptibilityExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
deleted file mode 100644
index 9a817c2f6550e8334c4e6d43dac2211b60b1d3f3..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMalignantHyperthermiaSusceptibilityExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
+++ /dev/null
@@ -1,178 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-RYR1 (HGNC:10483),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-RYR1 (HGNC:10483),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RYR1 (HGNC:10483),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change
-
-
-
-
-Previously established pathogenic variant must reach a classification of pathogenic without PS1",None
-RYR1 (HGNC:10483),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-RYR1 (HGNC:10483),PS2,Very Strong,"Each proven de novo case, 2 points, each assumed de novo case, 1 point, ≥8 points",Strength
-RYR1 (HGNC:10483),PS2,Strong,"Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 4-7 points",Strength
-RYR1 (HGNC:10483),PS2,Moderate,"Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 2-3 points",Strength
-RYR1 (HGNC:10483),PS2,Supporting,"Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 1 point",Strength
-RYR1 (HGNC:10483),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-RYR1 (HGNC:10483),PS3,Strong,"Well-established functional studies supportive of a damaging effect on protein function
-
-
-
-
-Knock-in mouse showing MH reaction in response to RYR1 agonist AND increased sensitivity to RYR1 agonists in ex vivo tisue/cells","Strength,Disease-specific"
-RYR1 (HGNC:10483),PS3,Moderate,"Well-established functional studies supportive of a damaging effect on protein function
-
-
-
-
-Increased sensitivity to RYR1 agonist in HEK293 in vitro assay, Ca2+ release significantly increased compared to WT, controls to include known pathogenic and benign variants, n≥3.
-
-
-Three or more independent ex vivo studies all showing release of Ca2+ in response to RYR1 agonist
-
-
-Knock-in mouse showing MH reaction in response to RYR1 agonist OR increased sensitivity to RYR1 agonists in ex vivo tissue/cells (but not both, which would be PS3_strong)","Strength,Disease-specific"
-RYR1 (HGNC:10483),PS3,Supporting,"Well-established functional studies supportive of a damaging effect on protein function
-
-
-
-
-Two independent ex vivo studies all showing release of Ca2+ in response to RYR1 agonist","Strength,Disease-specific"
-RYR1 (HGNC:10483),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-RYR1 (HGNC:10483),PS4,Strong,"The prevalence of the variant in affected individuals significantly increased compared with the prevalence in controls
-
-
-
-
-≥7 MH case points. Probands with a personal or family history of an MH event are awarded 0.5 points, probands with a personal or family history of a positive (MHS)IVCT/CHCT are awarded an additional 0.5 points. Popmax in gnomAD ≤0.00006.
-
-
-For variants with popmax MAF gnomAD >0.00006, an odds ratio of ≥18.7 when comparing MH case points to allele count in gnomAD can qualify. Popmax in gnomAD must be <0.0038.","Strength,Disease-specific"
-RYR1 (HGNC:10483),PS4,Moderate,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls
-
-
-
-
-2-6 MH case points. Probands with a personal or family history of an MH event are awarded 0.5 points, probands with a personal or family history of a positive (MHS) IVCT/CHCT are awarded an additional 0.5 points. Popmax in gnomAD ≤0.00006
-
-
-For variants with popmax MAF in gnomAD >0.00006, an odds ratio of ≥4.33 when comparing MH case points to allele count in gnomAD can qualify. Popmax in gnomAD must be <0.0038","Strength,Disease-specific"
-RYR1 (HGNC:10483),PS4,Supporting,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls
-
-
-
-
-1 MH case point. Probands with a personal or family history of an MH event are awarded 0.5 points, probands with a personal or family history of a positive (MHS) IVCT/CHCT are awarded an additional 0.5 points. Popmax in gnomAD ≤0.00006
-
-
-For variants with popmax MAF in gnomAD >0.00006, an odds ratio of ≥2.08 when comparing MH case points to allele count in gnomAD can qualify. Popmax in gnomAD must be <0.0038","Strength,Disease-specific"
-RYR1 (HGNC:10483),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-RYR1 (HGNC:10483),PM1,Moderate,"Located in a mutational hot spot and/or critical and well established functional domain
-
-
-
-
-Residues 1-552 (N-terminal region) and 2,101-2,458 (central region)",Disease-specific
-RYR1 (HGNC:10483),PM1,Supporting,"Located in a mutational hot spot and/or critical and well established functional domain
-
-
-
-
-Residues 4,631-4,991 (C-terminal region)","Strength,Disease-specific"
-RYR1 (HGNC:10483),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",NA
-RYR1 (HGNC:10483),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-RYR1 (HGNC:10483),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,NA
-RYR1 (HGNC:10483),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RYR1 (HGNC:10483),PM5,Moderate,"Missense change at an amino acid residue where a different missense varaint previously determined to be pathogenic
-
-
-
-
-Previously established pathogenic variant must reach a classification of pathogenicity without PM5
-
-
-Grantham score for alternate pathogenic variant must be less than for variant being assessed",None
-RYR1 (HGNC:10483),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-RYR1 (HGNC:10483),PM6,Very Strong,"Each proven de novo case, 2 points, each assumed de novo case, 1 point, ≥8 points",Strength
-RYR1 (HGNC:10483),PM6,Strong,"Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 4-7 points",Strength
-RYR1 (HGNC:10483),PM6,Moderate,"Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 2-3 points",Strength
-RYR1 (HGNC:10483),PM6,Supporting,"Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 1 point",Strength
-RYR1 (HGNC:10483),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-RYR1 (HGNC:10483),PP1,Strong,Co-segregation with disease in ≥7 reported meioses,Strength
-RYR1 (HGNC:10483),PP1,Moderate,Co-segregation with disease in 5-6 reported meioses,Strength
-RYR1 (HGNC:10483),PP1,Supporting,Co-segregation with disease in 3-4 reported meioses,Strength
-RYR1 (HGNC:10483),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-RYR1 (HGNC:10483),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-RYR1 (HGNC:10483),PP3,Moderate,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product
-
-
-
-
-Use REVEL score of >0.85",Strength
-RYR1 (HGNC:10483),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-RYR1 (HGNC:10483),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RYR1 (HGNC:10483),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-RYR1 (HGNC:10483),BA1,Stand Alone,Popmax allele frequency >0.0038 (0.38%),Disease-specific
-RYR1 (HGNC:10483),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-RYR1 (HGNC:10483),BS1,Strong,Popmax allele frequency >0.0008 (0.08%),Disease-specific
-RYR1 (HGNC:10483),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-RYR1 (HGNC:10483),BS2,Strong,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age.
-
-
-
-
-Two or more variant positive individuals with a negative IVCT/CHCT test",Disease-specific
-RYR1 (HGNC:10483),BS2,Moderate,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age.
-
-
-
-
-One variant positive individual with a negative IVCT/CHCT test","Strength,Disease-specific"
-RYR1 (HGNC:10483),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-RYR1 (HGNC:10483),BS3,Moderate,"Well-established functional studies show no damaging effect on protein function
-
-
-
-
-Three or more independent ex vivo studies, NO significant release of Ca2+ in response to agonist","Strength,Disease-specific"
-RYR1 (HGNC:10483),BS3,Supporting,"Well-established functional studies show no damaging effect on protein function
-
-
-
-
-No significant increased sensitivity to RYR1 agonist in an approved in vitro assay, Ca2+ release measured, n≥3
-
-
-One or two independent ex vivo studies, NO significant release of Ca2+ in response to agonist
-
-
-Knock-in mouse showing no MH reaction in response to RYR1 agonist AND no increased sensitivity to RYR1 agonists in ex vivo tissue/cells","Strength, Disease-specific"
-RYR1 (HGNC:10483),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",NA
-RYR1 (HGNC:10483),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-RYR1 (HGNC:10483),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-RYR1 (HGNC:10483),BP2,Supporting,Observed in cis with a pathogenic variant in any inheritance pattern,None
-RYR1 (HGNC:10483),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-RYR1 (HGNC:10483),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-RYR1 (HGNC:10483),BP4,Supporting,"Computational evidence suggest no impact on gene or gene product, REVEL score of <0.5",Disease-specific
-RYR1 (HGNC:10483),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-RYR1 (HGNC:10483),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RYR1 (HGNC:10483),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-RYR1 (HGNC:10483),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved,None
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMalignantHyperthermiaSusceptibilityExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRYR1Version2_version=2.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMalignantHyperthermiaSusceptibilityExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRYR1Version2_version=2.0.0.csv
deleted file mode 100644
index b5940a4f8a657918b50737e411109b6b2f696a23..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMalignantHyperthermiaSusceptibilityExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRYR1Version2_version=2.0.0.csv
+++ /dev/null
@@ -1,197 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-RYR1 (HGNC:10483),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-RYR1 (HGNC:10483),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RYR1 (HGNC:10483),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change
-
-
-
-
-Previously established pathogenic variant must reach a classification of pathogenic without PS1",None
-RYR1 (HGNC:10483),PS1,Moderate,"Same amino acid change as a previously established likely pathogenic variant regardless of nucleotide change.
-
-
-
-
-Previously established likely pathogenic variant must reach a classification of likely pathogenic without PS1.",Strength
-RYR1 (HGNC:10483),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-RYR1 (HGNC:10483),PS2,Very Strong,"Each proven de novo case, 2 points, each assumed de novo case, 1 point, ≥8 points",Strength
-RYR1 (HGNC:10483),PS2,Strong,"Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 4-7 points",Strength
-RYR1 (HGNC:10483),PS2,Moderate,"Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 2-3 points",Strength
-RYR1 (HGNC:10483),PS2,Supporting,"Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 1 point",Strength
-RYR1 (HGNC:10483),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-RYR1 (HGNC:10483),PS3,Strong,"Well-established functional studies supportive of a damaging effect on protein function
-
-
-
-
-Knock-in mouse showing MH reaction in response to RYR1 agonist AND increased sensitivity to RYR1 agonists in ex vivo tisue/cells","Strength,Disease-specific"
-RYR1 (HGNC:10483),PS3,Moderate,"Well-established functional studies supportive of a damaging effect on protein function
-
-
-
-
-Increased sensitivity to RYR1 agonist in HEK293 in vitro assay, Ca2+ release significantly increased compared to WT, controls to include known pathogenic and benign variants, n≥3.
-
-
-Three or more independent ex vivo studies all showing release of Ca2+ in response to RYR1 agonist
-
-
-Knock-in mouse showing MH reaction in response to RYR1 agonist OR increased sensitivity to RYR1 agonists in ex vivo tissue/cells (but not both, which would be PS3_strong)","Strength,Disease-specific"
-RYR1 (HGNC:10483),PS3,Supporting,"Well-established functional studies supportive of a damaging effect on protein function
-
-
-
-
-Two independent ex vivo studies all showing release of Ca2+ in response to RYR1 agonist","Strength,Disease-specific"
-RYR1 (HGNC:10483),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-RYR1 (HGNC:10483),PS4,Strong,"The prevalence of the variant in affected individuals significantly increased compared with the prevalence in controls.
-
-
-
-
-≥7 MH case points. Probands with a personal or family history of an MH event are awarded 0.5 points, probands with a personal or family history of a positive (MHS) IVCT/CHCT are awarded an additional 0.5 points. Probands with multiple variants in RYR1 classified as VUS, likely pathogenic or pathogenic are not considered. Popmax in gnomAD ≤0.00006.
-
-
-For variants with popmax MAF gnomAD >0.00006, an odds ratio of ≥18.7 when comparing MH case points to allele count in gnomAD can qualify. Popmax in gnomAD must be <0.0038.","Strength,Disease-specific"
-RYR1 (HGNC:10483),PS4,Moderate,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-2-6 MH case points. Probands with a personal or family history of an MH event are awarded 0.5 points, probands with a personal or family history of a positive (MHS) IVCT/CHCT are awarded an additional 0.5 points. Probands with multiple variants in RYR1 classified as VUS, likely pathogenic or pathogenic are not considered. Popmax in gnomAD ≤0.00006.
-
-
-For variants with popmax MAF in gnomAD >0.00006, an odds ratio of ≥4.33 when comparing MH case points to allele count in gnomAD can qualify. Popmax in gnomAD must be <0.0038.","Strength,Disease-specific"
-RYR1 (HGNC:10483),PS4,Supporting,"The prevalence of the variant in affected individuals is significantly increased compared withthe prevalence in controls.
-
-
-
-
-1 MH case point. Probands with a personal or family history of an MH event are awarded 0.5 points, probands with a personal or family history of a positive (MHS) IVCT/CHCT are awarded an additional 0.5 points. Probands with multiple variants in RYR1 classified as VUS, likely pathogenic or pathogenic are not considered. Popmax in gnomAD ≤0.00006.
-For variants with popmax MAF in gnomAD >0.00006, an odds ratio of ≥2.08 when comparing MH case points to allele count in gnomAD can qualify. Popmax in gnomAD must be <0.0038.","Strength,Disease-specific"
-RYR1 (HGNC:10483),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-RYR1 (HGNC:10483),PM1,Moderate,"Located in a mutational hot spot and/or critical and well established functional domain.
-
-
-
-
-Residues 1-552 (N-terminal region) and 2,101-2,458 (central region) 
-
-
-PM1 should not be applied at a moderate weight with PS1/PM5, see PM1_Supporting.",Disease-specific
-RYR1 (HGNC:10483),PM1,Supporting,"Located in a mutational hot spot and/or critical and well established functional domain.
-
-
-
-
-Residues 1-552 (N-terminal region) and 2,101-2,458 (central region), if PS1/PM5 applicable then PM1 should be used at supporting 
-
-
-Residues 4,631-4,991 (C-terminal region).","Strength,Disease-specific"
-RYR1 (HGNC:10483),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",NA
-RYR1 (HGNC:10483),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-RYR1 (HGNC:10483),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,NA
-RYR1 (HGNC:10483),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RYR1 (HGNC:10483),PM5,Moderate,"Missense change at an amino acid residue where a different missense varaint previously determined to be pathogenic
-
-
-
-
-Previously established pathogenic variant must reach a classification of pathogenicity without PM5
-
-
-Grantham score for alternate pathogenic variant must be less than for variant being assessed",None
-RYR1 (HGNC:10483),PM5,Supporting,"Missense change at an amino acid residue where a different missense variant previously determined to be pathogenic.
-
-
-
-
-Previously established likely pathogenic variant can be considered supporting evidence, must reach a classification of likely pathogenic without PM5.
-
-
-Grantham score for alternate likely pathogenic variant must be less than for variant being assessed.","Strength,Disease-specific"
-RYR1 (HGNC:10483),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-RYR1 (HGNC:10483),PM6,Very Strong,"Each proven de novo case, 2 points, each assumed de novo case, 1 point, ≥8 points",Strength
-RYR1 (HGNC:10483),PM6,Strong,"Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 4-7 points",Strength
-RYR1 (HGNC:10483),PM6,Moderate,"Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 2-3 points",Strength
-RYR1 (HGNC:10483),PM6,Supporting,"Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 1 point",Strength
-RYR1 (HGNC:10483),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-RYR1 (HGNC:10483),PP1,Strong,Co-segregation with disease in ≥7 reported meioses,Strength
-RYR1 (HGNC:10483),PP1,Moderate,Co-segregation with disease in 5-6 reported meioses,Strength
-RYR1 (HGNC:10483),PP1,Supporting,Co-segregation with disease in 3-4 reported meioses,Strength
-RYR1 (HGNC:10483),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-RYR1 (HGNC:10483),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-RYR1 (HGNC:10483),PP3,Moderate,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product
-
-
-
-
-Use REVEL score of >0.85",Strength
-RYR1 (HGNC:10483),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-RYR1 (HGNC:10483),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RYR1 (HGNC:10483),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-RYR1 (HGNC:10483),BA1,Stand Alone,Popmax allele frequency >0.0038 (0.38%),Disease-specific
-RYR1 (HGNC:10483),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-RYR1 (HGNC:10483),BS1,Strong,Popmax allele frequency >0.0008 (0.08%),Disease-specific
-RYR1 (HGNC:10483),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-RYR1 (HGNC:10483),BS2,Strong,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age.
-
-
-
-
-Two or more variant positive individuals with a negative IVCT/CHCT test",Disease-specific
-RYR1 (HGNC:10483),BS2,Moderate,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age.
-
-
-
-
-One variant positive individual with a negative IVCT/CHCT test","Strength,Disease-specific"
-RYR1 (HGNC:10483),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-RYR1 (HGNC:10483),BS3,Moderate,"Well-established functional studies show no damaging effect on protein function
-
-
-
-
-Three or more independent ex vivo studies, NO significant release of Ca2+ in response to agonist","Strength,Disease-specific"
-RYR1 (HGNC:10483),BS3,Supporting,"Well-established functional studies show no damaging effect on protein function
-
-
-
-
-No significant increased sensitivity to RYR1 agonist in an approved in vitro assay, Ca2+ release measured, n≥3
-
-
-One or two independent ex vivo studies, NO significant release of Ca2+ in response to agonist
-
-
-Knock-in mouse showing no MH reaction in response to RYR1 agonist AND no increased sensitivity to RYR1 agonists in ex vivo tissue/cells","Strength, Disease-specific"
-RYR1 (HGNC:10483),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",NA
-RYR1 (HGNC:10483),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-RYR1 (HGNC:10483),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-RYR1 (HGNC:10483),BP2,Supporting,Observed in cis with a pathogenic variant in any inheritance pattern,None
-RYR1 (HGNC:10483),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-RYR1 (HGNC:10483),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-RYR1 (HGNC:10483),BP4,Supporting,"Computational evidence suggest no impact on gene or gene product, REVEL score of <0.5",Disease-specific
-RYR1 (HGNC:10483),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-RYR1 (HGNC:10483),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RYR1 (HGNC:10483),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-RYR1 (HGNC:10483),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved,None
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMitochondrialDiseaseNuclearandMitochondrialExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_mtDNA_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMitochondrialDiseaseNuclearandMitochondrialExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_mtDNA_version=1.0.0.csv
deleted file mode 100644
index 7a5dda70d57b32e4e06b1a9dd8b1ef1b602497d6..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMitochondrialDiseaseNuclearandMitochondrialExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_mtDNA_version=1.0.0.csv
+++ /dev/null
@@ -1,83 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-Unknown,PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-Unknown,PVS1,Very Strong,"Large heteroplasmic mtDNA deletions, where at least one gene is completely deleted",
-Unknown,PVS1,Strong,"Assessment of small deletions, nonsense, and frameshift variants in protein-coding genes should follow established guidelines (Abou Tayoun et al., 2018)",
-Unknown,PVS1,Moderate,"Assessment of small deletions, nonsense, and frameshift variants in protein-coding genes should follow established guidelines (Abou Tayoun et al., 2018)",
-Unknown,PVS1,Supporting,"Assessment of small deletions, nonsense, and frameshift variants in protein-coding genes should follow established guidelines (Abou Tayoun et al., 2018)",
-Unknown,PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-Unknown,PS1,Strong,Applied per original ACMG/AMP guidelines,
-Unknown,PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-Unknown,PS2,Very Strong,De novo (maternity confirmed or identical full mtDNA sequence) in a patient with the disease and no family history; with weighting per ClinGen SVI guidance,
-Unknown,PS2,Strong,De novo (maternity confirmed or identical full mtDNA sequence) in a patient with the disease and no family history; with weighting per ClinGen SVI guidance,
-Unknown,PS2,Moderate,De novo (maternity confirmed or identical full mtDNA sequence) in a patient with the disease and no family history; with weighting per ClinGen SVI guidance,
-Unknown,PS2,Supporting,De novo (maternity confirmed or identical full mtDNA sequence) in a patient with the disease and no family history; with weighting per ClinGen SVI guidance,
-Unknown,PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-Unknown,PS3,Supporting,Functional validation is present in cybrid studies or single fiber analysis,
-Unknown,PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-Unknown,PS4,Strong,Variant present in ≥16 unrelated probands,
-Unknown,PS4,Moderate,Variant present in ≥4 unrelated probands,
-Unknown,PS4,Supporting,Variant present in 2 unrelated probands in different top-level haplogroups,
-Unknown,PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-Unknown,PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-Unknown,PM2,Supporting,"Frequency <0.00002 (0.002%, 1/50,000) from controls",
-Unknown,PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-Unknown,PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-Unknown,PM4,Moderate,Applied per original ACMG/AMP guidelines,
-Unknown,PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-Unknown,PM5,Moderate,Applied per original ACMG/AMP guidelines (protein-coding genes),
-Unknown,PM5,Supporting,Same nucleotide position as previously established pathogenic variant in a rRNA/tRNA,
-Unknown,PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-Unknown,PM6,Very Strong,"Assumed de novo, but without confirmation of maternity (maternal testing done by targeted variant analysis and/or targeted gene sequencing)",
-Unknown,PM6,Strong,"Assumed de novo, but without confirmation of maternity (maternal testing done by targeted variant analysis and/or targeted gene sequencing)",
-Unknown,PM6,Moderate,"Assumed de novo, but without confirmation of maternity (maternal testing done by targeted variant analysis and/or targeted gene sequencing)",
-Unknown,PM6,Supporting,"Assumed de novo, but without confirmation of maternity (maternal testing done by targeted variant analysis and/or targeted gene sequencing)",
-Unknown,PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-Unknown,PP1,Moderate,Co-segregation with disease in 5+ maternal family members and level of heteroplasmy segregating with disease manifestations,
-Unknown,PP1,Supporting,Co-segregation with disease in 2-4 maternal family members and level of heteroplasmy segregating with disease manifestations,
-Unknown,PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-Unknown,PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-Unknown,PP3,Supporting,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, etc)",
-Unknown,PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-Unknown,PP4,Supporting,"Decreased ETC enzyme activity (<20%) performed in a CLIA-approved (or equivalently-certified) laboratory in muscle, liver, and/or fibroblasts (for fibroblasts, must be seen in multiple unrelated probands and/or assayed in different individuals).",
-Unknown,PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-Unknown,BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-Unknown,BA1,Stand Alone,Top-level haplogroup defining variants in individuals that are members of that same top-level haplogroup OR Allele frequency > 0.01 (1%),
-Unknown,BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-Unknown,BS1,Strong,Allele frequency 0.005 - 0.0099 (0.5% - 0.99%),
-Unknown,BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-Unknown,BS2,Strong,"Observed at a higher heteroplasmy in a healthy adult individual, especially in healthy maternal family members, than in same tissue tested in an affected individual",
-Unknown,BS2,Supporting,"Observed at a higher heteroplasmy in a healthy adult individual, especially in healthy maternal family members, than in different tissue(s) tested in an affected individual",
-Unknown,BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-Unknown,BS3,Supporting,"No evidence of functional effect in cybrid studies or single fiber analysis is present (no statistically significant difference from control; mean values of <2 SD from control mean, or 50% enzyme activity compared to controls).",
-Unknown,BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-Unknown,BS4,Strong,Lack of segregation in affected members of a family and/or segregation of disease in paternal family members,
-Unknown,BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-Unknown,BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-Unknown,BP2,Supporting,Other mtDNA variant is observed in individual’s mtDNA that has previously been confirmed to be pathogenic,
-Unknown,BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-Unknown,BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-Unknown,BP4,Supporting,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, etc)",
-Unknown,BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-Unknown,BP5,Supporting,Mitochondrial DNA variant found in a case with a nuclear DNA-related disease,
-Unknown,BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-Unknown,BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-Unknown,BP7,Supporting,A synonymous (silent) variant.,
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMitochondrialDiseaseNuclearandMitochondrialExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_ntDNA_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMitochondrialDiseaseNuclearandMitochondrialExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_ntDNA_version=1.0.0.csv
deleted file mode 100644
index 1a2c940cc7c809db825ab19cc6071120818288a8..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMitochondrialDiseaseNuclearandMitochondrialExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_ntDNA_version=1.0.0.csv
+++ /dev/null
@@ -1,329 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-SLC19A3 (HGNC:16266),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-SLC19A3 (HGNC:16266),PVS1,Very Strong,Applied per PVS1 flowsheet of Abou Toyoun et al.,
-SLC19A3 (HGNC:16266),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SLC19A3 (HGNC:16266),PS1,Strong,Same amino acid change as a previously established pathogenic variant regardless of nucleotide change,
-SLC19A3 (HGNC:16266),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-SLC19A3 (HGNC:16266),PS2,Strong,De novo in a patient with the disease and no family history,
-SLC19A3 (HGNC:16266),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-SLC19A3 (HGNC:16266),PS3,Supporting,Transporter assay showing loss of function,
-SLC19A3 (HGNC:16266),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",NA
-SLC19A3 (HGNC:16266),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-SLC19A3 (HGNC:16266),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-SLC19A3 (HGNC:16266),PM2,Moderate,<0.00005 (<0.0050%),
-SLC19A3 (HGNC:16266),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-SLC19A3 (HGNC:16266),PM3,Moderate,Use per SVI guidance,
-SLC19A3 (HGNC:16266),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-SLC19A3 (HGNC:16266),PM4,Moderate,Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants,
-SLC19A3 (HGNC:16266),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SLC19A3 (HGNC:16266),PM5,Moderate,Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before,
-SLC19A3 (HGNC:16266),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-SLC19A3 (HGNC:16266),PM6,Strong,De novo in a patient with the disease and no family history,
-SLC19A3 (HGNC:16266),PM6,Moderate,"Assumed de novo, but without confirmation of paternity and maternity",
-SLC19A3 (HGNC:16266),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-SLC19A3 (HGNC:16266),PP1,Supporting,"For segregation, an affected is defined as an individual who 
-
-
-
-
-has brainstem or basal ganglia lesions compatible with SLC19A3-related Biotin-responsive basal ganglia disease OR 
-
-
-a person with neurodevelopmental regression or MRI lesions compatible with SLC19A3-related Biotin-responsive basal ganglia disease who had significant clinical improvement in either symptoms or MRI lesions from treatment with biotin and thiamine.",
-SLC19A3 (HGNC:16266),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-SLC19A3 (HGNC:16266),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-SLC19A3 (HGNC:16266),PP3,Supporting,"No gene-specific predictors; agree to utilize REVEL, with thresholds of >0.75 and <0.15 for PP3 and BP4, respectively",
-SLC19A3 (HGNC:16266),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-SLC19A3 (HGNC:16266),PP4,Supporting,Patient has/had MRI features of Leigh syndrome with clinical response to biotin/thiamine,
-SLC19A3 (HGNC:16266),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SLC19A3 (HGNC:16266),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-SLC19A3 (HGNC:16266),BA1,Stand Alone,0.001 (>0.1%),
-SLC19A3 (HGNC:16266),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-SLC19A3 (HGNC:16266),BS1,Strong,0.0005 (>0.050%),
-SLC19A3 (HGNC:16266),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-SLC19A3 (HGNC:16266),BS2,Strong,"Observed in a healthy, untreated, adult individual in the homozygous state",
-SLC19A3 (HGNC:16266),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-SLC19A3 (HGNC:16266),BS3,Supporting,Transporter assay showing no effect on the gene or gene product,
-SLC19A3 (HGNC:16266),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-SLC19A3 (HGNC:16266),BS4,Strong,Lack of segregation in affected and/or treated members of a family.,
-SLC19A3 (HGNC:16266),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-SLC19A3 (HGNC:16266),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-SLC19A3 (HGNC:16266),BP2,Supporting,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern,
-SLC19A3 (HGNC:16266),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-SLC19A3 (HGNC:16266),BP3,Supporting,In-frame deletions/insertions in a repetitive region without a known function,
-SLC19A3 (HGNC:16266),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SLC19A3 (HGNC:16266),BP4,Supporting,"No gene-specific predictors; agree to utilize REVEL, with thresholds of >0.75 and <0.15 for PP3 and BP4, respectively",
-SLC19A3 (HGNC:16266),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-SLC19A3 (HGNC:16266),BP5,Supporting,Variant found in a case with an alternate molecular basis for disease,
-SLC19A3 (HGNC:16266),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SLC19A3 (HGNC:16266),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-SLC19A3 (HGNC:16266),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved,
-PDHA1 (HGNC:8806),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-PDHA1 (HGNC:8806),PVS1,Very Strong,Applied per PVS1 flowsheet of Abou Toyoun et al.,
-PDHA1 (HGNC:8806),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-PDHA1 (HGNC:8806),PS1,Strong,Same amino acid change as a previously established pathogenic variant regardless of nucleotide change,
-PDHA1 (HGNC:8806),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-PDHA1 (HGNC:8806),PS2,Strong,De novo in a patient with the disease and no family history,
-PDHA1 (HGNC:8806),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",NA
-PDHA1 (HGNC:8806),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",NA
-PDHA1 (HGNC:8806),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-PDHA1 (HGNC:8806),PM1,Moderate,"Located in one of the following functional domains:
-
-
-
-
-thiamine pyrophosphate (TPP) binding site (aa positions 118Y, 119R, 165G, 167V, 195G, 196D, 197G, 198A, 225N, 227Y, 292H).
-
-
-α β heterodimer interface (aa positions 160F, 162G, 164N, 169A, 172P, 173L, 176G, 177I, 179L, 180A,183Y, 202G,203Q, 209N, 210M, 213L).
-
-
-α2 β2 heterotetramer interface (aa positions 88R, 140G, 165G, 166I, 197G, 199A, 200N, 201Q, 202G, 205F, 209N, 213L, 228G, 229M, 230G, 231T, 245R, 296D, 300S).
-
-
-Phosphorylation loop region (aa positions 287Y, 288R, 289Y, 290H, 291G, 292H, 293S, 295S, 296D, 297P, 298G, 299V, 300S, 301Y, 302R, 303T, 304R, 305E, 314S, 315D, 316P).",
-PDHA1 (HGNC:8806),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-PDHA1 (HGNC:8806),PM2,Moderate,0.0000092 (<0.00092%),
-PDHA1 (HGNC:8806),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-PDHA1 (HGNC:8806),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-PDHA1 (HGNC:8806),PM4,Moderate,Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants,
-PDHA1 (HGNC:8806),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-PDHA1 (HGNC:8806),PM5,Moderate,Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before,
-PDHA1 (HGNC:8806),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-PDHA1 (HGNC:8806),PM6,Strong,De novo in a patient with the disease and no family history,
-PDHA1 (HGNC:8806),PM6,Moderate,"Assumed de novo, but without confirmation of paternity and maternity",
-PDHA1 (HGNC:8806),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-PDHA1 (HGNC:8806),PP1,Supporting,Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease,
-PDHA1 (HGNC:8806),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-PDHA1 (HGNC:8806),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-PDHA1 (HGNC:8806),PP3,Supporting,"No gene-specific predictors; agree to utilize REVEL, with thresholds of >0.75 and <0.15 for PP3 and BP4, respectively",
-PDHA1 (HGNC:8806),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-PDHA1 (HGNC:8806),PP4,Supporting,"One of the following criteria are met: 
-(1) Pyruvate radioactive enzyme assay showing decreased (as defined as <3rd percentile of controls) for PDC, activated and decreased ratios (PDC/E3 and/or PDC/CS) in fibroblasts, muscle, and/or lymphocytes; 
-(2) other assays showing decrease in PDC activity (ie: western blot, immunocapture, and activity; commercial kits for research); 
-(3) abnormally high pyruvate and/or pyruvate/lactate ratio",
-PDHA1 (HGNC:8806),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-PDHA1 (HGNC:8806),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-PDHA1 (HGNC:8806),BA1,Stand Alone,0.00092 (>0.092%),
-PDHA1 (HGNC:8806),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-PDHA1 (HGNC:8806),BS1,Strong,0.000092 (>0.0092%),
-PDHA1 (HGNC:8806),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-PDHA1 (HGNC:8806),BS2,Strong,Observed in at least two healthy male adults. Note: Individual’s phenotype is well-characterized (not just seen in database of presumed healthy individuals) AND/OR ≥16 hemizygotes in gnomAD,
-PDHA1 (HGNC:8806),BS2,Supporting,"Observed in 4-15 hemizygotes in gnomAD AND/OR Pyruvate radioactive enzyme assay showing normal (defined as >3rd percentile of controls) for PDC, activated and normal ratios (PDC/E3 and/or PDC/CS) in fibroblasts with no evidence of skewed X-inactivation in fibroblasts.",
-PDHA1 (HGNC:8806),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-PDHA1 (HGNC:8806),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-PDHA1 (HGNC:8806),BS4,Strong,Lack of segregation in affected and/or treated members of a family.,
-PDHA1 (HGNC:8806),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-PDHA1 (HGNC:8806),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-PDHA1 (HGNC:8806),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-PDHA1 (HGNC:8806),BP3,Supporting,In-frame deletions/insertions in a repetitive region without a known function,
-PDHA1 (HGNC:8806),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-PDHA1 (HGNC:8806),BP4,Supporting,"No gene-specific predictors; agree to utilize REVEL, with thresholds of >0.75 and <0.15 for PP3 and BP4, respectively",
-PDHA1 (HGNC:8806),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-PDHA1 (HGNC:8806),BP5,Supporting,Variant found in a case with an alternate molecular basis for disease,
-PDHA1 (HGNC:8806),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-PDHA1 (HGNC:8806),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-PDHA1 (HGNC:8806),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved,
-POLG (HGNC:9179),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-POLG (HGNC:9179),PVS1,Very Strong,Applied per PVS1 flowsheet of Abou Toyoun et al.,
-POLG (HGNC:9179),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-POLG (HGNC:9179),PS1,Strong,Same amino acid change as a previously established pathogenic variant regardless of nucleotide change,
-POLG (HGNC:9179),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-POLG (HGNC:9179),PS2,Strong,De novo in a patient with the disease and no family history,
-POLG (HGNC:9179),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",NA
-POLG (HGNC:9179),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-POLG (HGNC:9179),PS4,Strong,"Rarely, pathogenic variants cause disease in an AD manner. For these variants only, presence in: 2 unrelated probands will be considered supporting evidence, 4 unrelated probands will be considered moderate evidence, 16 unrelated probands will be strong evidence.
-
-
-
-
-Note: This will only be utilized when there is segregation evidence supporting autosomal dominant inheritance",
-POLG (HGNC:9179),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-POLG (HGNC:9179),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-POLG (HGNC:9179),PM2,Moderate,<0.0005 (<0.05% ),
-POLG (HGNC:9179),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-POLG (HGNC:9179),PM3,Moderate,"Use per SVI guidance.
-Note: T251I and P587L are almost always in cis",
-POLG (HGNC:9179),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-POLG (HGNC:9179),PM4,Moderate,Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants,
-POLG (HGNC:9179),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-POLG (HGNC:9179),PM5,Moderate,Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before,
-POLG (HGNC:9179),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-POLG (HGNC:9179),PM6,Strong,De novo in a patient with the disease and no family history,
-POLG (HGNC:9179),PM6,Moderate,"Assumed de novo, but without confirmation of paternity and maternity",
-POLG (HGNC:9179),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-POLG (HGNC:9179),PP1,Supporting,"Further define “affected” as an individual in whom there is objective evidence of manifestations consistent with POLG-related disorders spectrum: Alpers-Huttenlocher syndrome (AHS), childhood myocerebrohepatopathy spectrum (MCHS), myoclonic epilepsy myopathy sensory ataxia (MEMSA), ataxia neuropathy spectrum (ANS), and/or progressive external ophthalmoplegia (PEO)",
-POLG (HGNC:9179),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-POLG (HGNC:9179),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-POLG (HGNC:9179),PP3,Supporting,"Agree to utilize REVEL, with thresholds of >0.75 and <0.15 for PP3 and BP4, respectively
-
-
-
-
-Will also utilize POLG pathogenicity prediction server if/when live again (PMID: 28480171); both tools (REVEL and server) will have to be in agreement to score",
-POLG (HGNC:9179),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-POLG (HGNC:9179),PP4,Moderate,"Mitochondrial DNA depletion showing ≤ 20% of controls, OR 
-
-
-Multiple mitochondrial DNA deletions (NOTE:depletion and/or deletion analysis must be performed in muscle and/or liver; other tissues such as blood, fibroblast, and buccal are not acceptable; Must be performed in child, as defined as <18 years old) 
-Note: For both scenarios 1 and 2, will only apply if other mtDNA maintenance disorders have been excluded (exome sequencing or comprehensive panel-based testing)",
-POLG (HGNC:9179),PP4,Supporting,"Mitochondrial DNA depletion showing 20-50% of controls in children (< 18 years of age), AND/OR 
-
-
-COX negative fibers in muscle in children and/or adults
-Note: Will only apply if other mtDNA maintenance disorders have been excluded (exome sequencing or comprehensive panel-based testing)",
-POLG (HGNC:9179),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-POLG (HGNC:9179),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-POLG (HGNC:9179),BA1,Stand Alone,0.01 (>1%),
-POLG (HGNC:9179),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-POLG (HGNC:9179),BS1,Strong,0.005 (>0.5% - AR),
-POLG (HGNC:9179),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-POLG (HGNC:9179),BS2,Strong,"Observed in a healthy adult individual in the homozygous state AND/OR Normal mtDNA content (1. Must be performed in muscle and/or liver; blood, fibroblast, and buccal not acceptable; 2. Must be performed in children only - defined as <18 years old; 3. A normal level is defined as >50%.)",
-POLG (HGNC:9179),BS2,Supporting,Lack of COX negative fibers in muscle (children and adults),
-POLG (HGNC:9179),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-POLG (HGNC:9179),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-POLG (HGNC:9179),BS4,Strong,Lack of segregation in affected and/or treated members of a family.,
-POLG (HGNC:9179),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-POLG (HGNC:9179),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-POLG (HGNC:9179),BP2,Supporting,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern,
-POLG (HGNC:9179),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-POLG (HGNC:9179),BP3,Supporting,In-frame deletions/insertions in a repetitive region without a known function,
-POLG (HGNC:9179),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-POLG (HGNC:9179),BP4,Supporting,"Agree to utilize REVEL, with thresholds of >0.75 and <0.15 for PP3 and BP4, respectively. Will also utilize POLG pathogenicity prediction server if/when live again (PMID: 28480171); both tools (REVEL and server) will have to be in agreement to score",
-POLG (HGNC:9179),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-POLG (HGNC:9179),BP5,Supporting,Variant found in a case with an alternate molecular basis for disease,
-POLG (HGNC:9179),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-POLG (HGNC:9179),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-POLG (HGNC:9179),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved,
-ETHE1 (HGNC:23287),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-ETHE1 (HGNC:23287),PVS1,Very Strong,Applied per PVS1 flowsheet of Abou Toyoun et al.,
-ETHE1 (HGNC:23287),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-ETHE1 (HGNC:23287),PS1,Strong,Same amino acid change as a previously established pathogenic variant regardless of nucleotide change,
-ETHE1 (HGNC:23287),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-ETHE1 (HGNC:23287),PS2,Strong,De novo in a patient with the disease and no family history,
-ETHE1 (HGNC:23287),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-ETHE1 (HGNC:23287),PS3,Supporting,Reduced ETHE1 persulfide dioxygenase,
-ETHE1 (HGNC:23287),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",NA
-ETHE1 (HGNC:23287),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-ETHE1 (HGNC:23287),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-ETHE1 (HGNC:23287),PM2,Moderate,<0.00002 (<0.0020%),
-ETHE1 (HGNC:23287),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-ETHE1 (HGNC:23287),PM3,Moderate,Use per SVI guidance,
-ETHE1 (HGNC:23287),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-ETHE1 (HGNC:23287),PM4,Moderate,Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants,
-ETHE1 (HGNC:23287),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-ETHE1 (HGNC:23287),PM5,Moderate,Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before,
-ETHE1 (HGNC:23287),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-ETHE1 (HGNC:23287),PM6,Strong,De novo in a patient with the disease and no family history,
-ETHE1 (HGNC:23287),PM6,Moderate,"Assumed de novo, but without confirmation of paternity and maternity",
-ETHE1 (HGNC:23287),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-ETHE1 (HGNC:23287),PP1,Supporting,Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease,
-ETHE1 (HGNC:23287),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-ETHE1 (HGNC:23287),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-ETHE1 (HGNC:23287),PP3,Supporting,"No gene-specific predictors; agree to utilize REVEL, with thresholds of >0.75 and <0.15 f or PP3 and BP4, respectively",
-ETHE1 (HGNC:23287),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-ETHE1 (HGNC:23287),PP4,Moderate,"Individual has abnormally high urinary ethylmalonic acid AND one of the following: 
-(1) All of the following symptoms present: -Acrocyanosis -Petechiae -Chronic diarrhea -Developmental delay 
-(2) ≥3 or more of the following biochemical studies: -Abnormally high blood C4-Acylcarnitine esters -Abnormally high blood C5-acylcarnitine -Abnormally high plasma thiosulphate -Abnormally low cytochrome oxidase activity in skeletal muscle (without evidence of other complexes decreased)",
-ETHE1 (HGNC:23287),PP4,Supporting,"Individual has abnoramlly high urinary ethylmalonic acid AND one of the following: 
-(1) 3 of the following features present: -Acrocyanosis -Petechiae -Chronic diarrhea -Developmental delay 
-(2) abnormal laboratory studies in 2 of the following biochemical studies: -Abnormally high blood C4-Acylcarnitine esters -Abnormally high blood C5-acylcarnitine -Abnormally high plasma thiosulphate -Abnormally low cytochrome oxidase activity in skeletal muscle, without evidence of other complexes decreased",
-ETHE1 (HGNC:23287),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-ETHE1 (HGNC:23287),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-ETHE1 (HGNC:23287),BA1,Stand Alone,0.001 (>0.1%),
-ETHE1 (HGNC:23287),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-ETHE1 (HGNC:23287),BS1,Strong,0.0002 (>0.020%),
-ETHE1 (HGNC:23287),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-ETHE1 (HGNC:23287),BS2,Strong,Observed in a healthy adult individual in the homozygous state,
-ETHE1 (HGNC:23287),BS2,Supporting,Normal laboratory values (specific labs outlined in PP4),
-ETHE1 (HGNC:23287),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-ETHE1 (HGNC:23287),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-ETHE1 (HGNC:23287),BS4,Strong,Lack of segregation in affected and/or treated members of a family.,
-ETHE1 (HGNC:23287),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-ETHE1 (HGNC:23287),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-ETHE1 (HGNC:23287),BP2,Supporting,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern,
-ETHE1 (HGNC:23287),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-ETHE1 (HGNC:23287),BP3,Supporting,In-frame deletions/insertions in a repetitive region without a known function,
-ETHE1 (HGNC:23287),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-ETHE1 (HGNC:23287),BP4,Supporting,"No gene-specific predictors; agree to utilize REVEL, with thresholds of >0.75 and <0.15 f or PP3 and BP4, respectively",
-ETHE1 (HGNC:23287),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-ETHE1 (HGNC:23287),BP5,Supporting,Variant found in a case with an alternate molecular basis for disease,
-ETHE1 (HGNC:23287),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-ETHE1 (HGNC:23287),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-ETHE1 (HGNC:23287),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved,
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1_version=1.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1_version=1.1.0.csv
deleted file mode 100644
index 103f0de16920ecca9c881e9d2d222beff5c96333..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1_version=1.1.0.csv
+++ /dev/null
@@ -1,166 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-HNF1A (HGNC:11621),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-HNF1A (HGNC:11621),PVS1,Very Strong,See HNF1A PVS1 decision tree.,"Gene-Specific,Strength"
-HNF1A (HGNC:11621),PVS1,Strong,See HNF1A PVS1 decision tree.,"Gene-Specific,Strength"
-HNF1A (HGNC:11621),PVS1,Supporting,Use HNF1A PVS1 decision tree.,"Gene-Specific,Strength"
-HNF1A (HGNC:11621),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-HNF1A (HGNC:11621),PS1,Strong,No change,
-HNF1A (HGNC:11621),PS1,Supporting,PS1 may also be used at a supporting level for canonical and non-canonical splicing variants when a different variant at the same nucleotide has been previously classified as pathogenic and the variant being assessed is predicted by SpliceAI to have a similar (SpliceAI score within 10% of the original variant) or greater deleterious impact.,Strength
-HNF1A (HGNC:11621),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-HNF1A (HGNC:11621),PS2,Very Strong,Use SVI recommended point-based system with specifications for “Phenotype Consistency” described in PP4 specifications.,"Gene-specific,Strength"
-HNF1A (HGNC:11621),PS2,Strong,Use SVI recommended point-based system with specifications for “Phenotype Consistency” described in PP4 specifications.,"Gene-specific,Strength"
-HNF1A (HGNC:11621),PS2,Moderate,Use SVI recommended point-based system with specifications for “Phenotype Consistency” described in PP4 specifications.,"Gene-specific,Strength"
-HNF1A (HGNC:11621),PS2,Supporting,Use SVI recommended point-based system with specifications for “Phenotype Consistency” described in PP4 specifications.,"Gene-specific,Strength"
-HNF1A (HGNC:11621),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-HNF1A (HGNC:11621),PS3,Strong,Applicable to non-canonical splice site variants that have RNA and in silico evidence of aberrant splicing.,"Gene-specific,Strength"
-HNF1A (HGNC:11621),PS3,Moderate,"Applicable for variants with luciferase assay data (evidence of decreased transactivation (<=40% of wild type) by the Gloyn/Oxford group (Althari et al 2020 
-https://pubmed.ncbi.nlm.nih.gov/32910913/
-)","Gene-specific,Strength"
-HNF1A (HGNC:11621),PS3,Supporting,"See list of approved functional studies and guidelines for interpretation of data (below).
-(1) Luciferase assays for transactivation - ""Decreased function"" is defined as activity less than 40% of wildtype. Assays should include controls for WT, T2DM-risk, and known MODY variants. For additional specifications and recommendations, please see the HNF1A rules.
-(2) EMSA for DNA binding - ""Decreased function"" is defined as activity lesss than 405 of wildtype. We recommend that at least two of the following variants be used as positive controls for reduced DNA binding activity: c.335C>T (p.Pro112Leu), c.608G>A (p.Arg203His), c.787C>T (p.Arg263Cys) and c.686G>A (p.Arg229Gln) (PMID: 11162430, 12574234, 24915262). For additional specifications and recommendations, please see the HNF1A rules.
-(3) Western blotting and indirect immunoflorescence for protein expression and localization - Determining appropriate thresholds for protein expression is more difficult due to variability in results between experimental protocols. Altered protein expression can be indirectly captured through the read-out frame from transactivation assay, and reduced protein expression can provide an explanation for reduced transactivation. When exploring protein mis-localization, we recommend that the c.589_615del (p.Lys197_Lys205del) variant is included as a positive control for impaired nuclear localization (cytosolic retention).","Gene-specific,Strength"
-HNF1A (HGNC:11621),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-HNF1A (HGNC:11621),PS4,Strong,"Seven or more= Strong. Variant should meet PM2_Supporting in order to use PS4 at any level (careful review of gnomAD QC data may be necessary to assess whether variant is real or an artifact, especially if variant is in a polyC region). Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology (see below).","Gene-specific,Strength"
-HNF1A (HGNC:11621),PS4,Moderate,4-6 unrelated occurrences = Moderate.,"Gene-specific,Strength"
-HNF1A (HGNC:11621),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-HNF1A (HGNC:11621),PM1,Moderate,"This criterion can be used for variants in residues that directly bind DNA:   Gln130, Arg131, Glu132, His143, Leu144, Ser145, Gln146, His147, Leu148, Asn149, Lys155, Thr156, Gln157, Lys158, Arg203, Phe204, Lys205, Trp206, Arg263, Val264, Tyr265, Asn270, Arg271, Arg272, Lys273","Gene-specific,Strength"
-HNF1A (HGNC:11621),PM1,Supporting,"Use for defined regions in the DNA binding and dimerization domains. 
-
-
-
-
-Dimerization: codons 1-32, NM_000545.8 
-
-
-Subset of DNA binding domains: codons 107-174 and 201-280, NM_000545.8 
-It can also be used for variants within certain transcription factor binding sites of the promoter.  
-
-
-–c.-187 to c.-195 (AP1 binding site) 
-
-
-–c.-209 to c.-227 (Overlapping HNF3 & NF-Y sites) 
-
-
-–c.-238 to c.-259 (HNF1A binding site) 
-
-
-–c.-276 to c.-288 (HNF4A binding site)","Gene-specific,Strength"
-HNF1A (HGNC:11621),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-HNF1A (HGNC:11621),PM2,Supporting,"Prevalence ≤ 1:50,000 (≤ 0.00002 or 0.002%) in gnomAD v2.1.1 European Non-Finnish population AND ≤ 1 copy in other founder and non-founder populations (would require ≤ 1/50,000 in non-European populations if/when they surpass 100,000 alleles).","General recommendation,Gene-specific"
-HNF1A (HGNC:11621),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-HNF1A (HGNC:11621),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-HNF1A (HGNC:11621),PM4,Moderate,"For single amino acid deletions, use as supporting level of evidence.",Strength
-HNF1A (HGNC:11621),PM4,Supporting,"For single amino acid deletions/insertions, use as supporting level of evidence",Strength
-HNF1A (HGNC:11621),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-HNF1A (HGNC:11621),PM5,Strong,Applicable once two amino acid changes have been classified as pathogenic at the same amino acid residue,Strength
-HNF1A (HGNC:11621),PM5,Moderate,The novel amino acid change must have a Grantham distance greater than or equal to the previously classified pathogenic variant.,Strength
-HNF1A (HGNC:11621),PM5,Supporting,Apply if the previously classified amino acid change is likely pathogenic (rather than pathogenic) or if the previously classified variant is pathogenic but has a greater Grantham distance.,Strength
-HNF1A (HGNC:11621),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-HNF1A (HGNC:11621),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-HNF1A (HGNC:11621),PP1,Strong,"Use thresholds suggested by Jarvik and Browning (PMID: 27236918)
-
-
-
-
-Single Family : ≤ 1/32 (5 meioses) 
-
-
-
-
-1 Family : ≤ 1/16 (4 meioses)","Gene-specific,Stength,General recommendation"
-HNF1A (HGNC:11621),PP1,Moderate,"Use thresholds suggested by Jarvik and Browning (PMID: 27236918)
-
-
-
-
-Single Family : ≤ 1/16 (4 meioses)
-
-
-
-
-1 Family : ≤ 1/8 (3 meioses)","Gene-specific,Stength,General recommendation"
-HNF1A (HGNC:11621),PP1,Supporting,"Use thresholds suggested by Jarvik and Browning (PMID: 27236918)
-
-
-
-
-Single Family : ≤ 1/8 (3 meioses)          
-
-
-
-
-1 Family : ≤ ¼ (2 meioses)","Gene-specific,Stength,General recommendation"
-HNF1A (HGNC:11621),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-HNF1A (HGNC:11621),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-HNF1A (HGNC:11621),PP3,Supporting,Use REVEL score of ≥0.70 as supportive evidence of pathogenicity. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply PP3 when the predicted change is above 0.2 (Wai et al. 2020 PMID: 32123317; Jaganathan et al. 2019 PMID: 30661751).,General recommendation
-HNF1A (HGNC:11621),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-HNF1A (HGNC:11621),PP4,Moderate,"MODY Probability Calculator (MPC) result ≥50% chance of testing positive 
-https://www.diabetesgenes.org/mody-probability-calculator/
-) AND negative HNF4A testing AND presence of at least one additional feature characteristic of HNF1A-MODY:
-
-
-
-
-Antibody negative and/or persistent C-peptide after five years post- T1DM diagnosis
-
-
-Response to low-dose SU (extreme response- hypoglycemia)
-
-
-Low hsCRP in patient with clinical diagnosis of T2DM
-
-
-Biochemical/Molecular phenotypic evidence from patient cell lines
-
-
-Hepatocellular adenomas","Gene-specific,strength"
-HNF1A (HGNC:11621),PP4,Supporting,"MODY Probability Calculator (MPC) result ≥50% chance of testing positive 
-https://www.diabetesgenes.org/mody-probability-calculator/
-) AND negative HNF4A testing","Gene-specific,strength"
-HNF1A (HGNC:11621),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-HNF1A (HGNC:11621),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-HNF1A (HGNC:11621),BA1,Stand Alone,"MAF ≥ 1:10,000 (≥ 0.01% or 0.0001) in gnomAD Popmax Filtering AF.",Gene-specific
-HNF1A (HGNC:11621),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-HNF1A (HGNC:11621),BS1,Strong,"MAF ≥ 1:30,000 (≥0.0033% or 0.000033) in gnomAD Popmax Filtering AF.",Gene-specific
-HNF1A (HGNC:11621),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-HNF1A (HGNC:11621),BS2,Strong,"Apply to normoglycemic individuals age 70 or older (i.e., genotype positive, phenotype negative)",Gene-specific
-HNF1A (HGNC:11621),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-HNF1A (HGNC:11621),BS3,Strong,Applicable to non-canonical splice site variants that have RNA and in silico evidence of normal splicing.,"Gene-specific,strength"
-HNF1A (HGNC:11621),BS3,Supporting,"See HNF1A rules for full list of approved functional studies and guidelines for interpretation of data. 
-(1) Luciferase assays for transactivation - ""No functional impact"" is defined as ≥ 75% activity of wildtype
-(2) EMSA for DNA binding - ""No functional impact"" is defined as ≥ 75% activity of wildtype.
-(3) Western blotting and indirect immunoflorescence for protein expression and localization - Determining appropriate thresholds for protein expression is more difficult due to variability in results between different experimental protocols. Altered protein expression can be indirectly captured through the read-out from a transactivation assay and reduced protein expression can provide an explanation for reduced transactivation.","Gene-specific,strength"
-HNF1A (HGNC:11621),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-HNF1A (HGNC:11621),BS4,Strong,"Applicable to family members without variant who have MPC score >50% (i.e., genotype negative, phenotype positive).",Gene-specific
-HNF1A (HGNC:11621),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-HNF1A (HGNC:11621),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-HNF1A (HGNC:11621),BP2,Supporting,Also applicable when in cis or trans with a likely pathogenic variant.,General recommendation
-HNF1A (HGNC:11621),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-HNF1A (HGNC:11621),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-HNF1A (HGNC:11621),BP4,Supporting,Use a REVEL score of ≤0.15 as supportive evidence of no predicted impact on the gene or gene product. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply BP4 when the predicted change is below 0.2 (Wai et al. 2020 PMID: 32123317; Jaganathan et al. 2019 PMID: 30661751).,General recommendation
-HNF1A (HGNC:11621),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-HNF1A (HGNC:11621),BP5,Supporting,A variant in other monogenic diabetes gene is P/LP.,General recommendation
-HNF1A (HGNC:11621),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-HNF1A (HGNC:11621),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-HNF1A (HGNC:11621),BP7,Supporting,Use with no specifications.,
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.2_version=1.2.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.2_version=1.2.0.csv
deleted file mode 100644
index 74737468fdb72f45da8ad8ec004e187bec208753..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.2_version=1.2.0.csv
+++ /dev/null
@@ -1,250 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-HNF1A (HGNC:11621),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-HNF1A (HGNC:11621),PVS1,Very Strong,"Use HNF1A PVS1 decision tree.
-
-
-
-
-Variants generating PTCs 3’ of c.1714 of NM_000545.8, which includes the last 55 nucleotides of exon 9 and all of exon 10, are not expected to cause NMD (PMID: 24274751). The transactivation domain (TAD) of the protein overlaps with this region. The last 55 nucleotides of exon 9 (c.1714-1768) is enriched for disease-causing variants and loss-of function variants in this region have been found in patients/families with a MODY phenotype. Therefore, a “very strong” level of evidence will be used for loss-of-function variants 5’ of c.1768 regardless of where the premature termination codon occurs.
-
-
-PVS1_Strong will be applied to nonsense variants at c.1803 (p.601) and 5’ and frameshift variants at c.1854 (p.618) and 5’. The distinction of nonsense and frameshift variants was made following a careful review of the phenotypes of individuals with loss-of-function variants in exon 10, which lead to our prediction that the addition of new amino acids from a frameshift will disrupt the TAD and cause a MODY phenotype more so than the deletion of a small part of the end of the TAD. Moderate phenotypic evidence was applied to the c.1802del (p.601Ter) variant, but the individual with the next nonsense variant (p.Gln625Ter) was unaffected. Frameshift variants at p.Ile618 and 5’ have been identified in patients with a phenotype consistent with MODY.
-
-
-
-
-
-
-“Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame”
-
-
-Deletions of exon 1 would lead at least to loss of the initiation codon (see below for recommendations for initiation codon variants). Deletions of single exons 2, 3, 4, 5, 6, 8 or 9 all cause frameshift, and thus PVS1 would be used. In HNF1A, only exon 7 (LRG_522t1) is surrounded by introns of the same phase. Skipping or deletion of exon 7 would remove 64 amino acids in the TAD, which is >10% of the protein and 18% of the TAD. Given the significance of the TAD, we support still using PVS1 instead of PVS1_Strong in this situation. A deletion of exon 10 would remove part of the TAD but less than 10% of the protein. Since the TAD is critical to protein function, and variants that disrupt all of exon 10 have been found in patients with a MODY phenotype, we will use PVS1_Strong for deletions of exon 10 and splicing variants that would predict the skipping of exon 10. This specification is in accordance with Tayoun’s recommendation to use PVS1_Strong in cases in which the truncated region is critical to protein function.
-
-
-
-
-
-
-Apply PVS1 to initiation codon variants. Four initiation codon variants have been identified in patients with a MODY phenotype. The closest potential in-frame start codon is p.Met118. Starting the protein at p.Met118 would remove 18% of the protein, including the entire dimerization domain. There are many P/LP variants upstream of p.Met118.
-
-
-Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.","Gene-Specific,Strength"
-HNF1A (HGNC:11621),PVS1,Strong,"Use HNF1A PVS1 decision tree.
-
-
-
-
-Variants generating PTCs 3’ of c.1714 of NM_000545.8, which includes the last 55 nucleotides of exon 9 and all of exon 10, are not expected to cause NMD (PMID: 24274751). The transactivation domain (TAD) of the protein overlaps with this region. The last 55 nucleotides of exon 9 (c.1714-1768) is enriched for disease-causing variants and loss-of function variants in this region have been found in patients/families with a MODY phenotype. Therefore, a “very strong” level of evidence will be used for loss-of-function variants 5’ of c.1768 regardless of where the premature termination codon occurs.
-
-
-PVS1_Strong will be applied to nonsense variants at c.1803 (p.601) and 5’ and frameshift variants at c.1854 (p.618) and 5’. The distinction of nonsense and frameshift variants was made following a careful review of the phenotypes of individuals with loss-of-function variants in exon 10, which lead to our prediction that the addition of new amino acids from a frameshift will disrupt the TAD and cause a MODY phenotype more so than the deletion of a small part of the end of the TAD. Moderate phenotypic evidence was applied to the c.1802del (p.601Ter) variant, but the individual with the next nonsense variant (p.Gln625Ter) was unaffected. Frameshift variants at p.Ile618 and 5’ have been identified in patients with a phenotype consistent with MODY.
-
-
-
-
-
-
-“Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame”
-
-
-Deletions of exon 1 would lead at least to loss of the initiation codon (see below for recommendations for initiation codon variants). Deletions of single exons 2, 3, 4, 5, 6, 8 or 9 all cause frameshift, and thus PVS1 would be used. In HNF1A, only exon 7 (LRG_522t1) is surrounded by introns of the same phase. Skipping or deletion of exon 7 would remove 64 amino acids in the TAD, which is >10% of the protein and 18% of the TAD. Given the significance of the TAD, we support still using PVS1 instead of PVS1_Strong in this situation. A deletion of exon 10 would remove part of the TAD but less than 10% of the protein. Since the TAD is critical to protein function, and variants that disrupt all of exon 10 have been found in patients with a MODY phenotype, we will use PVS1_Strong for deletions of exon 10 and splicing variants that would predict the skipping of exon 10. This specification is in accordance with Tayoun’s recommendation to use PVS1_Strong in cases in which the truncated region is critical to protein function.
-
-
-
-
-
-
-Apply PVS1 to initiation codon variants. Four initiation codon variants have been identified in patients with a MODY phenotype. The closest potential in-frame start codon is p.Met118. Starting the protein at p.Met118 would remove 18% of the protein, including the entire dimerization domain. There are many P/LP variants upstream of p.Met118.
-
-
-Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.","Gene-Specific,Strength"
-HNF1A (HGNC:11621),PVS1,Supporting,"Use HNF1A PVS1 decision tree.
-
-
-
-
-Variants generating PTCs 3’ of c.1714 of NM_000545.8, which includes the last 55 nucleotides of exon 9 and all of exon 10, are not expected to cause NMD (PMID: 24274751). The transactivation domain (TAD) of the protein overlaps with this region. The last 55 nucleotides of exon 9 (c.1714-1768) is enriched for disease-causing variants and loss-of function variants in this region have been found in patients/families with a MODY phenotype. Therefore, a “very strong” level of evidence will be used for loss-of-function variants 5’ of c.1768 regardless of where the premature termination codon occurs.
-
-
-PVS1_Strong will be applied to nonsense variants at c.1803 (p.601) and 5’ and frameshift variants at c.1854 (p.618) and 5’. The distinction of nonsense and frameshift variants was made following a careful review of the phenotypes of individuals with loss-of-function variants in exon 10, which lead to our prediction that the addition of new amino acids from a frameshift will disrupt the TAD and cause a MODY phenotype more so than the deletion of a small part of the end of the TAD. Moderate phenotypic evidence was applied to the c.1802del (p.601Ter) variant, but the individual with the next nonsense variant (p.Gln625Ter) was unaffected. Frameshift variants at p.Ile618 and 5’ have been identified in patients with a phenotype consistent with MODY.
-
-
-
-
-
-
-“Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame”
-
-
-Deletions of exon 1 would lead at least to loss of the initiation codon (see below for recommendations for initiation codon variants). Deletions of single exons 2, 3, 4, 5, 6, 8 or 9 all cause frameshift, and thus PVS1 would be used. In HNF1A, only exon 7 (LRG_522t1) is surrounded by introns of the same phase. Skipping or deletion of exon 7 would remove 64 amino acids in the TAD, which is >10% of the protein and 18% of the TAD. Given the significance of the TAD, we support still using PVS1 instead of PVS1_Strong in this situation. A deletion of exon 10 would remove part of the TAD but less than 10% of the protein. Since the TAD is critical to protein function, and variants that disrupt all of exon 10 have been found in patients with a MODY phenotype, we will use PVS1_Strong for deletions of exon 10 and splicing variants that would predict the skipping of exon 10. This specification is in accordance with Tayoun’s recommendation to use PVS1_Strong in cases in which the truncated region is critical to protein function.
-
-
-
-
-
-
-Apply PVS1 to initiation codon variants. Four initiation codon variants have been identified in patients with a MODY phenotype. The closest potential in-frame start codon is p.Met118. Starting the protein at p.Met118 would remove 18% of the protein, including the entire dimerization domain. There are many P/LP variants upstream of p.Met118.
-
-
-Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.","Gene-Specific,Strength"
-HNF1A (HGNC:11621),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-HNF1A (HGNC:11621),PS1,Strong,No change,
-HNF1A (HGNC:11621),PS1,Supporting,PS1 may also be used at a supporting level for canonical and non-canonical splicing variants when a different variant at the same nucleotide has been previously classified as pathogenic and the variant being assessed is predicted by SpliceAI to have a similar (SpliceAI score within 10% of the original variant) or greater deleterious impact.,Strength
-HNF1A (HGNC:11621),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-HNF1A (HGNC:11621),PS2,Very Strong,Use SVI recommended point-based system with specifications for “Phenotype Consistency” described in PP4 specifications.,"Gene-specific,Strength"
-HNF1A (HGNC:11621),PS2,Strong,Use SVI recommended point-based system with specifications for “Phenotype Consistency” described in PP4 specifications.,"Gene-specific,Strength"
-HNF1A (HGNC:11621),PS2,Moderate,Use SVI recommended point-based system with specifications for “Phenotype Consistency” described in PP4 specifications.,"Gene-specific,Strength"
-HNF1A (HGNC:11621),PS2,Supporting,Use SVI recommended point-based system with specifications for “Phenotype Consistency” described in PP4 specifications.,"Gene-specific,Strength"
-HNF1A (HGNC:11621),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-HNF1A (HGNC:11621),PS3,Strong,Applicable to non-canonical splice site variants that have RNA and in silico evidence of aberrant splicing.,"Gene-specific,Strength"
-HNF1A (HGNC:11621),PS3,Moderate,"Applicable for variants with luciferase assay data (evidence of decreased transactivation (<=40% of wild type) by the Gloyn/Oxford group (Althari et al 2020 
-https://pubmed.ncbi.nlm.nih.gov/32910913/
-)","Gene-specific,Strength"
-HNF1A (HGNC:11621),PS3,Supporting,"See list of approved functional studies and guidelines for interpretation of data (below).
-(1) Luciferase assays for transactivation - ""Decreased function"" is defined as activity less than 40% of wildtype. Assays should include controls for WT, T2DM-risk, and known MODY variants. For additional specifications and recommendations, please see the HNF1A rules.
-(2) EMSA for DNA binding - ""Decreased function"" is defined as activity lesss than 405 of wildtype. We recommend that at least two of the following variants be used as positive controls for reduced DNA binding activity: c.335C>T (p.Pro112Leu), c.608G>A (p.Arg203His), c.787C>T (p.Arg263Cys) and c.686G>A (p.Arg229Gln) (PMID: 11162430, 12574234, 24915262). For additional specifications and recommendations, please see the HNF1A rules.
-(3) Western blotting and indirect immunoflorescence for protein expression and localization - Determining appropriate thresholds for protein expression is more difficult due to variability in results between experimental protocols. Altered protein expression can be indirectly captured through the read-out frame from transactivation assay, and reduced protein expression can provide an explanation for reduced transactivation. When exploring protein mis-localization, we recommend that the c.589_615del (p.Lys197_Lys205del) variant is included as a positive control for impaired nuclear localization (cytosolic retention).","Gene-specific,Strength"
-HNF1A (HGNC:11621),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-HNF1A (HGNC:11621),PS4,Strong,"Seven or more= Strong. Variant should meet PM2_Supporting in order to use PS4 at any level (careful review of gnomAD QC data may be necessary to assess whether variant is real or an artifact, especially if variant is in a polyC region). Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology (see below).","Gene-specific,Strength"
-HNF1A (HGNC:11621),PS4,Moderate,4-6 unrelated occurrences = Moderate.,"Gene-specific,Strength"
-HNF1A (HGNC:11621),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-HNF1A (HGNC:11621),PM1,Moderate,"This criterion can be used for variants in residues that directly bind DNA:   Gln130, Arg131, Glu132, His143, Leu144, Ser145, Gln146, His147, Leu148, Asn149, Lys155, Thr156, Gln157, Lys158, Arg203, Phe204, Lys205, Trp206, Arg263, Val264, Tyr265, Asn270, Arg271, Arg272, Lys273","Gene-specific,Strength"
-HNF1A (HGNC:11621),PM1,Supporting,"Use for defined regions in the DNA binding and dimerization domains. 
-
-
-
-
-Dimerization: codons 1-32, NM_000545.8 
-
-
-Subset of DNA binding domains: codons 107-174 and 201-280, NM_000545.8 
-It can also be used for variants within certain transcription factor binding sites of the promoter.  
-
-
-–c.-187 to c.-195 (AP1 binding site) 
-
-
-–c.-209 to c.-227 (Overlapping HNF3 & NF-Y sites) 
-
-
-–c.-238 to c.-259 (HNF1A binding site) 
-
-
-–c.-276 to c.-288 (HNF4A binding site)","Gene-specific,Strength"
-HNF1A (HGNC:11621),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-HNF1A (HGNC:11621),PM2,Supporting,"Prevalence ≤ 1:50,000 (≤ 0.00002 or 0.002%) in gnomAD v2.1.1 European Non-Finnish population AND ≤ 1 copy in other founder and non-founder populations (would require ≤ 1/50,000 in non-European populations if/when they surpass 100,000 alleles).","General recommendation,Gene-specific"
-HNF1A (HGNC:11621),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-HNF1A (HGNC:11621),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-HNF1A (HGNC:11621),PM4,Moderate,"For single amino acid deletions, use as supporting level of evidence.",Strength
-HNF1A (HGNC:11621),PM4,Supporting,"For single amino acid deletions/insertions, use as supporting level of evidence",Strength
-HNF1A (HGNC:11621),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-HNF1A (HGNC:11621),PM5,Strong,Applicable once two amino acid changes have been classified as pathogenic at the same amino acid residue,Strength
-HNF1A (HGNC:11621),PM5,Moderate,The novel amino acid change must have a Grantham distance greater than or equal to the previously classified pathogenic variant.,Strength
-HNF1A (HGNC:11621),PM5,Supporting,Apply if the previously classified amino acid change is likely pathogenic (rather than pathogenic) or if the previously classified variant is pathogenic but has a greater Grantham distance.,Strength
-HNF1A (HGNC:11621),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-HNF1A (HGNC:11621),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-HNF1A (HGNC:11621),PP1,Strong,"Use thresholds suggested by Jarvik and Browning (PMID: 27236918)
-
-
-
-
-Single Family : ≤ 1/32 (5 meioses) 
-
-
-
-
-1 Family : ≤ 1/16 (4 meioses)","Gene-specific,Stength,General recommendation"
-HNF1A (HGNC:11621),PP1,Moderate,"Use thresholds suggested by Jarvik and Browning (PMID: 27236918)
-
-
-
-
-Single Family : ≤ 1/16 (4 meioses)
-
-
-
-
-1 Family : ≤ 1/8 (3 meioses)","Gene-specific,Stength,General recommendation"
-HNF1A (HGNC:11621),PP1,Supporting,"Use thresholds suggested by Jarvik and Browning (PMID: 27236918)
-
-
-
-
-Single Family : ≤ 1/8 (3 meioses)          
-
-
-
-
-1 Family : ≤ ¼ (2 meioses)","Gene-specific,Stength,General recommendation"
-HNF1A (HGNC:11621),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-HNF1A (HGNC:11621),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-HNF1A (HGNC:11621),PP3,Supporting,Use REVEL score of ≥0.70 as supportive evidence of pathogenicity. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply PP3 when the predicted change is above 0.2 (Wai et al. 2020 PMID: 32123317; Jaganathan et al. 2019 PMID: 30661751).,General recommendation
-HNF1A (HGNC:11621),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-HNF1A (HGNC:11621),PP4,Moderate,"MODY Probability Calculator (MPC) result ≥50% chance of testing positive 
-https://www.diabetesgenes.org/mody-probability-calculator/
-) AND negative HNF4A testing AND presence of at least one additional feature characteristic of HNF1A-MODY:
-
-
-
-
-Antibody negative and/or persistent C-peptide after five years post- T1DM diagnosis
-
-
-Response to low-dose SU (extreme response- hypoglycemia)
-
-
-Low hsCRP in patient with clinical diagnosis of T2DM
-
-
-Biochemical/Molecular phenotypic evidence from patient cell lines
-
-
-Hepatocellular adenomas","Gene-specific,strength"
-HNF1A (HGNC:11621),PP4,Supporting,"MODY Probability Calculator (MPC) result ≥50% chance of testing positive 
-https://www.diabetesgenes.org/mody-probability-calculator/
-) AND negative HNF4A testing","Gene-specific,strength"
-HNF1A (HGNC:11621),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-HNF1A (HGNC:11621),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-HNF1A (HGNC:11621),BA1,Stand Alone,"MAF ≥ 1:10,000 (≥ 0.01% or 0.0001) in gnomAD Popmax Filtering AF.",Gene-specific
-HNF1A (HGNC:11621),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-HNF1A (HGNC:11621),BS1,Strong,"MAF ≥ 1:30,000 (≥0.0033% or 0.000033) in gnomAD Popmax Filtering AF.",Gene-specific
-HNF1A (HGNC:11621),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-HNF1A (HGNC:11621),BS2,Strong,"Apply to normoglycemic individuals age 70 or older (i.e., genotype positive, phenotype negative)",Gene-specific
-HNF1A (HGNC:11621),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-HNF1A (HGNC:11621),BS3,Strong,Applicable to non-canonical splice site variants that have RNA and in silico evidence of normal splicing.,"Gene-specific,strength"
-HNF1A (HGNC:11621),BS3,Supporting,"See HNF1A rules for full list of approved functional studies and guidelines for interpretation of data. 
-(1) Luciferase assays for transactivation - ""No functional impact"" is defined as ≥ 75% activity of wildtype
-(2) EMSA for DNA binding - ""No functional impact"" is defined as ≥ 75% activity of wildtype.
-(3) Western blotting and indirect immunoflorescence for protein expression and localization - Determining appropriate thresholds for protein expression is more difficult due to variability in results between different experimental protocols. Altered protein expression can be indirectly captured through the read-out from a transactivation assay and reduced protein expression can provide an explanation for reduced transactivation.","Gene-specific,strength"
-HNF1A (HGNC:11621),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-HNF1A (HGNC:11621),BS4,Strong,"Applicable to family members without variant who have MPC score >50% (i.e., genotype negative, phenotype positive).",Gene-specific
-HNF1A (HGNC:11621),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-HNF1A (HGNC:11621),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-HNF1A (HGNC:11621),BP2,Supporting,Also applicable when in cis or trans with a likely pathogenic variant.,General recommendation
-HNF1A (HGNC:11621),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-HNF1A (HGNC:11621),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-HNF1A (HGNC:11621),BP4,Supporting,Use a REVEL score of ≤0.15 as supportive evidence of no predicted impact on the gene or gene product. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply BP4 when the predicted change is below 0.2 (Wai et al. 2020 PMID: 32123317; Jaganathan et al. 2019 PMID: 30661751).,General recommendation
-HNF1A (HGNC:11621),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-HNF1A (HGNC:11621),BP5,Supporting,A variant in other monogenic diabetes gene is P/LP.,General recommendation
-HNF1A (HGNC:11621),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-HNF1A (HGNC:11621),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-HNF1A (HGNC:11621),BP7,Supporting,Use with no specifications.,
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGCKVersion1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGCKVersion1.0.0_version=1.0.0.csv
deleted file mode 100644
index 181d7e4a322817a5146f74b252b7f945501769b7..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGCKVersion1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,259 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-GCK (HGNC:4195),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-GCK (HGNC:4195),PVS1,Very Strong,"Use 
-GCK
- PVS1 decision tree created based on PVS1 decision tree from ClinGen SVI group
-1
-
-
-
-
-Variants generating PTCs 3’ of c.1198 (p.Asp400) of NM_000162.3, which includes the last 55 nucleotides of exon 9 and exon 10, are not expected to cause NMD
-2
-. The α13 helix (p.444-456), located at the C-end of the protein, has a critical role in GCK conformational change upon glucose binding.  Individuals with PTCs in exon 10 have a MODY phenotype. Therefore, a “very strong” level of evidence will be applied for PTCs in exon 10.
-
-
-“Exon skipping or  “use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame” 
-
-
-single exon deletions 
-
-
-deletion of exon 1 is in-frame but over 20 families with GCK-MODY phenotype and exon 1 deletion (some also have promoter deletions) --> PVS1 
-
-
-deletions of single 
-exons 2,3,6 and 7
- cause frameshift --> 
-PVS1
- 
-
-
-deletions or skipping of 
-exons 8 and 9
- are in-frame and the proportion is >10 % (52 AA and 78 AA, respectively) --> 
-PVS1
- 
-
-
-deletions or skipping of 
-exons 4 and 5
- are in-frame and the proportion is <10 % (40 AA and 32 AA, respectively). Exon 4 (p.122-161) and exon 5 (p.162-193) contain each a part of the active site that binds glucose /p.151-180
-3
- according to Beck et al., Biochemistry 2013/ --> 
-PVS1
- 
-
-
-deletion of exon 10 (47 AA) – There are a number of patients with a GCK-MODY phenotype with reported with missense, frameshift, PTC, splice acceptor, and stop loss variants in exon 10  --> 
-PVS1
-
-
-
-
-
-
-
-
-
-
-Apply PVS1_Supporting to initiation codon variants given MDEP has only reviewed one variant and classified as VUS (c.3G>A, PVS1_Supporting + PM2_Supporting; one case submitted, dx.53 and no other info provided to lab).  The next methionine is at codon 8 and there are no variants classified as pathogenic 5' of p.Met8. 
-
-
-Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.",Gene-specific
-GCK (HGNC:4195),PVS1,Strong,"Use 
-GCK
- PVS1 decision tree.
-
-
-Per the SVI standard PVS1 decision tree, apply PVS1_Strong to duplications ≥ 1 exon in size, contained completely within gene, proven not in tandem, reading frame presumed disrupted, and NMD predicted to occur.",Strength
-GCK (HGNC:4195),PVS1,Supporting,"Use 
-GCK
- PVS1 decision tree.
-
-
-
-
-Apply PVS1_Supporting to initiation codon variants given MDEP has only reviewed one variant and classified as VUS (c.3G>A, PVS1_Supporting + PM2_Supporting; one case submitted, dx.53 and no other info provided to lab).  The next methionine is at codon 8 and there are no variants classified as pathogenic 5' of p.Met8. 
-
-
-Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.",Strength
-GCK (HGNC:4195),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-GCK (HGNC:4195),PS1,Strong,No change,None
-GCK (HGNC:4195),PS1,Supporting,PS1 may be used at a supporting level for canonical and non-canonical splicing variants when a different variant at the same nucleotide has been previously classified as pathogenic and the variant being assessed is predicted by SpliceAI to have a similar (SpliceAI score within 10% of the original variant) or greater deleterious impact.,Strength
-GCK (HGNC:4195),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-GCK (HGNC:4195),PS2,Very Strong,"Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions.
-.","Gene-specific,Strength"
-GCK (HGNC:4195),PS2,Strong,Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions.,"Gene-specific,Strength"
-GCK (HGNC:4195),PS2,Moderate,Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions.,"Gene-specific,Strength"
-GCK (HGNC:4195),PS2,Supporting,Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions.,"Gene-specific,Strength"
-GCK (HGNC:4195),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-GCK (HGNC:4195),PS3,Strong,Applicable to non-canonical splice site variants that have RNA and in silico evidence of aberrant splicing.,"Gene-specific,Strength"
-GCK (HGNC:4195),PS3,Moderate,See list of approved functional studies and guidelines for interpretation of data.,"Gene-specific,Strength"
-GCK (HGNC:4195),PS3,Supporting,See list of approved functional studies and guidelines for interpretation of data (below).,"Gene-specific,Strength"
-GCK (HGNC:4195),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-GCK (HGNC:4195),PS4,Strong,7 or more occurrences in unrelated individuals = Strong.,"Gene-specific,Strength"
-GCK (HGNC:4195),PS4,Moderate,4-6 occurrences in unrelated individuals = Moderate.,"Gene-specific,Strength"
-GCK (HGNC:4195),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-GCK (HGNC:4195),PM1,Moderate,Applicable for glucose- and ATP-binding sites (see attached chart).,Gene-specific
-GCK (HGNC:4195),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-GCK (HGNC:4195),PM2,Supporting,"gnomAD 2.1.1 Popmax FAF ≤ 1:333,000 (≤ 0.000003 or 0.0003%) in European Non-Finnish population AND ≤ 2 copies observed in ENF AND ≤ 1 copy in any other founder or non-founder population.",Gene-specific
-GCK (HGNC:4195),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-GCK (HGNC:4195),PM3,Very Strong,Use SVI-recommended point-based system.,Strength
-GCK (HGNC:4195),PM3,Strong,Use SVI-recommended point-based system.,Strength
-GCK (HGNC:4195),PM3,Moderate,Use SVI-recommended point-based system.,Strength
-GCK (HGNC:4195),PM3,Supporting,Use SVI-recommended point-based system.,Strength
-GCK (HGNC:4195),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-GCK (HGNC:4195),PM4,Moderate,"For single amino acid deletions, use as supporting level of evidence.",Strength
-GCK (HGNC:4195),PM4,Supporting,"For single amino acid deletions/insertions, use as supporting level of evidence",Strength
-GCK (HGNC:4195),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-GCK (HGNC:4195),PM5,Strong,Applicable once two amino acid changes have been classified as pathogenic at the same amino acid residue.,Strength
-GCK (HGNC:4195),PM5,Moderate,The novel amino acid change must have a Grantham distance greater than or equal to the previously classified pathogenic variant.,Strength
-GCK (HGNC:4195),PM5,Supporting,Apply if the previously classified amino acid change is likely pathogenic (rather than pathogenic) or if the previously classified variant is pathogenic but has a greater Grantham distance.,Strength
-GCK (HGNC:4195),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-GCK (HGNC:4195),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-GCK (HGNC:4195),PP1,Strong,"Use thresholds suggested by Jarvik and Browning
-8
-
-
-
-
-Single Family : ≤ 1/32 (5 meioses)
-
-
->1 Family : ≤ 1/16 (4 meioses)","General recommendation,Gene-specific"
-GCK (HGNC:4195),PP1,Moderate,"Use thresholds suggested by Jarvik and Browning
-8
-
-
-
-
-Single Family : ≤ 1/16 (4 meioses)
-
-
->1 Family : ≤ 1/8 (3 meioses)","General recommendation,Gene-specific"
-GCK (HGNC:4195),PP1,Supporting,"Use thresholds suggested by Jarvik and Browning
-8
-
-
-
-
-Single Family : ≤ 1/8 (3 meioses)
-
-
->1 Family : ≤ ¼ (2 meioses)","General recommendation,Gene-specific"
-GCK (HGNC:4195),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,
-GCK (HGNC:4195),PP2,Supporting,"Apply to all missense variants in GCK. gnomAD missense constraint score for 
-GCK
- is 3.07 (observed/expected= 0.5), which is significant.",Gene-specific
-GCK (HGNC:4195),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-GCK (HGNC:4195),PP3,Supporting,"Use REVEL score of ≥0.70 as supportive evidence of pathogenicity. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply PP3 when the predicted change is at least 0.2
-9
-,
-10",General recommendation
-GCK (HGNC:4195),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-GCK (HGNC:4195),PP4,Moderate,"HbA1C 5.6 – 7.6% (38-60 mmol/mol) (if given multiple results, use maximum value) AND Fasting glucose 5.5-8 mmol/L (100-144 mg/dL) AND presence of any of the following additional features:
-
-
-
-
-PP4 phenotype found in pediatric patient (prepubertal or <10 years) (incidentally) AND 
-
-
-Not treated with insulin AND antibody negative 
-
-
-OR treated with insulin, antibody negative, and detectable C-peptide (> 0.6ng/mL) after 3 years
-
-
-
-
-
-
-Multiple values (= persistent)—multiple levels (>=2 counts) or well-documented persistent impaired fasting glucose (IFG) 
-
-
-OGTT with minimal increment <3 mmol/l (54 mg/dl) 
-
-
-Antibody negative 
-
-
-Macrosomia in normoglycemic offspring of hyperglycemic gestational parent
-
-
-Low birthweight in hyperglycemic offspring of hyperglycemic gestational parent. 
-
-
-Three-generation, dominant family history of diabetes or hyperglycemia (in a family not used for PP1)","Gene-specific,Strength"
-GCK (HGNC:4195),PP4,Supporting,"HbA1C 5.6 – 7.6% (38-60 mmol/mol) (if given multiple results, use maximum value) AND Fasting glucose 5.5-8 mmol/L (100-144 mg/dL)",Gene-specific
-GCK (HGNC:4195),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-GCK (HGNC:4195),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-GCK (HGNC:4195),BA1,Stand Alone,"gnomAD 2.1.1 Popmax Filtering AF ≥ 1:10,000 (≥ 0.01% or 0.0001).",Gene-specific
-GCK (HGNC:4195),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-GCK (HGNC:4195),BS1,Strong,"gnomAD 2.1.1 Popmax Filtering AF ≥ 1:25,000 (0.004% or 0.00004).",Gene-specific
-GCK (HGNC:4195),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-GCK (HGNC:4195),BS2,Strong,"We expect to see hyperglycemia at birth in an individual with _GCK_-MODY and therefore consider an individual unaffected if euglycemic in childhood or adulthood.  Since individuals typically do not present with symptoms of diabetes, evidence that someone is “nondiabetic” is insufficient; fasting glucose must be tested and found to be within normal limits (<100 mg/dl / 5.6 mmol/L).",Gene-specific
-GCK (HGNC:4195),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-GCK (HGNC:4195),BS3,Strong,Applicable to non-canonical splice site variants that have RNA and in silico evidence of normal splicing (see BP4).,Gene-specific
-GCK (HGNC:4195),BS3,Supporting,"Use GCK PS3 decision tree, which incorporates the relative activity index (RAI), relative stability index (RSI) and assays that measure the impact of variants on binding with GKRP and GKA.
-
-
-Evidence of no impact on function:
-
-
-
-
-Normal RAI (>0.5) + normal RSI (>0.5) + normal inhibition/activation with GKRP/GKA = BS3_Supporting 
-
-
-Normal RAI (>0.5) + normal RSI (>0.5) but no studies investigating GKRP/GKA = Cannot use PS3 or BS3
-
-
-
-
-Gloyn, et al. 2005 
-5
-; Beer, et al. 2012 
-6
-; Raimondo, et al. 2014 
-7
-; Gloyn, et al. (2004)
-12
-.",Gene-specific
-GCK (HGNC:4195),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-GCK (HGNC:4195),BS4,Strong,"Applicable to family members without variant who meet PP4 criteria (HbA1C 5.6 – 7.6% (38-60 mmol/mol) (if given multiple results, use maximum value) AND Fasting glucose 5.5-8 mmol/L (100-144 mg/dL))",Gene-specific
-GCK (HGNC:4195),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-GCK (HGNC:4195),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-GCK (HGNC:4195),BP2,Supporting,Also applicable when in cis or trans with a likely pathogenic variant.,General recommendation
-GCK (HGNC:4195),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-GCK (HGNC:4195),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-GCK (HGNC:4195),BP4,Supporting,"Use a REVEL score of ≤0.15 as supportive evidence of no predicted impact on the gene or gene product. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply BP4 when the predicted change is below 0.2
-9
-,
-10
-.",General recommendation
-GCK (HGNC:4195),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-GCK (HGNC:4195),BP5,Supporting,A variant in another monogenic diabetes gene is P/LP.,General recommendation
-GCK (HGNC:4195),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-GCK (HGNC:4195),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-GCK (HGNC:4195),BP7,Supporting,Apply BP7 when the predicted change from SpliceAI is below 0.2 AND phyloP100 way < 2.0.,Gene-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGCKVersion1.1.0_version=1.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGCKVersion1.1.0_version=1.1.0.csv
deleted file mode 100644
index 181d7e4a322817a5146f74b252b7f945501769b7..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGCKVersion1.1.0_version=1.1.0.csv
+++ /dev/null
@@ -1,259 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-GCK (HGNC:4195),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-GCK (HGNC:4195),PVS1,Very Strong,"Use 
-GCK
- PVS1 decision tree created based on PVS1 decision tree from ClinGen SVI group
-1
-
-
-
-
-Variants generating PTCs 3’ of c.1198 (p.Asp400) of NM_000162.3, which includes the last 55 nucleotides of exon 9 and exon 10, are not expected to cause NMD
-2
-. The α13 helix (p.444-456), located at the C-end of the protein, has a critical role in GCK conformational change upon glucose binding.  Individuals with PTCs in exon 10 have a MODY phenotype. Therefore, a “very strong” level of evidence will be applied for PTCs in exon 10.
-
-
-“Exon skipping or  “use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame” 
-
-
-single exon deletions 
-
-
-deletion of exon 1 is in-frame but over 20 families with GCK-MODY phenotype and exon 1 deletion (some also have promoter deletions) --> PVS1 
-
-
-deletions of single 
-exons 2,3,6 and 7
- cause frameshift --> 
-PVS1
- 
-
-
-deletions or skipping of 
-exons 8 and 9
- are in-frame and the proportion is >10 % (52 AA and 78 AA, respectively) --> 
-PVS1
- 
-
-
-deletions or skipping of 
-exons 4 and 5
- are in-frame and the proportion is <10 % (40 AA and 32 AA, respectively). Exon 4 (p.122-161) and exon 5 (p.162-193) contain each a part of the active site that binds glucose /p.151-180
-3
- according to Beck et al., Biochemistry 2013/ --> 
-PVS1
- 
-
-
-deletion of exon 10 (47 AA) – There are a number of patients with a GCK-MODY phenotype with reported with missense, frameshift, PTC, splice acceptor, and stop loss variants in exon 10  --> 
-PVS1
-
-
-
-
-
-
-
-
-
-
-Apply PVS1_Supporting to initiation codon variants given MDEP has only reviewed one variant and classified as VUS (c.3G>A, PVS1_Supporting + PM2_Supporting; one case submitted, dx.53 and no other info provided to lab).  The next methionine is at codon 8 and there are no variants classified as pathogenic 5' of p.Met8. 
-
-
-Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.",Gene-specific
-GCK (HGNC:4195),PVS1,Strong,"Use 
-GCK
- PVS1 decision tree.
-
-
-Per the SVI standard PVS1 decision tree, apply PVS1_Strong to duplications ≥ 1 exon in size, contained completely within gene, proven not in tandem, reading frame presumed disrupted, and NMD predicted to occur.",Strength
-GCK (HGNC:4195),PVS1,Supporting,"Use 
-GCK
- PVS1 decision tree.
-
-
-
-
-Apply PVS1_Supporting to initiation codon variants given MDEP has only reviewed one variant and classified as VUS (c.3G>A, PVS1_Supporting + PM2_Supporting; one case submitted, dx.53 and no other info provided to lab).  The next methionine is at codon 8 and there are no variants classified as pathogenic 5' of p.Met8. 
-
-
-Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.",Strength
-GCK (HGNC:4195),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-GCK (HGNC:4195),PS1,Strong,No change,None
-GCK (HGNC:4195),PS1,Supporting,PS1 may be used at a supporting level for canonical and non-canonical splicing variants when a different variant at the same nucleotide has been previously classified as pathogenic and the variant being assessed is predicted by SpliceAI to have a similar (SpliceAI score within 10% of the original variant) or greater deleterious impact.,Strength
-GCK (HGNC:4195),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-GCK (HGNC:4195),PS2,Very Strong,"Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions.
-.","Gene-specific,Strength"
-GCK (HGNC:4195),PS2,Strong,Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions.,"Gene-specific,Strength"
-GCK (HGNC:4195),PS2,Moderate,Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions.,"Gene-specific,Strength"
-GCK (HGNC:4195),PS2,Supporting,Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions.,"Gene-specific,Strength"
-GCK (HGNC:4195),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-GCK (HGNC:4195),PS3,Strong,Applicable to non-canonical splice site variants that have RNA and in silico evidence of aberrant splicing.,"Gene-specific,Strength"
-GCK (HGNC:4195),PS3,Moderate,See list of approved functional studies and guidelines for interpretation of data.,"Gene-specific,Strength"
-GCK (HGNC:4195),PS3,Supporting,See list of approved functional studies and guidelines for interpretation of data (below).,"Gene-specific,Strength"
-GCK (HGNC:4195),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-GCK (HGNC:4195),PS4,Strong,7 or more occurrences in unrelated individuals = Strong.,"Gene-specific,Strength"
-GCK (HGNC:4195),PS4,Moderate,4-6 occurrences in unrelated individuals = Moderate.,"Gene-specific,Strength"
-GCK (HGNC:4195),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-GCK (HGNC:4195),PM1,Moderate,Applicable for glucose- and ATP-binding sites (see attached chart).,Gene-specific
-GCK (HGNC:4195),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-GCK (HGNC:4195),PM2,Supporting,"gnomAD 2.1.1 Popmax FAF ≤ 1:333,000 (≤ 0.000003 or 0.0003%) in European Non-Finnish population AND ≤ 2 copies observed in ENF AND ≤ 1 copy in any other founder or non-founder population.",Gene-specific
-GCK (HGNC:4195),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-GCK (HGNC:4195),PM3,Very Strong,Use SVI-recommended point-based system.,Strength
-GCK (HGNC:4195),PM3,Strong,Use SVI-recommended point-based system.,Strength
-GCK (HGNC:4195),PM3,Moderate,Use SVI-recommended point-based system.,Strength
-GCK (HGNC:4195),PM3,Supporting,Use SVI-recommended point-based system.,Strength
-GCK (HGNC:4195),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-GCK (HGNC:4195),PM4,Moderate,"For single amino acid deletions, use as supporting level of evidence.",Strength
-GCK (HGNC:4195),PM4,Supporting,"For single amino acid deletions/insertions, use as supporting level of evidence",Strength
-GCK (HGNC:4195),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-GCK (HGNC:4195),PM5,Strong,Applicable once two amino acid changes have been classified as pathogenic at the same amino acid residue.,Strength
-GCK (HGNC:4195),PM5,Moderate,The novel amino acid change must have a Grantham distance greater than or equal to the previously classified pathogenic variant.,Strength
-GCK (HGNC:4195),PM5,Supporting,Apply if the previously classified amino acid change is likely pathogenic (rather than pathogenic) or if the previously classified variant is pathogenic but has a greater Grantham distance.,Strength
-GCK (HGNC:4195),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-GCK (HGNC:4195),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-GCK (HGNC:4195),PP1,Strong,"Use thresholds suggested by Jarvik and Browning
-8
-
-
-
-
-Single Family : ≤ 1/32 (5 meioses)
-
-
->1 Family : ≤ 1/16 (4 meioses)","General recommendation,Gene-specific"
-GCK (HGNC:4195),PP1,Moderate,"Use thresholds suggested by Jarvik and Browning
-8
-
-
-
-
-Single Family : ≤ 1/16 (4 meioses)
-
-
->1 Family : ≤ 1/8 (3 meioses)","General recommendation,Gene-specific"
-GCK (HGNC:4195),PP1,Supporting,"Use thresholds suggested by Jarvik and Browning
-8
-
-
-
-
-Single Family : ≤ 1/8 (3 meioses)
-
-
->1 Family : ≤ ¼ (2 meioses)","General recommendation,Gene-specific"
-GCK (HGNC:4195),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,
-GCK (HGNC:4195),PP2,Supporting,"Apply to all missense variants in GCK. gnomAD missense constraint score for 
-GCK
- is 3.07 (observed/expected= 0.5), which is significant.",Gene-specific
-GCK (HGNC:4195),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-GCK (HGNC:4195),PP3,Supporting,"Use REVEL score of ≥0.70 as supportive evidence of pathogenicity. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply PP3 when the predicted change is at least 0.2
-9
-,
-10",General recommendation
-GCK (HGNC:4195),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-GCK (HGNC:4195),PP4,Moderate,"HbA1C 5.6 – 7.6% (38-60 mmol/mol) (if given multiple results, use maximum value) AND Fasting glucose 5.5-8 mmol/L (100-144 mg/dL) AND presence of any of the following additional features:
-
-
-
-
-PP4 phenotype found in pediatric patient (prepubertal or <10 years) (incidentally) AND 
-
-
-Not treated with insulin AND antibody negative 
-
-
-OR treated with insulin, antibody negative, and detectable C-peptide (> 0.6ng/mL) after 3 years
-
-
-
-
-
-
-Multiple values (= persistent)—multiple levels (>=2 counts) or well-documented persistent impaired fasting glucose (IFG) 
-
-
-OGTT with minimal increment <3 mmol/l (54 mg/dl) 
-
-
-Antibody negative 
-
-
-Macrosomia in normoglycemic offspring of hyperglycemic gestational parent
-
-
-Low birthweight in hyperglycemic offspring of hyperglycemic gestational parent. 
-
-
-Three-generation, dominant family history of diabetes or hyperglycemia (in a family not used for PP1)","Gene-specific,Strength"
-GCK (HGNC:4195),PP4,Supporting,"HbA1C 5.6 – 7.6% (38-60 mmol/mol) (if given multiple results, use maximum value) AND Fasting glucose 5.5-8 mmol/L (100-144 mg/dL)",Gene-specific
-GCK (HGNC:4195),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-GCK (HGNC:4195),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-GCK (HGNC:4195),BA1,Stand Alone,"gnomAD 2.1.1 Popmax Filtering AF ≥ 1:10,000 (≥ 0.01% or 0.0001).",Gene-specific
-GCK (HGNC:4195),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-GCK (HGNC:4195),BS1,Strong,"gnomAD 2.1.1 Popmax Filtering AF ≥ 1:25,000 (0.004% or 0.00004).",Gene-specific
-GCK (HGNC:4195),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-GCK (HGNC:4195),BS2,Strong,"We expect to see hyperglycemia at birth in an individual with _GCK_-MODY and therefore consider an individual unaffected if euglycemic in childhood or adulthood.  Since individuals typically do not present with symptoms of diabetes, evidence that someone is “nondiabetic” is insufficient; fasting glucose must be tested and found to be within normal limits (<100 mg/dl / 5.6 mmol/L).",Gene-specific
-GCK (HGNC:4195),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-GCK (HGNC:4195),BS3,Strong,Applicable to non-canonical splice site variants that have RNA and in silico evidence of normal splicing (see BP4).,Gene-specific
-GCK (HGNC:4195),BS3,Supporting,"Use GCK PS3 decision tree, which incorporates the relative activity index (RAI), relative stability index (RSI) and assays that measure the impact of variants on binding with GKRP and GKA.
-
-
-Evidence of no impact on function:
-
-
-
-
-Normal RAI (>0.5) + normal RSI (>0.5) + normal inhibition/activation with GKRP/GKA = BS3_Supporting 
-
-
-Normal RAI (>0.5) + normal RSI (>0.5) but no studies investigating GKRP/GKA = Cannot use PS3 or BS3
-
-
-
-
-Gloyn, et al. 2005 
-5
-; Beer, et al. 2012 
-6
-; Raimondo, et al. 2014 
-7
-; Gloyn, et al. (2004)
-12
-.",Gene-specific
-GCK (HGNC:4195),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-GCK (HGNC:4195),BS4,Strong,"Applicable to family members without variant who meet PP4 criteria (HbA1C 5.6 – 7.6% (38-60 mmol/mol) (if given multiple results, use maximum value) AND Fasting glucose 5.5-8 mmol/L (100-144 mg/dL))",Gene-specific
-GCK (HGNC:4195),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-GCK (HGNC:4195),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-GCK (HGNC:4195),BP2,Supporting,Also applicable when in cis or trans with a likely pathogenic variant.,General recommendation
-GCK (HGNC:4195),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-GCK (HGNC:4195),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-GCK (HGNC:4195),BP4,Supporting,"Use a REVEL score of ≤0.15 as supportive evidence of no predicted impact on the gene or gene product. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply BP4 when the predicted change is below 0.2
-9
-,
-10
-.",General recommendation
-GCK (HGNC:4195),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-GCK (HGNC:4195),BP5,Supporting,A variant in another monogenic diabetes gene is P/LP.,General recommendation
-GCK (HGNC:4195),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-GCK (HGNC:4195),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-GCK (HGNC:4195),BP7,Supporting,Apply BP7 when the predicted change from SpliceAI is below 0.2 AND phyloP100 way < 2.0.,Gene-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGCKVersion1.2.0_version=1.2.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGCKVersion1.2.0_version=1.2.0.csv
deleted file mode 100644
index 181d7e4a322817a5146f74b252b7f945501769b7..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGCKVersion1.2.0_version=1.2.0.csv
+++ /dev/null
@@ -1,259 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-GCK (HGNC:4195),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-GCK (HGNC:4195),PVS1,Very Strong,"Use 
-GCK
- PVS1 decision tree created based on PVS1 decision tree from ClinGen SVI group
-1
-
-
-
-
-Variants generating PTCs 3’ of c.1198 (p.Asp400) of NM_000162.3, which includes the last 55 nucleotides of exon 9 and exon 10, are not expected to cause NMD
-2
-. The α13 helix (p.444-456), located at the C-end of the protein, has a critical role in GCK conformational change upon glucose binding.  Individuals with PTCs in exon 10 have a MODY phenotype. Therefore, a “very strong” level of evidence will be applied for PTCs in exon 10.
-
-
-“Exon skipping or  “use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame” 
-
-
-single exon deletions 
-
-
-deletion of exon 1 is in-frame but over 20 families with GCK-MODY phenotype and exon 1 deletion (some also have promoter deletions) --> PVS1 
-
-
-deletions of single 
-exons 2,3,6 and 7
- cause frameshift --> 
-PVS1
- 
-
-
-deletions or skipping of 
-exons 8 and 9
- are in-frame and the proportion is >10 % (52 AA and 78 AA, respectively) --> 
-PVS1
- 
-
-
-deletions or skipping of 
-exons 4 and 5
- are in-frame and the proportion is <10 % (40 AA and 32 AA, respectively). Exon 4 (p.122-161) and exon 5 (p.162-193) contain each a part of the active site that binds glucose /p.151-180
-3
- according to Beck et al., Biochemistry 2013/ --> 
-PVS1
- 
-
-
-deletion of exon 10 (47 AA) – There are a number of patients with a GCK-MODY phenotype with reported with missense, frameshift, PTC, splice acceptor, and stop loss variants in exon 10  --> 
-PVS1
-
-
-
-
-
-
-
-
-
-
-Apply PVS1_Supporting to initiation codon variants given MDEP has only reviewed one variant and classified as VUS (c.3G>A, PVS1_Supporting + PM2_Supporting; one case submitted, dx.53 and no other info provided to lab).  The next methionine is at codon 8 and there are no variants classified as pathogenic 5' of p.Met8. 
-
-
-Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.",Gene-specific
-GCK (HGNC:4195),PVS1,Strong,"Use 
-GCK
- PVS1 decision tree.
-
-
-Per the SVI standard PVS1 decision tree, apply PVS1_Strong to duplications ≥ 1 exon in size, contained completely within gene, proven not in tandem, reading frame presumed disrupted, and NMD predicted to occur.",Strength
-GCK (HGNC:4195),PVS1,Supporting,"Use 
-GCK
- PVS1 decision tree.
-
-
-
-
-Apply PVS1_Supporting to initiation codon variants given MDEP has only reviewed one variant and classified as VUS (c.3G>A, PVS1_Supporting + PM2_Supporting; one case submitted, dx.53 and no other info provided to lab).  The next methionine is at codon 8 and there are no variants classified as pathogenic 5' of p.Met8. 
-
-
-Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.",Strength
-GCK (HGNC:4195),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-GCK (HGNC:4195),PS1,Strong,No change,None
-GCK (HGNC:4195),PS1,Supporting,PS1 may be used at a supporting level for canonical and non-canonical splicing variants when a different variant at the same nucleotide has been previously classified as pathogenic and the variant being assessed is predicted by SpliceAI to have a similar (SpliceAI score within 10% of the original variant) or greater deleterious impact.,Strength
-GCK (HGNC:4195),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-GCK (HGNC:4195),PS2,Very Strong,"Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions.
-.","Gene-specific,Strength"
-GCK (HGNC:4195),PS2,Strong,Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions.,"Gene-specific,Strength"
-GCK (HGNC:4195),PS2,Moderate,Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions.,"Gene-specific,Strength"
-GCK (HGNC:4195),PS2,Supporting,Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions.,"Gene-specific,Strength"
-GCK (HGNC:4195),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-GCK (HGNC:4195),PS3,Strong,Applicable to non-canonical splice site variants that have RNA and in silico evidence of aberrant splicing.,"Gene-specific,Strength"
-GCK (HGNC:4195),PS3,Moderate,See list of approved functional studies and guidelines for interpretation of data.,"Gene-specific,Strength"
-GCK (HGNC:4195),PS3,Supporting,See list of approved functional studies and guidelines for interpretation of data (below).,"Gene-specific,Strength"
-GCK (HGNC:4195),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-GCK (HGNC:4195),PS4,Strong,7 or more occurrences in unrelated individuals = Strong.,"Gene-specific,Strength"
-GCK (HGNC:4195),PS4,Moderate,4-6 occurrences in unrelated individuals = Moderate.,"Gene-specific,Strength"
-GCK (HGNC:4195),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-GCK (HGNC:4195),PM1,Moderate,Applicable for glucose- and ATP-binding sites (see attached chart).,Gene-specific
-GCK (HGNC:4195),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-GCK (HGNC:4195),PM2,Supporting,"gnomAD 2.1.1 Popmax FAF ≤ 1:333,000 (≤ 0.000003 or 0.0003%) in European Non-Finnish population AND ≤ 2 copies observed in ENF AND ≤ 1 copy in any other founder or non-founder population.",Gene-specific
-GCK (HGNC:4195),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-GCK (HGNC:4195),PM3,Very Strong,Use SVI-recommended point-based system.,Strength
-GCK (HGNC:4195),PM3,Strong,Use SVI-recommended point-based system.,Strength
-GCK (HGNC:4195),PM3,Moderate,Use SVI-recommended point-based system.,Strength
-GCK (HGNC:4195),PM3,Supporting,Use SVI-recommended point-based system.,Strength
-GCK (HGNC:4195),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-GCK (HGNC:4195),PM4,Moderate,"For single amino acid deletions, use as supporting level of evidence.",Strength
-GCK (HGNC:4195),PM4,Supporting,"For single amino acid deletions/insertions, use as supporting level of evidence",Strength
-GCK (HGNC:4195),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-GCK (HGNC:4195),PM5,Strong,Applicable once two amino acid changes have been classified as pathogenic at the same amino acid residue.,Strength
-GCK (HGNC:4195),PM5,Moderate,The novel amino acid change must have a Grantham distance greater than or equal to the previously classified pathogenic variant.,Strength
-GCK (HGNC:4195),PM5,Supporting,Apply if the previously classified amino acid change is likely pathogenic (rather than pathogenic) or if the previously classified variant is pathogenic but has a greater Grantham distance.,Strength
-GCK (HGNC:4195),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-GCK (HGNC:4195),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-GCK (HGNC:4195),PP1,Strong,"Use thresholds suggested by Jarvik and Browning
-8
-
-
-
-
-Single Family : ≤ 1/32 (5 meioses)
-
-
->1 Family : ≤ 1/16 (4 meioses)","General recommendation,Gene-specific"
-GCK (HGNC:4195),PP1,Moderate,"Use thresholds suggested by Jarvik and Browning
-8
-
-
-
-
-Single Family : ≤ 1/16 (4 meioses)
-
-
->1 Family : ≤ 1/8 (3 meioses)","General recommendation,Gene-specific"
-GCK (HGNC:4195),PP1,Supporting,"Use thresholds suggested by Jarvik and Browning
-8
-
-
-
-
-Single Family : ≤ 1/8 (3 meioses)
-
-
->1 Family : ≤ ¼ (2 meioses)","General recommendation,Gene-specific"
-GCK (HGNC:4195),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,
-GCK (HGNC:4195),PP2,Supporting,"Apply to all missense variants in GCK. gnomAD missense constraint score for 
-GCK
- is 3.07 (observed/expected= 0.5), which is significant.",Gene-specific
-GCK (HGNC:4195),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-GCK (HGNC:4195),PP3,Supporting,"Use REVEL score of ≥0.70 as supportive evidence of pathogenicity. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply PP3 when the predicted change is at least 0.2
-9
-,
-10",General recommendation
-GCK (HGNC:4195),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-GCK (HGNC:4195),PP4,Moderate,"HbA1C 5.6 – 7.6% (38-60 mmol/mol) (if given multiple results, use maximum value) AND Fasting glucose 5.5-8 mmol/L (100-144 mg/dL) AND presence of any of the following additional features:
-
-
-
-
-PP4 phenotype found in pediatric patient (prepubertal or <10 years) (incidentally) AND 
-
-
-Not treated with insulin AND antibody negative 
-
-
-OR treated with insulin, antibody negative, and detectable C-peptide (> 0.6ng/mL) after 3 years
-
-
-
-
-
-
-Multiple values (= persistent)—multiple levels (>=2 counts) or well-documented persistent impaired fasting glucose (IFG) 
-
-
-OGTT with minimal increment <3 mmol/l (54 mg/dl) 
-
-
-Antibody negative 
-
-
-Macrosomia in normoglycemic offspring of hyperglycemic gestational parent
-
-
-Low birthweight in hyperglycemic offspring of hyperglycemic gestational parent. 
-
-
-Three-generation, dominant family history of diabetes or hyperglycemia (in a family not used for PP1)","Gene-specific,Strength"
-GCK (HGNC:4195),PP4,Supporting,"HbA1C 5.6 – 7.6% (38-60 mmol/mol) (if given multiple results, use maximum value) AND Fasting glucose 5.5-8 mmol/L (100-144 mg/dL)",Gene-specific
-GCK (HGNC:4195),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-GCK (HGNC:4195),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-GCK (HGNC:4195),BA1,Stand Alone,"gnomAD 2.1.1 Popmax Filtering AF ≥ 1:10,000 (≥ 0.01% or 0.0001).",Gene-specific
-GCK (HGNC:4195),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-GCK (HGNC:4195),BS1,Strong,"gnomAD 2.1.1 Popmax Filtering AF ≥ 1:25,000 (0.004% or 0.00004).",Gene-specific
-GCK (HGNC:4195),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-GCK (HGNC:4195),BS2,Strong,"We expect to see hyperglycemia at birth in an individual with _GCK_-MODY and therefore consider an individual unaffected if euglycemic in childhood or adulthood.  Since individuals typically do not present with symptoms of diabetes, evidence that someone is “nondiabetic” is insufficient; fasting glucose must be tested and found to be within normal limits (<100 mg/dl / 5.6 mmol/L).",Gene-specific
-GCK (HGNC:4195),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-GCK (HGNC:4195),BS3,Strong,Applicable to non-canonical splice site variants that have RNA and in silico evidence of normal splicing (see BP4).,Gene-specific
-GCK (HGNC:4195),BS3,Supporting,"Use GCK PS3 decision tree, which incorporates the relative activity index (RAI), relative stability index (RSI) and assays that measure the impact of variants on binding with GKRP and GKA.
-
-
-Evidence of no impact on function:
-
-
-
-
-Normal RAI (>0.5) + normal RSI (>0.5) + normal inhibition/activation with GKRP/GKA = BS3_Supporting 
-
-
-Normal RAI (>0.5) + normal RSI (>0.5) but no studies investigating GKRP/GKA = Cannot use PS3 or BS3
-
-
-
-
-Gloyn, et al. 2005 
-5
-; Beer, et al. 2012 
-6
-; Raimondo, et al. 2014 
-7
-; Gloyn, et al. (2004)
-12
-.",Gene-specific
-GCK (HGNC:4195),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-GCK (HGNC:4195),BS4,Strong,"Applicable to family members without variant who meet PP4 criteria (HbA1C 5.6 – 7.6% (38-60 mmol/mol) (if given multiple results, use maximum value) AND Fasting glucose 5.5-8 mmol/L (100-144 mg/dL))",Gene-specific
-GCK (HGNC:4195),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-GCK (HGNC:4195),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-GCK (HGNC:4195),BP2,Supporting,Also applicable when in cis or trans with a likely pathogenic variant.,General recommendation
-GCK (HGNC:4195),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-GCK (HGNC:4195),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-GCK (HGNC:4195),BP4,Supporting,"Use a REVEL score of ≤0.15 as supportive evidence of no predicted impact on the gene or gene product. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply BP4 when the predicted change is below 0.2
-9
-,
-10
-.",General recommendation
-GCK (HGNC:4195),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-GCK (HGNC:4195),BP5,Supporting,A variant in another monogenic diabetes gene is P/LP.,General recommendation
-GCK (HGNC:4195),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-GCK (HGNC:4195),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-GCK (HGNC:4195),BP7,Supporting,Apply BP7 when the predicted change from SpliceAI is below 0.2 AND phyloP100 way < 2.0.,Gene-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGCKVersion1.3.0_version=1.3.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGCKVersion1.3.0_version=1.3.0.csv
deleted file mode 100644
index 08e15bd5d1d599a41a777f552e625a0a51145adf..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGCKVersion1.3.0_version=1.3.0.csv
+++ /dev/null
@@ -1,268 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-GCK (HGNC:4195),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-GCK (HGNC:4195),PVS1,Very Strong,"Use 
-GCK
- PVS1 decision tree created based on PVS1 decision tree from ClinGen SVI group
-1
-
-
-
-
-Variants generating PTCs 3’ of c.1198 (p.Asp400) of NM_000162.3, which includes the last 55 nucleotides of exon 9 and exon 10, are not expected to cause NMD
-2
-. The α13 helix (p.444-456), located at the C-end of the protein, has a critical role in GCK conformational change upon glucose binding.  Individuals with PTCs in exon 10 have a MODY phenotype. Therefore, a “very strong” level of evidence will be applied for PTCs in exon 10.
-
-
-“Exon skipping or  “use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame” 
-
-
-single exon deletions 
-
-
-deletion of exon 1 is in-frame but over 20 families with GCK-MODY phenotype and exon 1 deletion (some also have promoter deletions) --> PVS1 
-
-
-deletions of single 
-exons 2,3,6 and 7
- cause frameshift --> 
-PVS1
- 
-
-
-deletions or skipping of 
-exons 8 and 9
- are in-frame and the proportion is >10 % (52 AA and 78 AA, respectively) --> 
-PVS1
- 
-
-
-deletions or skipping of 
-exons 4 and 5
- are in-frame and the proportion is <10 % (40 AA and 32 AA, respectively). Exon 4 (p.122-161) and exon 5 (p.162-193) contain each a part of the active site that binds glucose /p.151-180
-3
- according to Beck et al., Biochemistry 2013/ --> 
-PVS1
- 
-
-
-deletion of exon 10 (47 AA) – There are a number of patients with a GCK-MODY phenotype with reported with missense, frameshift, PTC, splice acceptor, and stop loss variants in exon 10  --> 
-PVS1
-
-
-
-
-
-
-
-
-
-
-Apply PVS1_Supporting to initiation codon variants given MDEP has only reviewed one variant and classified as VUS (c.3G>A, PVS1_Supporting + PM2_Supporting; one case submitted, dx.53 and no other info provided to lab).  The next methionine is at codon 8 and there are no variants classified as pathogenic 5' of p.Met8. 
-
-
-Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.",Gene-specific
-GCK (HGNC:4195),PVS1,Strong,"Use 
-GCK
- PVS1 decision tree.
-
-
-Per the SVI standard PVS1 decision tree, apply PVS1_Strong to duplications ≥ 1 exon in size, contained completely within gene, proven not in tandem, reading frame presumed disrupted, and NMD predicted to occur.",Strength
-GCK (HGNC:4195),PVS1,Supporting,"Use 
-GCK
- PVS1 decision tree.
-
-
-
-
-Apply PVS1_Supporting to initiation codon variants given MDEP has only reviewed one variant and classified as VUS (c.3G>A, PVS1_Supporting + PM2_Supporting; one case submitted, dx.53 and no other info provided to lab).  The next methionine is at codon 8 and there are no variants classified as pathogenic 5' of p.Met8. 
-
-
-Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.",Strength
-GCK (HGNC:4195),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-GCK (HGNC:4195),PS1,Strong,No change,None
-GCK (HGNC:4195),PS1,Supporting,PS1 may be used at a supporting level for canonical and non-canonical splicing variants when a different variant at the same nucleotide has been previously classified as pathogenic and the variant being assessed is predicted by SpliceAI to have a similar (SpliceAI score within 10% of the original variant) or greater deleterious impact.,Strength
-GCK (HGNC:4195),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-GCK (HGNC:4195),PS2,Very Strong,"Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions.
-.","Gene-specific,Strength"
-GCK (HGNC:4195),PS2,Strong,Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions.,"Gene-specific,Strength"
-GCK (HGNC:4195),PS2,Moderate,Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions.,"Gene-specific,Strength"
-GCK (HGNC:4195),PS2,Supporting,Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions.,"Gene-specific,Strength"
-GCK (HGNC:4195),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-GCK (HGNC:4195),PS3,Strong,Applicable to non-canonical splice site variants that have RNA and in silico evidence of aberrant splicing.,"Gene-specific,Strength"
-GCK (HGNC:4195),PS3,Moderate,See list of approved functional studies and guidelines for interpretation of data.,"Gene-specific,Strength"
-GCK (HGNC:4195),PS3,Supporting,See list of approved functional studies and guidelines for interpretation of data (below).,"Gene-specific,Strength"
-GCK (HGNC:4195),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-GCK (HGNC:4195),PS4,Strong,7 or more occurrences in unrelated individuals = Strong.,"Gene-specific,Strength"
-GCK (HGNC:4195),PS4,Moderate,4-6 occurrences in unrelated individuals = Moderate.,"Gene-specific,Strength"
-GCK (HGNC:4195),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-GCK (HGNC:4195),PM1,Moderate,Applicable for glucose- and ATP-binding sites (see attached chart).,Gene-specific
-GCK (HGNC:4195),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-GCK (HGNC:4195),PM2,Supporting,"gnomAD 2.1.1* Popmax FAF ≤ 1:333,000 (≤ 0.000003 or 0.0003%) in European Non-Finnish population AND ≤ 2 copies observed in ENF AND ≤ 1 copy in any other founder or non-founder population.
-
-
-*Use gnomAD 2.1.1 exome data unless the region is not covered in the exome, in which case gnomAD 3.1.2 genome data should be used.",Gene-specific
-GCK (HGNC:4195),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-GCK (HGNC:4195),PM3,Very Strong,Use SVI-recommended point-based system.,Strength
-GCK (HGNC:4195),PM3,Strong,Use SVI-recommended point-based system.,Strength
-GCK (HGNC:4195),PM3,Moderate,Use SVI-recommended point-based system.,Strength
-GCK (HGNC:4195),PM3,Supporting,Use SVI-recommended point-based system.,Strength
-GCK (HGNC:4195),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-GCK (HGNC:4195),PM4,Moderate,"For single amino acid deletions, use as supporting level of evidence.",Strength
-GCK (HGNC:4195),PM4,Supporting,"For single amino acid deletions/insertions, use as supporting level of evidence",Strength
-GCK (HGNC:4195),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-GCK (HGNC:4195),PM5,Strong,Applicable once two amino acid changes have been classified as pathogenic at the same amino acid residue.,Strength
-GCK (HGNC:4195),PM5,Moderate,The novel amino acid change must have a Grantham distance greater than or equal to the previously classified pathogenic variant.,Strength
-GCK (HGNC:4195),PM5,Supporting,Apply if the previously classified amino acid change is likely pathogenic (rather than pathogenic) or if the previously classified variant is pathogenic but has a greater Grantham distance.,Strength
-GCK (HGNC:4195),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-GCK (HGNC:4195),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-GCK (HGNC:4195),PP1,Strong,"Use thresholds suggested by Jarvik and Browning
-8
-
-
-
-
-Single Family : ≤ 1/32 (5 meioses)
-
-
->1 Family : ≤ 1/16 (4 meioses)","General recommendation,Gene-specific"
-GCK (HGNC:4195),PP1,Moderate,"Use thresholds suggested by Jarvik and Browning
-8
-
-
-
-
-Single Family : ≤ 1/16 (4 meioses)
-
-
->1 Family : ≤ 1/8 (3 meioses)","General recommendation,Gene-specific"
-GCK (HGNC:4195),PP1,Supporting,"Use thresholds suggested by Jarvik and Browning
-8
-
-
-
-
-Single Family : ≤ 1/8 (3 meioses)
-
-
->1 Family : ≤ ¼ (2 meioses)","General recommendation,Gene-specific"
-GCK (HGNC:4195),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,
-GCK (HGNC:4195),PP2,Supporting,"Apply to all missense variants in GCK. gnomAD missense constraint score for 
-GCK
- is 3.07 (observed/expected= 0.5), which is significant.",Gene-specific
-GCK (HGNC:4195),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-GCK (HGNC:4195),PP3,Supporting,"Use REVEL score of ≥0.70 as supportive evidence of pathogenicity. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply PP3 when the predicted change is at least 0.2
-9
-,
-10",General recommendation
-GCK (HGNC:4195),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-GCK (HGNC:4195),PP4,Moderate,"HbA1C 5.6 – 7.6% (38-60 mmol/mol) (if given multiple results, use maximum value) AND Fasting glucose 5.5-8 mmol/L (100-144 mg/dL) AND presence of any of the following additional features:
-
-
-
-
-PP4 phenotype found in pediatric patient (prepubertal or <10 years) (incidentally) AND 
-
-
-Not treated with insulin AND antibody negative 
-
-
-OR treated with insulin, antibody negative, and detectable C-peptide (> 0.6ng/mL) after 3 years
-
-
-
-
-
-
-Multiple values (= persistent)—multiple levels (>=2 counts) or well-documented persistent impaired fasting glucose (IFG) 
-
-
-OGTT with minimal increment <3 mmol/l (54 mg/dl) 
-
-
-Antibody negative 
-
-
-Macrosomia in normoglycemic offspring of hyperglycemic gestational parent
-
-
-Low birthweight in hyperglycemic offspring of hyperglycemic gestational parent. 
-
-
-Three-generation, dominant family history of diabetes or hyperglycemia (in a family not used for PP1)","Gene-specific,Strength"
-GCK (HGNC:4195),PP4,Supporting,"HbA1C 5.6 – 7.6% (38-60 mmol/mol) (if given multiple results, use maximum value) AND Fasting glucose 5.5-8 mmol/L (100-144 mg/dL)",Gene-specific
-GCK (HGNC:4195),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-GCK (HGNC:4195),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-GCK (HGNC:4195),BA1,Stand Alone,"gnomAD 2.1.1* Popmax Filtering AF ≥ 1:10,000 (≥ 0.01% or 0.0001).
-
-
-*Use gnomAD 2.1.1 exome data unless the region is not covered in the exome, in which case gnomAD 3.1.2 genome data should be used.",Gene-specific
-GCK (HGNC:4195),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-GCK (HGNC:4195),BS1,Strong,"gnomAD 2.1.1* Popmax Filtering AF ≥ 1:25,000 (0.004% or 0.00004).
-
-
-*Use gnomAD 2.1.1 exome data unless the region is not covered in the exome, in which case gnomAD 3.1.2 genome data should be used.",Gene-specific
-GCK (HGNC:4195),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-GCK (HGNC:4195),BS2,Strong,"We expect to see hyperglycemia at birth in an individual with _GCK_-MODY and therefore consider an individual unaffected if euglycemic in childhood or adulthood.  Since individuals typically do not present with symptoms of diabetes, evidence that someone is “nondiabetic” is insufficient; fasting glucose must be tested and found to be within normal limits (<100 mg/dl / 5.6 mmol/L).",Gene-specific
-GCK (HGNC:4195),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-GCK (HGNC:4195),BS3,Strong,Applicable to non-canonical splice site variants that have RNA and in silico evidence of normal splicing (see BP4).,Gene-specific
-GCK (HGNC:4195),BS3,Supporting,"Use GCK PS3 decision tree, which incorporates the relative activity index (RAI), relative stability index (RSI) and assays that measure the impact of variants on binding with GKRP and GKA.
-
-
-Evidence of no impact on function:
-
-
-
-
-Normal RAI (>0.5) + normal RSI (>0.5) + normal inhibition/activation with GKRP/GKA = BS3_Supporting 
-
-
-Normal RAI (>0.5) + normal RSI (>0.5) but no studies investigating GKRP/GKA = Cannot use PS3 or BS3
-
-
-
-
-Gloyn, et al. 2005 
-5
-; Beer, et al. 2012 
-6
-; Raimondo, et al. 2014 
-7
-; Gloyn, et al. (2004)
-12
-.",Gene-specific
-GCK (HGNC:4195),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-GCK (HGNC:4195),BS4,Strong,"Applicable to family members without variant who meet PP4 criteria (HbA1C 5.6 – 7.6% (38-60 mmol/mol) (if given multiple results, use maximum value) AND Fasting glucose 5.5-8 mmol/L (100-144 mg/dL))",Gene-specific
-GCK (HGNC:4195),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-GCK (HGNC:4195),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-GCK (HGNC:4195),BP2,Supporting,Also applicable when in cis or trans with a likely pathogenic variant.,General recommendation
-GCK (HGNC:4195),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-GCK (HGNC:4195),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-GCK (HGNC:4195),BP4,Supporting,"Use a REVEL score of ≤0.15 as supportive evidence of no predicted impact on the gene or gene product. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply BP4 when the predicted change is below 0.2
-9
-,
-10
-.",General recommendation
-GCK (HGNC:4195),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-GCK (HGNC:4195),BP5,Supporting,A variant in another monogenic diabetes gene is P/LP.,General recommendation
-GCK (HGNC:4195),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-GCK (HGNC:4195),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-GCK (HGNC:4195),BP7,Supporting,Apply BP7 when the predicted change from SpliceAI is below 0.2 AND phyloP100 way < 2.0.,Gene-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGCKVersion2.0.0_version=2.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGCKVersion2.0.0_version=2.0.0.csv
deleted file mode 100644
index 7179248a652f44460ba94a9307b59fd3c4e83434..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGCKVersion2.0.0_version=2.0.0.csv
+++ /dev/null
@@ -1,268 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-GCK (HGNC:4195),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-GCK (HGNC:4195),PVS1,Very Strong,"Use 
-GCK
- PVS1 decision tree created based on PVS1 decision tree from ClinGen SVI group
-1
-
-
-
-
-Variants generating PTCs 3’ of c.1198 (p.Asp400) of NM_000162.3, which includes the last 55 nucleotides of exon 9 and exon 10, are not expected to cause NMD
-2
-. The α13 helix (p.444-456), located at the C-end of the protein, has a critical role in GCK conformational change upon glucose binding.  Individuals with PTCs in exon 10 have a MODY phenotype. Therefore, a “very strong” level of evidence will be applied for PTCs in exon 10.
-
-
-“Exon skipping or  “use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame” 
-
-
-single exon deletions 
-
-
-deletion of exon 1 is in-frame but over 20 families with GCK-MODY phenotype and exon 1 deletion (some also have promoter deletions) --> PVS1 
-
-
-deletions of single 
-exons 2,3,6 and 7
- cause frameshift --> 
-PVS1
- 
-
-
-deletions or skipping of 
-exons 8 and 9
- are in-frame and the proportion is >10 % (52 AA and 78 AA, respectively) --> 
-PVS1
- 
-
-
-deletions or skipping of 
-exons 4 and 5
- are in-frame and the proportion is <10 % (40 AA and 32 AA, respectively). Exon 4 (p.122-161) and exon 5 (p.162-193) contain each a part of the active site that binds glucose /p.151-180
-3
- according to Beck et al., Biochemistry 2013/ --> 
-PVS1
- 
-
-
-deletion of exon 10 (47 AA) – There are a number of patients with a GCK-MODY phenotype with reported with missense, frameshift, PTC, splice acceptor, and stop loss variants in exon 10  --> 
-PVS1
-
-
-
-
-
-
-
-
-
-
-Apply PVS1_Supporting to initiation codon variants given MDEP has only reviewed one variant and classified as VUS (c.3G>A, PVS1_Supporting + PM2_Supporting; one case submitted, dx.53 and no other info provided to lab).  The next methionine is at codon 8 and there are no variants classified as pathogenic 5' of p.Met8. 
-
-
-Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.",Gene-specific
-GCK (HGNC:4195),PVS1,Strong,"Use 
-GCK
- PVS1 decision tree.
-
-
-Per the SVI standard PVS1 decision tree, apply PVS1_Strong to duplications ≥ 1 exon in size, contained completely within gene, presumed in tandem, reading frame presumed disrupted, and NMD predicted to occur.",Strength
-GCK (HGNC:4195),PVS1,Supporting,"Use 
-GCK
- PVS1 decision tree.
-
-
-
-
-Apply PVS1_Supporting to initiation codon variants given MDEP has only reviewed one variant and classified as VUS (c.3G>A, PVS1_Supporting + PM2_Supporting; one case submitted, dx.53 and no other info provided to lab).  The next methionine is at codon 8 and there are no variants classified as pathogenic 5' of p.Met8. 
-
-
-Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.",Strength
-GCK (HGNC:4195),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-GCK (HGNC:4195),PS1,Strong,No change,None
-GCK (HGNC:4195),PS1,Supporting,"PS1 may be used at a supporting level for canonical and non-canonical splicing variants when a different variant at the same nucleotide has been previously classified as pathogenic and the variant being assessed is predicted by SpliceAI to have a similar (SpliceAI score within 10% of the original variant) or greater deleterious impact.  For canonical splicing variants, PS1 may also be used at the supporting level if a variant at the other nucleotide in the same splice site has been previously classified as pathogenic and the variant being assessed is predicted by SpliceAI to have a similar (SpliceAI score within 10% of the original variant) or greater deleterious impact.",Strength
-GCK (HGNC:4195),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-GCK (HGNC:4195),PS2,Very Strong,"Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions.
-.","Gene-specific,Strength"
-GCK (HGNC:4195),PS2,Strong,Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions.,"Gene-specific,Strength"
-GCK (HGNC:4195),PS2,Moderate,Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions.,"Gene-specific,Strength"
-GCK (HGNC:4195),PS2,Supporting,Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions.,"Gene-specific,Strength"
-GCK (HGNC:4195),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-GCK (HGNC:4195),PS3,Strong,Applicable to non-canonical splice site variants that have RNA and in silico evidence of aberrant splicing.,"Gene-specific,Strength"
-GCK (HGNC:4195),PS3,Moderate,See list of approved functional studies and guidelines for interpretation of data.,"Gene-specific,Strength"
-GCK (HGNC:4195),PS3,Supporting,See list of approved functional studies and guidelines for interpretation of data (below).,"Gene-specific,Strength"
-GCK (HGNC:4195),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-GCK (HGNC:4195),PS4,Strong,7 or more occurrences in unrelated individuals = Strong.,"Gene-specific,Strength"
-GCK (HGNC:4195),PS4,Moderate,4-6 occurrences in unrelated individuals = Moderate.,"Gene-specific,Strength"
-GCK (HGNC:4195),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-GCK (HGNC:4195),PM1,Moderate,"Applicable for glucose- and ATP-binding sites (see attached chart for details).
-
-
-Glucose-binding sites:  Ser151 - Pro153; Thr168 - Lys169;  Asn204 - Thr206; Ile225 - Asn231; Asn254 - Gly258; Gln287; Glu290
-
-
-ATP-binding sites:  Asp78 - Arg85; Ser151; Lys169; Asp205; Ile225 - Gly229; Gly295 - Lys296; Glu331 - Arg333; Ser336; Gly410 - His416",Gene-specific
-GCK (HGNC:4195),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-GCK (HGNC:4195),PM2,Supporting,"gnomAD v4.1 Grpmax FAF ≤ 1:333,000 (≤ 0.000003 or 0.0003%)",Gene-specific
-GCK (HGNC:4195),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-GCK (HGNC:4195),PM3,Very Strong,Use SVI-recommended point-based system.,Strength
-GCK (HGNC:4195),PM3,Strong,Use SVI-recommended point-based system.,Strength
-GCK (HGNC:4195),PM3,Moderate,Use SVI-recommended point-based system.,Strength
-GCK (HGNC:4195),PM3,Supporting,Use SVI-recommended point-based system.,Strength
-GCK (HGNC:4195),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-GCK (HGNC:4195),PM4,Moderate,"For deletions/insertions of more than one amino acid in a non-repeat region, use as moderate level of evidence.",Strength
-GCK (HGNC:4195),PM4,Supporting,Apply at the Supporting level when there is an insertion or deletion of a single amino acid in a non-repeat region.,Strength
-GCK (HGNC:4195),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-GCK (HGNC:4195),PM5,Strong,Applicable once two amino acid changes have been classified as pathogenic at the same amino acid residue.,Strength
-GCK (HGNC:4195),PM5,Moderate,The novel amino acid change must have a Grantham distance greater than or equal to the previously classified pathogenic variant.,Strength
-GCK (HGNC:4195),PM5,Supporting,Apply if the previously classified amino acid change is likely pathogenic (rather than pathogenic) or if the previously classified variant is pathogenic but has a greater Grantham distance.,Strength
-GCK (HGNC:4195),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-GCK (HGNC:4195),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-GCK (HGNC:4195),PP1,Strong,"Use thresholds suggested by Jarvik and Browning
-8
-
-
-
-
-Single Family : ≤ 1/32 (5 meioses)
-
-
->1 Family : ≤ 1/16 (4 meioses)","General recommendation,Gene-specific"
-GCK (HGNC:4195),PP1,Moderate,"Use thresholds suggested by Jarvik and Browning
-8
-
-
-
-
-Single Family : ≤ 1/16 (4 meioses)
-
-
->1 Family : ≤ 1/8 (3 meioses)","General recommendation,Gene-specific"
-GCK (HGNC:4195),PP1,Supporting,"Use thresholds suggested by Jarvik and Browning
-8
-
-
-
-
-Single Family : ≤ 1/8 (3 meioses)
-
-
->1 Family : ≤ ¼ (2 meioses)","General recommendation,Gene-specific"
-GCK (HGNC:4195),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,
-GCK (HGNC:4195),PP2,Supporting,"Apply to all missense variants in GCK. gnomAD missense constraint score for 
-GCK
- is 3.07 (observed/expected= 0.5), which is significant.",Gene-specific
-GCK (HGNC:4195),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-GCK (HGNC:4195),PP3,Supporting,"Use REVEL score of ≥0.70 as supportive evidence of pathogenicity. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply PP3 when the predicted change is at least 0.2
-9
-,
-10",General recommendation
-GCK (HGNC:4195),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-GCK (HGNC:4195),PP4,Moderate,"HbA1C 5.6 – 7.6% (38-60 mmol/mol) (if given multiple results, use maximum value) AND fasting plasma glucose always (FPG) 5.5-8 mmol/L (100-144 mg/dL) AND presence of any of the following additional features:
-
-
-
-
-Pediatric patient (prepubertal or <10 years) (picked up in the absence of symptoms, either incidentally during workup for an unrelated indication or during routine screening)
-
-
-Multiple values (=persistent) of mild fasting hyperglycemia in PP4 range
-
-
-Either (≥ 1 HbA1c + ≥ 2 FPG) OR (≥ 2 HbA1c + ≥ 1 FPG)
-
-
-Only 1 HbA1c and 1 FPG in range but they are at least 6 months apart
-
-
-Patient in literature is described as having a multi-year history of impaired fasting glucose (IFG)
-
-
-
-
-
-
-OGTT (oral glucose tolerance test) with 2-hour increment <3 mmol/L (54 mg/dl) 
-
-
-Antibody negative 
-
-
-Macrosomia in normoglycemic offspring of hyperglycemic gestational parent
-
-
-Low birthweight in hyperglycemic offspring of hyperglycemic gestational parent. 
-
-
-Three-generation, dominant family history of diabetes or hyperglycemia (in a family not used for PP1)","Gene-specific,Strength"
-GCK (HGNC:4195),PP4,Supporting,"HbA1C 5.6 – 7.6% (38-60 mmol/mol) (if given multiple results, use maximum value) AND fasting plasma glucose always (FPG) 5.5-8 mmol/L (100-144 mg/dL)",Gene-specific
-GCK (HGNC:4195),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-GCK (HGNC:4195),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-GCK (HGNC:4195),BA1,Stand Alone,"gnomAD v4.1 Grpmax FAF ≥ 1:10,000 (≥ 0.01% or 0.0001)",Gene-specific
-GCK (HGNC:4195),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-GCK (HGNC:4195),BS1,Strong,"gnomAD v4.1 Grpmax FAF ≥ 1:25,000 (0.004% or 0.00004)",Gene-specific
-GCK (HGNC:4195),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-GCK (HGNC:4195),BS2,Strong,"We expect to see hyperglycemia at birth in an individual with _GCK_-MODY and therefore consider an individual unaffected if euglycemic in childhood or adulthood.  Since individuals typically do not present with symptoms of diabetes, evidence that someone is “nondiabetic” is insufficient; fasting glucose must be tested and found to be within normal limits (<100 mg/dl / 5.6 mmol/L).",Gene-specific
-GCK (HGNC:4195),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-GCK (HGNC:4195),BS3,Strong,Applicable to non-canonical splice site variants that have RNA and in silico evidence of normal splicing (see BP4).,Gene-specific
-GCK (HGNC:4195),BS3,Supporting,"Use GCK PS3 decision tree, which incorporates the relative activity index (RAI), relative stability index (RSI) and assays that measure the impact of variants on binding with GKRP and GKA.
-
-
-Evidence of no impact on function:
-
-
-
-
-Normal RAI (>0.5) + normal RSI (>0.5) + normal inhibition/activation with GKRP/GKA = BS3_Supporting 
-
-
-Normal RAI (>0.5) + normal RSI (>0.5) but no studies investigating GKRP/GKA = Cannot use PS3 or BS3
-
-
-
-
-Gloyn, et al. 2005 
-5
-; Beer, et al. 2012 
-6
-; Raimondo, et al. 2014 
-7
-; Gloyn, et al. (2004)
-12
-.",Gene-specific
-GCK (HGNC:4195),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-GCK (HGNC:4195),BS4,Strong,"Applicable to family members without variant who meet PP4 criteria (HbA1C 5.6 – 7.6% (38-60 mmol/mol) (if given multiple results, use maximum value) AND Fasting glucose 5.5-8 mmol/L (100-144 mg/dL))",Gene-specific
-GCK (HGNC:4195),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-GCK (HGNC:4195),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-GCK (HGNC:4195),BP2,Supporting,Also applicable when in cis or trans with a likely pathogenic variant.,General recommendation
-GCK (HGNC:4195),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-GCK (HGNC:4195),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-GCK (HGNC:4195),BP4,Supporting,"Use a REVEL score of ≤0.15 as supportive evidence of no predicted impact on the gene or gene product. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply BP4 when the predicted change is below 0.2
-9
-,
-10
-.",General recommendation
-GCK (HGNC:4195),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-GCK (HGNC:4195),BP5,Supporting,A variant in another monogenic diabetes gene is P/LP.,General recommendation
-GCK (HGNC:4195),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-GCK (HGNC:4195),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-GCK (HGNC:4195),BP7,Supporting,Apply BP7 when the predicted change from SpliceAI is below 0.2 AND phyloP100 way < 2.0.,Gene-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF1AVersion1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF1AVersion1.0.0_version=1.0.0.csv
deleted file mode 100644
index f5801ebc30c41eb6c8daeb7c42de8cc0a375d1f2..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF1AVersion1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,420 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-HNF1A (HGNC:11621),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-HNF1A (HGNC:11621),PVS1,Very Strong,"Use HNF1A PVS1 decision tree.
-
-
-
-
-See below for adapted flowchart from ClinGen SVI group (Abou Tayoun, et al. 2018)
-
-
-Variants generating PTCs 5’ of c.1714 of NM_000545.8, which includes the last 55 nucleotides of exon 9 and all of exon 10, are not expected to cause NMD (PMID: 24274751). The transactivation domain (TAD) of the protein overlaps with this region. The last 55 nucleotides of exon 9 (c.1714-1768) is enriched for disease-causing variants and loss-of function variants in this region have been found in patients/families with a MODY phenotype. Therefore, a “very strong” level of evidence will be used for loss-of-function variants 5’ of c.1768 regardless of where the premature termination codon occurs.
-
-
-PVS1_Strong will be applied to nonsense variants at c.1803 (p.601) and 5’ and frameshift variants at c.1854 (p.618) and 5’. The distinction of nonsense and frameshift variants was made following a careful review of the phenotypes of individuals with loss-of-function variants in exon 10, which lead to our prediction that the addition of new amino acids from a frameshift will disrupt the TAD and cause a MODY phenotype more so than the deletion of a small part of the end of the TAD. Moderate phenotypic evidence was applied to the c.1802del (p.601Ter) variant, but the individual with the next nonsense variant (p.Gln625Ter) was unaffected. Frameshift variants at p.Ile618 and 5’ have been identified in patients with a phenotype consistent with MODY.
-
-
-
-
-
-
- “Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame”
-
-
-Deletions of exon 1 would lead at least to loss of the initiation codon (see below for recommendations for initiation codon variants). Deletions of single exons 2, 3, 4, 5, 6, 8 or 9 all cause frameshift, and thus PVS1 would be used. In HNF1A, only exon 7 (LRG_522t1) is surrounded by introns of the same phase. Skipping or deletion of exon 7 would remove 64 amino acids in the TAD, which is >10% of the protein and 18% of the TAD. Given the significance of the TAD, we support still using PVS1 instead of PVS1_Strong in this situation. A deletion of exon 10 would remove part of the TAD but less than 10% of the protein. Since the TAD is critical to protein function, and variants that disrupt all of exon 10 have been found in patients with a MODY phenotype, we will use PVS1_Strong for deletions of exon 10 and splicing variants that would predict the skipping of exon 10. This specification is in accordance with Tayoun’s recommendation to use PVS1_Strong in cases in which the truncated region is critical to protein function.
-
-
-
-
-
-
-Apply PVS1 to initiation codon variants. Four initiation codon variants have been identified in patients with a MODY phenotype. The closest potential in-frame start codon is p.Met118. Starting the protein at p.Met118 would remove 18% of the protein, including the entire dimerization domain. There are many P/LP variants upstream of p.Met118.
-
-
-Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.",Strength
-HNF1A (HGNC:11621),PVS1,Strong,"Use HNF1A PVS1 decision tree.
-
-
-
-
-See below for adapted flowchart from ClinGen SVI group (Abou Tayoun, et al. 2018)
-
-
-Variants generating PTCs 5’ of c.1714 of NM_000545.8, which includes the last 55 nucleotides of exon 9 and all of exon 10, are not expected to cause NMD (PMID: 24274751). The transactivation domain (TAD) of the protein overlaps with this region. The last 55 nucleotides of exon 9 (c.1714-1768) is enriched for disease-causing variants and loss-of function variants in this region have been found in patients/families with a MODY phenotype. Therefore, a “very strong” level of evidence will be used for loss-of-function variants 5’ of c.1768 regardless of where the premature termination codon occurs.
-
-
-PVS1_Strong will be applied to nonsense variants at c.1803 (p.601) and 5’ and frameshift variants at c.1854 (p.618) and 5’. The distinction of nonsense and frameshift variants was made following a careful review of the phenotypes of individuals with loss-of-function variants in exon 10, which lead to our prediction that the addition of new amino acids from a frameshift will disrupt the TAD and cause a MODY phenotype more so than the deletion of a small part of the end of the TAD. Moderate phenotypic evidence was applied to the c.1802del (p.601Ter) variant, but the individual with the next nonsense variant (p.Gln625Ter) was unaffected. Frameshift variants at p.Ile618 and 5’ have been identified in patients with a phenotype consistent with MODY.
-
-
-
-
-
-
- “Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame”
-
-
-Deletions of exon 1 would lead at least to loss of the initiation codon (see below for recommendations for initiation codon variants). Deletions of single exons 2, 3, 4, 5, 6, 8 or 9 all cause frameshift, and thus PVS1 would be used. In HNF1A, only exon 7 (LRG_522t1) is surrounded by introns of the same phase. Skipping or deletion of exon 7 would remove 64 amino acids in the TAD, which is >10% of the protein and 18% of the TAD. Given the significance of the TAD, we support still using PVS1 instead of PVS1_Strong in this situation. A deletion of exon 10 would remove part of the TAD but less than 10% of the protein. Since the TAD is critical to protein function, and variants that disrupt all of exon 10 have been found in patients with a MODY phenotype, we will use PVS1_Strong for deletions of exon 10 and splicing variants that would predict the skipping of exon 10. This specification is in accordance with Tayoun’s recommendation to use PVS1_Strong in cases in which the truncated region is critical to protein function.
-
-
-
-
-
-
-Apply PVS1 to initiation codon variants. Four initiation codon variants have been identified in patients with a MODY phenotype. The closest potential in-frame start codon is p.Met118. Starting the protein at p.Met118 would remove 18% of the protein, including the entire dimerization domain. There are many P/LP variants upstream of p.Met118.
-
-
-Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.",Strength
-HNF1A (HGNC:11621),PVS1,Supporting,"Use HNF1A PVS1 decision tree.
-
-
-
-
-See below for adapted flowchart from ClinGen SVI group (Abou Tayoun, et al. 2018)
-
-
-Variants generating PTCs 5’ of c.1714 of NM_000545.8, which includes the last 55 nucleotides of exon 9 and all of exon 10, are not expected to cause NMD (PMID: 24274751). The transactivation domain (TAD) of the protein overlaps with this region. The last 55 nucleotides of exon 9 (c.1714-1768) is enriched for disease-causing variants and loss-of function variants in this region have been found in patients/families with a MODY phenotype. Therefore, a “very strong” level of evidence will be used for loss-of-function variants 5’ of c.1768 regardless of where the premature termination codon occurs.
-
-
-PVS1_Strong will be applied to nonsense variants at c.1803 (p.601) and 5’ and frameshift variants at c.1854 (p.618) and 5’. The distinction of nonsense and frameshift variants was made following a careful review of the phenotypes of individuals with loss-of-function variants in exon 10, which lead to our prediction that the addition of new amino acids from a frameshift will disrupt the TAD and cause a MODY phenotype more so than the deletion of a small part of the end of the TAD. Moderate phenotypic evidence was applied to the c.1802del (p.601Ter) variant, but the individual with the next nonsense variant (p.Gln625Ter) was unaffected. Frameshift variants at p.Ile618 and 5’ have been identified in patients with a phenotype consistent with MODY.
-
-
-
-
-
-
- “Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame”
-
-
-Deletions of exon 1 would lead at least to loss of the initiation codon (see below for recommendations for initiation codon variants). Deletions of single exons 2, 3, 4, 5, 6, 8 or 9 all cause frameshift, and thus PVS1 would be used. In HNF1A, only exon 7 (LRG_522t1) is surrounded by introns of the same phase. Skipping or deletion of exon 7 would remove 64 amino acids in the TAD, which is >10% of the protein and 18% of the TAD. Given the significance of the TAD, we support still using PVS1 instead of PVS1_Strong in this situation. A deletion of exon 10 would remove part of the TAD but less than 10% of the protein. Since the TAD is critical to protein function, and variants that disrupt all of exon 10 have been found in patients with a MODY phenotype, we will use PVS1_Strong for deletions of exon 10 and splicing variants that would predict the skipping of exon 10. This specification is in accordance with Tayoun’s recommendation to use PVS1_Strong in cases in which the truncated region is critical to protein function.
-
-
-
-
-
-
-Apply PVS1 to initiation codon variants. Four initiation codon variants have been identified in patients with a MODY phenotype. The closest potential in-frame start codon is p.Met118. Starting the protein at p.Met118 would remove 18% of the protein, including the entire dimerization domain. There are many P/LP variants upstream of p.Met118.
-
-
-Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.",Strength
-HNF1A (HGNC:11621),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-HNF1A (HGNC:11621),PS1,Strong,No change,No change
-HNF1A (HGNC:11621),PS1,Supporting,PS1 may also be used at a supporting level for canonical and non-canonical splicing variants when a different variant at the same nucleotide has been previously classified as pathogenic and the variant being assessed is predicted by SpliceAI to have a similar (SpliceAI score within 10% of the original variant) or greater deleterious impact.,Strength
-HNF1A (HGNC:11621),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-HNF1A (HGNC:11621),PS2,Very Strong,Use SVI recommended point-based system with specifications for “Phenotype Consistency” described below.,"Gene-specific,Strength"
-HNF1A (HGNC:11621),PS2,Strong,Use SVI recommended point-based system with specifications for “Phenotype Consistency” described below.,"Gene-specific,Strength"
-HNF1A (HGNC:11621),PS2,Moderate,Use SVI recommended point-based system with specifications for “Phenotype Consistency” described below.,"Gene-specific,Strength"
-HNF1A (HGNC:11621),PS2,Supporting,Use SVI recommended point-based system with specifications for “Phenotype Consistency” described below.,"Gene-specific,Strength"
-HNF1A (HGNC:11621),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-HNF1A (HGNC:11621),PS3,Strong,Applicable to non-canonical splice site variants that have RNA and in silico evidence of aberrant splicing.,"Gene-specific,Strength"
-HNF1A (HGNC:11621),PS3,Moderate,"Applicable for variants with luciferase assay data (evidence of decreased transactivation (<=40% of wild type) by the Gloyn/Oxford group (Althari et al, (2020) (DOI: 
-https://doi.org/10.1016/j.ajhg.2020.08.016
- (DOI: 
-https://doi.org/10.1016/j.ajhg.2020.08.016
-).)).","Gene-specific,Strength"
-HNF1A (HGNC:11621),PS3,Supporting,"See list of approved functional studies and guidelines for interpretation of data (below).
-
-
-
-
-Luciferase assays for transactivation
-
-
-“Decreased function” is defined as activity less than 40% of wildtype (WT).
-
-
-Note: this threshold is not 100% specific for transactivation (TA) activity and is complicated by the fact that TA activity will vary depending on many factors, for instance cell line (HeLa, INS, MIN6, etc.) and reporter construct that is used. Commonly used promoters include rat/human albumin (PMID:12574234) and HNF4A-P2 (PMID: 32910913). Experiments should be designed to include more than one promoter and more than one cell line; any data less than 40% of WT warrants use of PS3_Supporting or PS3_Moderate, with more weight given to assays that have appropriate controls (see below).
-
-
-Assays should include controls for WT (human HNF1A cDNA (NM_000545.8)), T2DM-risk and known MODY variants, which represent the range of behaviours across the HNF1A allelic spectrum. When calculating an OddsPath or counting the total number of control variants per Brnich et al. 2020 (PMID: 31892348) the following are well-characterized pathogenic HNF1A-MODY variants: c.335C>T (p.Pro112Leu), c.779C>A (p.Thr260Met), c.1340C>T (p.Pro447Leu), c.1556C>T (p.Pro519Leu), c.787C>T p.(Arg263Cys) and c.686G>A p.(Arg229Gln). We also recommend that assays include the following variants to capture dysfunction which increases risk for T2D but is insufficient to cause monogenic diabetes: c.293C>T (p.Ala98Val) and c.1522G>A (p.Glu508Lys) (PMID: 24915262, 26551672). The degree of TA impairment of HNF1A should correlate positively with the severity of the diabetes phenotype: disease-causing HNF1A variants impair TA activity more severely (<30-40% compared to WT) than T2D risk variants (40-75% compared to WT).
-
-
- We note that the data presented by the Oxford/Gloyn group in Althari et al (PMID:32910913) have four controls that can be classified as pathogenic based on non-functional data and 10 controls that can be classified as benign based on non-functional data. Using either HeLa or INS1 cells and cutoffs of 0.40/0.75, only ≤2 variants fall outside the expected range, and OddsPath based on the recommendations by Brnich et al 2020 (PMID: 31892348) can be achieved (>4.3) that enable the use of PS3_Moderate and BS3_Supporting. The data presented by the Bergen group in Althari et al (PMID: 32910913) used six controls that can be classified as pathogenic based on non-functional data and 18 controls that can be classified as benign based on non-functional data. Using either HeLa or INS1 cells and cutoffs of 0.40/0.75, the pathogenic variants in the Bergen data consistently fell into the expected TA range (<40%). However, two benign variants (not including T2D-risk variant p.Glu508Lys) fell into the pathogenic range and 14 out of 16 of the benign variants fell into the indeterminate range. We hence recommend applying PS3_Supporting and BS3_Supporting only at this time to data from this group. 
-
-
-Validation of luciferase assay performed by Bergen and Oxford groups reported in Althari et al, with cutoffs of <40% of WT for functionally abnormal and ≥75% of WT for functionally normal
-
-
-
-
-
-
-
-
-
-
-EMSA for DNA binding
-
-
-“Decreased function” is defined as activity less than 40% of WT.
-
-
-Note: the effect of the variant on DNA binding will be highly dependent on whether the variant is located within the DNA binding domain. Our experience is that for HNF1A-MODY causal variants located in the DNA binding domain, we observe DNA binding from 0-35% compared to WT. The following variants can be used as positive controls for reduced DNA binding ability (<40%): c.335C>T (p.Pro112Leu), c.608G>A (p.Arg203His), c.787C>T (p.Arg263Cys) and c.686G>A (p.Arg229Gln) (PMID: 11162430, 12574234, 24915262); we recommend the assay contain at least two. We also recommend that the assay include variants whose DNA binding ability has previously been assessed (e.g., c.298C>A (p.Gln100Lys) (70% of WT) and c.392G>A (p.Arg131Gln) (58% of WT) (PMID: 27899486).
-
-
-
-
-
-
-Western blotting and indirect immunofluorescence for protein expression & localization
-
-
-Determining appropriate thresholds for protein expression is more difficult due to variability in results between different experimental protocols. Sample preparations, gel loading, transfer efficiency, antibody specificity, choice of internal control and quantification method are some of the factors that can contribute to varying and inconsistent results between labs. Altered protein expression can be indirectly captured through the read-out from a transactivation assay and reduced protein expression can provide an explanation for reduced transactivation.
-
-
-When exploring protein mis-localisation we recommend that the c.589_615del (p.Leu197_Leu205del) variant is included as a positive control for impaired nuclear localization (cytosolic retention) (PMID: 16274290).
-
-
-
-
-
-
-Studies performed on a cell line generated from a patient sample (which will be heterozygous and also contain other variants in the patient’s genome which could modify function) will not count as PS3 but instead will count toward PP4_Moderate.
-
-
-For canonical splice site variants, do not use PS3 for RNA studies demonstrating abnormal splicing, since PVS1 will already be used at some level. Per SVI recommendations, we will apply PS3 at the Strong level to non-canonical splice site variants that have RNA and in silico evidence of aberrant splicing.
-
-
- References
-
-
-Najmi et al (2017) (PMID: 27899486)
-
-
-Bjorkhaug et al (2003) (PMID: 12574234)
-
-
-Brnich et al (2020) (PMID: 31892348)
-
-
-Althari et al (2020) (PMID: 32910913)","Gene-specific,Strength"
-HNF1A (HGNC:11621),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-HNF1A (HGNC:11621),PS4,Strong,"Seven or more= Strong. Variant should meet PM2_Supporting in order to use PS4 at any level (careful review of gnomAD QC data may be necessary to assess whether variant is real or an artifact, especially if variant is in a polyC region). Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology (see below).
-
-
-
-
-Prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-
-
- 4-6 unrelated occurrences = Moderate, 7 or more = Strong
-
-
-
-
-
-
-Phenotype of the affected individual must include diabetes, with evidence of an autoimmune etiology and/or absolute or near-absolute insulin deficiency considered exclusionary (see above).
-
-
- Variant should meet PM2_Supporting in order to use PS4 at any level (careful review of gnomAD QC data may be necessary to assess whether variant is real or an artifact, especially if variant is in a polyC region).
-
-
- References
-
-
-McDonald et al (2011) (PMID: 21395678)
-
-
-Shields et al (2017) (PMID: 28701371)
-
-
-Patel et al (2019) (PMID: 30409810)","Gene-specific,Strength"
-HNF1A (HGNC:11621),PS4,Moderate,"4-6 unrelated occurrences = Moderate. Variant should meet PM2_Supporting in order to use PS4 at any level. Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology (see below).","Gene-specific,Strength"
-HNF1A (HGNC:11621),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-HNF1A (HGNC:11621),PM1,Moderate,"This criterion can be used for variants in residues that directly bind DNA (see below).
-
-
-PM1: Applicable to amino acids that directly bind DNA (PMID: 12453420)
-o Gln130, Arg131, Glu132, His143, Leu144, Ser145, Gln146, His147, Leu148, Asn149, Lys155, Thr156, Gln157, Lys158, Arg203, Phe204, Lys205, Trp206, Arg263, Val264, Tyr265, Asn270, Arg271, Arg272, Lys273","Gene-specific,Strength"
-HNF1A (HGNC:11621),PM1,Supporting,"Use for defined regions in the DNA binding and dimerization domains. It can also be used for variants within certain transcription factor binding sites of the promoter.
-
-
-PM1_Supporting: Applicable for SNV and non-frameshift indel variants in the promoter, DNA binding and dimerization domains (PMID: 18003757)  
-
-
-
-
-Promoter 
-
-
-–c.-187 to c.-195 (AP1 binding site) 
-
-
-–c.-209 to c.-227 (Overlapping HNF3 & NF-Y sites) 
-
-
-–c.-238 to c.-259 (HNF1A binding site) 
-
-
-–c.-276 to c.-288 (HNF4A binding site)
-
-
-
-
-
-
-Dimerization: codons 1-32, NM_000545.8
-
-
-Subset of DNA binding domains: codons 107-174 and 201-280, NM_000545.8","Gene-specific,Strength"
-HNF1A (HGNC:11621),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-HNF1A (HGNC:11621),PM2,Supporting,"Prevalence ≤ 1:50,000 (≤ 0.00002 or 0.002%) in gnomAD European Non-Finnish population AND ≤ 1 copy in other founder and non-founder populations (would require ≤ 1/50,000 in non-European populations if/when they surpass 100,000 alleles).","General recommendation,Gene-specific"
-HNF1A (HGNC:11621),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-HNF1A (HGNC:11621),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-HNF1A (HGNC:11621),PM4,Moderate,"For single amino acid deletions, use as supporting level of evidence.",Strength
-HNF1A (HGNC:11621),PM4,Supporting,"For single amino acid deletions/insertions, use as supporting level of evidence",Strength
-HNF1A (HGNC:11621),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-HNF1A (HGNC:11621),PM5,Strong,Applicable once two amino acid changes have been classified as pathogenic at the same amino acid residue,Strength
-HNF1A (HGNC:11621),PM5,Moderate,The novel amino acid change must have a Grantham distance greater than or equal to the previously classified pathogenic variant.,Strength
-HNF1A (HGNC:11621),PM5,Supporting,Apply if the previously classified amino acid change is likely pathogenic (rather than pathogenic) or if the previously classified variant is pathogenic but has a greater Grantham distance.,Strength
-HNF1A (HGNC:11621),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-HNF1A (HGNC:11621),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-HNF1A (HGNC:11621),PP1,Strong,"Use thresholds suggested by Jarvik and Browning (PMID: 27236918)
-
-
-
-
-Single Family : ≤ 1/32 (5 meioses)
-
-
-1 Family : ≤ 1/16 (4 meioses)","General recommendation,Gene-specific"
-HNF1A (HGNC:11621),PP1,Moderate,"Use thresholds suggested by Jarvik and Browning (PMID: 27236918)
-
-
-
-
-Single Family : ≤ 1/16 (4 meioses)
-
-
-1 Family : ≤ 1/8 (3 meioses)","General recommendation,Gene-specific"
-HNF1A (HGNC:11621),PP1,Supporting,"Use thresholds suggested by Jarvik and Browning (PMID: 27236918)
-
-
-
-
-Single Family : ≤ 1/8 (3 meioses)
-
-
-1 Family : ≤ ¼ (2 meioses)","General recommendation,Gene-specific"
-HNF1A (HGNC:11621),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-HNF1A (HGNC:11621),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-HNF1A (HGNC:11621),PP3,Supporting,Use REVEL score of ≥0.70 as supportive evidence of pathogenicity. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply PP3 when the predicted change is above 0.2 (Wai et al. 2020 PMID: 32123317; Jaganathan et al. 2019 PMID: 30661751).,General recommendation
-HNF1A (HGNC:11621),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-HNF1A (HGNC:11621),PP4,Moderate,"MODY Probability Calculator (MPC) result ≥50% chance of testing positive 
-https://www.diabetesgenes.org/mody-probability-calculator/
-) AND negative HNF4A testing AND presence of at least one additional feature characteristic of HNF1A-MODY:
-
-
-
-
-Antibody negative and/or persistent C-peptide after five years post- T1DM diagnosis
-
-
-Response to low-dose SU (extreme response- hypoglycemia)
-
-
-Low hsCRP in patient with clinical diagnosis of T2DM
-
-
-Biochemical/Molecular phenotypic evidence from patient cell lines
-
-
-Hepatocellular adenomas",Gene-specific
-HNF1A (HGNC:11621),PP4,Supporting,"MODY Probability Calculator (MPC) result ≥50% chance of testing positive 
-https://www.diabetesgenes.org/mody-probability-calculator/
-) AND negative HNF4A testing",Gene-specific
-HNF1A (HGNC:11621),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-HNF1A (HGNC:11621),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-HNF1A (HGNC:11621),BA1,Stand Alone,"MAF ≥ 1:10,000 (≥ 0.01% or 0.0001) in gnomAD Popmax Filtering AF.",Gene-specific
-HNF1A (HGNC:11621),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-HNF1A (HGNC:11621),BS1,Strong,"MAF ≥ 1:30,000 (≥0.0033% or 0.000033) in gnomAD Popmax Filtering AF.",Gene-specific
-HNF1A (HGNC:11621),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-HNF1A (HGNC:11621),BS2,Strong,"Apply to normoglycemic individuals age 70 or older (i.e., genotype positive, phenotype negative).",Gene-specific
-HNF1A (HGNC:11621),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-HNF1A (HGNC:11621),BS3,Strong,Applicable to non-canonical splice site variants that have RNA and in silico evidence of normal splicing.,Gene-specific
-HNF1A (HGNC:11621),BS3,Supporting,"See list of approved functional studies and guidelines for interpretation of data.
-
-
-
-
-Luciferase assays for transactivation
-
-
-“No functional impact” is defined as ≥75% activity of wildtype. If data from more than one experiment is available, do not apply BS3_Supporting if one result is ≥75% and the other is not.
-
-
-Note: this threshold is not 100% specific for transactivation (TA) activity and is complicated by the fact that TA activity will vary depending on many factors, for instance cell line used (HeLa, INS, MIN6 etc). Please see PS3_Supporting section above for recommendations on controls. The degree of TA impairment of HNF1A tends to correlate positively with severity of phenotype: that is MODY causal HNF1A variants impair TA activity more severely (<40% compared to WT) than T2D risk variants (40-75% compared to WT).
-
-
-
-
-
-
-EMSA for DNA binding
-
-
-“No functional impact” is defined as ≥75% activity of wildtype.
-
-
-Note: the effect of the variant on DNA binding will be highly dependent on whether the variant is located within the DNA binding domain. Please see PS3_Supporting section above for recommendations on controls.
-
-
-
-
-
-
-Western blotting and indirect immunofluorescence for protein expression & localization
-
-
-Determining appropriate thresholds for protein expression is more difficult due to variability in results between different experimental protocols. Sample preparations, gel loading, transfer efficiency, antibody specificity, choice of internal control and quantification method are some of the factors that can contribute to varying and inconsistent results between labs. Altered protein expression can be indirectly captured through the read-out from a transactivation assay and reduced protein expression can provide an explanation for reduced transactivation.To use BS3, functional study must have been performed on a transfected variant. If a study was performed on a cell line generated from a patient sample (and therefore contains the variant plus wild-type allele and other variants in the patient’s genome) it cannot count as BS3.
-
-
-
-
-
-
-References
-
-
-Najmi et al (2017) (PMID: 27899486)
-
-
-Bjorkhaug et al (2003) (PMID: 12574234)
-
-
-Brnich et al (2020) (PMID: 31892348)
-
-
-Althari et al (2020) (PMID: 32910913)",Gene-specific
-HNF1A (HGNC:11621),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-HNF1A (HGNC:11621),BS4,Strong,"Applicable to family members without variant who have MPC score >50% (i.e., genotype negative, phenotype positive).",Gene-specific
-HNF1A (HGNC:11621),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-HNF1A (HGNC:11621),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-HNF1A (HGNC:11621),BP2,Supporting,Also applicable when in cis or trans with a likely pathogenic variant.,General recommendation
-HNF1A (HGNC:11621),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-HNF1A (HGNC:11621),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-HNF1A (HGNC:11621),BP4,Supporting,Use a REVEL score of ≤0.15 as supportive evidence of no predicted impact on the gene or gene product. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply BP4 when the predicted change is below 0.2 (Wai et al. 2020 PMID: 32123317; Jaganathan et al. 2019 PMID: 30661751).,General recommendation
-HNF1A (HGNC:11621),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-HNF1A (HGNC:11621),BP5,Supporting,A variant in other monogenic diabetes gene is P/LP.,General recommendation
-HNF1A (HGNC:11621),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-HNF1A (HGNC:11621),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-HNF1A (HGNC:11621),BP7,Supporting,Use with no specifications.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF1AVersion2.0.0_version=2.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF1AVersion2.0.0_version=2.0.0.csv
deleted file mode 100644
index 059cdc044fdf1a03ed2c753f7c43220e5642a5b8..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF1AVersion2.0.0_version=2.0.0.csv
+++ /dev/null
@@ -1,250 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-HNF1A (HGNC:11621),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-HNF1A (HGNC:11621),PVS1,Very Strong,"Use HNF1A PVS1 decision tree.
-
-
-
-
-Variants generating PTCs 3’ of c.1714 of NM_000545.8, which includes the last 55 nucleotides of exon 9 and all of exon 10, are not expected to cause NMD (PMID: 24274751). The transactivation domain (TAD) of the protein overlaps with this region. The last 55 nucleotides of exon 9 (c.1714-1768) is enriched for disease-causing variants and loss-of function variants in this region have been found in patients/families with a MODY phenotype. Therefore, a “very strong” level of evidence will be used for loss-of-function variants 5’ of c.1768 regardless of where the premature termination codon occurs.
-
-
-PVS1_Strong will be applied to nonsense variants at c.1803 (p.601) and 5’ and frameshift variants at c.1854 (p.618) and 5’. The distinction of nonsense and frameshift variants was made following a careful review of the phenotypes of individuals with loss-of-function variants in exon 10, which lead to our prediction that the addition of new amino acids from a frameshift will disrupt the TAD and cause a MODY phenotype more so than the deletion of a small part of the end of the TAD. Moderate phenotypic evidence was applied to the c.1802del (p.601Ter) variant, but the individual with the next nonsense variant (p.Gln625Ter) was unaffected. Frameshift variants at p.Ile618 and 5’ have been identified in patients with a phenotype consistent with MODY.
-
-
-
-
-
-
-“Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame”
-
-
-Deletions of exon 1 would lead at least to loss of the initiation codon (see below for recommendations for initiation codon variants). Deletions of single exons 2, 3, 4, 5, 6, 8 or 9 all cause frameshift, and thus PVS1 would be used. In HNF1A, only exon 7 (LRG_522t1) is surrounded by introns of the same phase. Skipping or deletion of exon 7 would remove 64 amino acids in the TAD, which is >10% of the protein and 18% of the TAD. Given the significance of the TAD, we support still using PVS1 instead of PVS1_Strong in this situation. A deletion of exon 10 would remove part of the TAD but less than 10% of the protein. Since the TAD is critical to protein function, and variants that disrupt all of exon 10 have been found in patients with a MODY phenotype, we will use PVS1_Strong for deletions of exon 10 and splicing variants that would predict the skipping of exon 10. This specification is in accordance with Tayoun’s recommendation to use PVS1_Strong in cases in which the truncated region is critical to protein function.
-
-
-
-
-
-
-Apply PVS1 to initiation codon variants. Four initiation codon variants have been identified in patients with a MODY phenotype. The closest potential in-frame start codon is p.Met118. Starting the protein at p.Met118 would remove 18% of the protein, including the entire dimerization domain. There are many P/LP variants upstream of p.Met118.
-
-
-Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.",Strength
-HNF1A (HGNC:11621),PVS1,Strong,"Use HNF1A PVS1 decision tree.
-
-
-
-
-Variants generating PTCs 3’ of c.1714 of NM_000545.8, which includes the last 55 nucleotides of exon 9 and all of exon 10, are not expected to cause NMD (PMID: 24274751). The transactivation domain (TAD) of the protein overlaps with this region. The last 55 nucleotides of exon 9 (c.1714-1768) is enriched for disease-causing variants and loss-of function variants in this region have been found in patients/families with a MODY phenotype. Therefore, a “very strong” level of evidence will be used for loss-of-function variants 5’ of c.1768 regardless of where the premature termination codon occurs.
-
-
-PVS1_Strong will be applied to nonsense variants at c.1803 (p.601) and 5’ and frameshift variants at c.1854 (p.618) and 5’. The distinction of nonsense and frameshift variants was made following a careful review of the phenotypes of individuals with loss-of-function variants in exon 10, which lead to our prediction that the addition of new amino acids from a frameshift will disrupt the TAD and cause a MODY phenotype more so than the deletion of a small part of the end of the TAD. Moderate phenotypic evidence was applied to the c.1802del (p.601Ter) variant, but the individual with the next nonsense variant (p.Gln625Ter) was unaffected. Frameshift variants at p.Ile618 and 5’ have been identified in patients with a phenotype consistent with MODY.
-
-
-
-
-
-
-“Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame”
-
-
-Deletions of exon 1 would lead at least to loss of the initiation codon (see below for recommendations for initiation codon variants). Deletions of single exons 2, 3, 4, 5, 6, 8 or 9 all cause frameshift, and thus PVS1 would be used. In HNF1A, only exon 7 (LRG_522t1) is surrounded by introns of the same phase. Skipping or deletion of exon 7 would remove 64 amino acids in the TAD, which is >10% of the protein and 18% of the TAD. Given the significance of the TAD, we support still using PVS1 instead of PVS1_Strong in this situation. A deletion of exon 10 would remove part of the TAD but less than 10% of the protein. Since the TAD is critical to protein function, and variants that disrupt all of exon 10 have been found in patients with a MODY phenotype, we will use PVS1_Strong for deletions of exon 10 and splicing variants that would predict the skipping of exon 10. This specification is in accordance with Tayoun’s recommendation to use PVS1_Strong in cases in which the truncated region is critical to protein function.
-
-
-
-
-
-
-Apply PVS1 to initiation codon variants. Four initiation codon variants have been identified in patients with a MODY phenotype. The closest potential in-frame start codon is p.Met118. Starting the protein at p.Met118 would remove 18% of the protein, including the entire dimerization domain. There are many P/LP variants upstream of p.Met118.
-
-
-Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.",Strength
-HNF1A (HGNC:11621),PVS1,Supporting,"Use HNF1A PVS1 decision tree.
-
-
-
-
-Variants generating PTCs 3’ of c.1714 of NM_000545.8, which includes the last 55 nucleotides of exon 9 and all of exon 10, are not expected to cause NMD (PMID: 24274751). The transactivation domain (TAD) of the protein overlaps with this region. The last 55 nucleotides of exon 9 (c.1714-1768) is enriched for disease-causing variants and loss-of function variants in this region have been found in patients/families with a MODY phenotype. Therefore, a “very strong” level of evidence will be used for loss-of-function variants 5’ of c.1768 regardless of where the premature termination codon occurs.
-
-
-PVS1_Strong will be applied to nonsense variants at c.1803 (p.601) and 5’ and frameshift variants at c.1854 (p.618) and 5’. The distinction of nonsense and frameshift variants was made following a careful review of the phenotypes of individuals with loss-of-function variants in exon 10, which lead to our prediction that the addition of new amino acids from a frameshift will disrupt the TAD and cause a MODY phenotype more so than the deletion of a small part of the end of the TAD. Moderate phenotypic evidence was applied to the c.1802del (p.601Ter) variant, but the individual with the next nonsense variant (p.Gln625Ter) was unaffected. Frameshift variants at p.Ile618 and 5’ have been identified in patients with a phenotype consistent with MODY.
-
-
-
-
-
-
-“Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame”
-
-
-Deletions of exon 1 would lead at least to loss of the initiation codon (see below for recommendations for initiation codon variants). Deletions of single exons 2, 3, 4, 5, 6, 8 or 9 all cause frameshift, and thus PVS1 would be used. In HNF1A, only exon 7 (LRG_522t1) is surrounded by introns of the same phase. Skipping or deletion of exon 7 would remove 64 amino acids in the TAD, which is >10% of the protein and 18% of the TAD. Given the significance of the TAD, we support still using PVS1 instead of PVS1_Strong in this situation. A deletion of exon 10 would remove part of the TAD but less than 10% of the protein. Since the TAD is critical to protein function, and variants that disrupt all of exon 10 have been found in patients with a MODY phenotype, we will use PVS1_Strong for deletions of exon 10 and splicing variants that would predict the skipping of exon 10. This specification is in accordance with Tayoun’s recommendation to use PVS1_Strong in cases in which the truncated region is critical to protein function.
-
-
-
-
-
-
-Apply PVS1 to initiation codon variants. Four initiation codon variants have been identified in patients with a MODY phenotype. The closest potential in-frame start codon is p.Met118. Starting the protein at p.Met118 would remove 18% of the protein, including the entire dimerization domain. There are many P/LP variants upstream of p.Met118.
-
-
-Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.",Strength
-HNF1A (HGNC:11621),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-HNF1A (HGNC:11621),PS1,Strong,No change,No change
-HNF1A (HGNC:11621),PS1,Supporting,PS1 may also be used at a supporting level for canonical and non-canonical splicing variants when a different variant at the same nucleotide has been previously classified as pathogenic and the variant being assessed is predicted by SpliceAI to have a similar (SpliceAI score within 10% of the original variant) or greater deleterious impact.,Strength
-HNF1A (HGNC:11621),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-HNF1A (HGNC:11621),PS2,Very Strong,Use SVI recommended point-based system with specifications for “Phenotype Consistency” described in PP4 specifications.,"Gene-specific,Strength"
-HNF1A (HGNC:11621),PS2,Strong,Use SVI recommended point-based system with specifications for “Phenotype Consistency” described in PP4 specifications.,"Gene-specific,Strength"
-HNF1A (HGNC:11621),PS2,Moderate,Use SVI recommended point-based system with specifications for “Phenotype Consistency” described in PP4 specifications.,"Gene-specific,Strength"
-HNF1A (HGNC:11621),PS2,Supporting,Use SVI recommended point-based system with specifications for “Phenotype Consistency” described in PP4 specifications.,"Gene-specific,Strength"
-HNF1A (HGNC:11621),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-HNF1A (HGNC:11621),PS3,Strong,Applicable to non-canonical splice site variants that have RNA and in silico evidence of aberrant splicing.,"Gene-specific,Strength"
-HNF1A (HGNC:11621),PS3,Moderate,"Applicable for variants with luciferase assay data (evidence of decreased transactivation (<=40% of wild type) by the Gloyn/Oxford group (Althari et al 2020 
-https://pubmed.ncbi.nlm.nih.gov/32910913/
-)","Gene-specific,Strength"
-HNF1A (HGNC:11621),PS3,Supporting,"See list of approved functional studies and guidelines for interpretation of data (below).
-(1) Luciferase assays for transactivation - ""Decreased function"" is defined as activity less than 40% of wildtype. Assays should include controls for WT, T2DM-risk, and known MODY variants. For additional specifications and recommendations, please see the HNF1A rules.
-(2) EMSA for DNA binding - ""Decreased function"" is defined as activity lesss than 405 of wildtype. We recommend that at least two of the following variants be used as positive controls for reduced DNA binding activity: c.335C>T (p.Pro112Leu), c.608G>A (p.Arg203His), c.787C>T (p.Arg263Cys) and c.686G>A (p.Arg229Gln) (PMID: 11162430, 12574234, 24915262). For additional specifications and recommendations, please see the HNF1A rules.
-(3) Western blotting and indirect immunoflorescence for protein expression and localization - Determining appropriate thresholds for protein expression is more difficult due to variability in results between experimental protocols. Altered protein expression can be indirectly captured through the read-out frame from transactivation assay, and reduced protein expression can provide an explanation for reduced transactivation. When exploring protein mis-localization, we recommend that the c.589_615del (p.Lys197_Lys205del) variant is included as a positive control for impaired nuclear localization (cytosolic retention).","Gene-specific,Strength"
-HNF1A (HGNC:11621),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-HNF1A (HGNC:11621),PS4,Strong,"Seven or more= Strong. Variant should meet PM2_Supporting in order to use PS4 at any level (careful review of gnomAD QC data may be necessary to assess whether variant is real or an artifact, especially if variant is in a polyC region). Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology (see below).","Gene-specific,Strength"
-HNF1A (HGNC:11621),PS4,Moderate,4-6 unrelated occurrences = Moderate.,"Gene-specific,Strength"
-HNF1A (HGNC:11621),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-HNF1A (HGNC:11621),PM1,Moderate,"This criterion can be used for variants in residues that directly bind DNA:   Gln130, Arg131, Glu132, His143, Leu144, Ser145, Gln146, His147, Leu148, Asn149, Lys155, Thr156, Gln157, Lys158, Arg203, Phe204, Lys205, Trp206, Arg263, Val264, Tyr265, Asn270, Arg271, Arg272, Lys273","Gene-specific,Strength"
-HNF1A (HGNC:11621),PM1,Supporting,"Use for defined regions in the DNA binding and dimerization domains. 
-
-
-
-
-Dimerization: codons 1-32, NM_000545.8 
-
-
-Subset of DNA binding domains: codons 107-174 and 201-280, NM_000545.8 
-It can also be used for variants within certain transcription factor binding sites of the promoter.  
-
-
-–c.-187 to c.-195 (AP1 binding site) 
-
-
-–c.-209 to c.-227 (Overlapping HNF3 & NF-Y sites) 
-
-
-–c.-238 to c.-259 (HNF1A binding site) 
-
-
-–c.-276 to c.-288 (HNF4A binding site)","Gene-specific,Strength"
-HNF1A (HGNC:11621),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-HNF1A (HGNC:11621),PM2,Supporting,"gnomAD 2.1.1 Popmax FAF ≤ 1:333,000 (≤ 0.000003 or 0.0003%) in gnomAD European Non-Finnish population AND ≤ 2 copies observed in ENF AND ≤ 1 copy in any other founder or non-founder population.","General recommendation,Gene-specific"
-HNF1A (HGNC:11621),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-HNF1A (HGNC:11621),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-HNF1A (HGNC:11621),PM4,Moderate,"For single amino acid deletions, use as supporting level of evidence.",Strength
-HNF1A (HGNC:11621),PM4,Supporting,"For single amino acid deletions/insertions, use as supporting level of evidence",Strength
-HNF1A (HGNC:11621),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-HNF1A (HGNC:11621),PM5,Strong,Applicable once two amino acid changes have been classified as pathogenic at the same amino acid residue,Strength
-HNF1A (HGNC:11621),PM5,Moderate,The novel amino acid change must have a Grantham distance greater than or equal to the previously classified pathogenic variant.,Strength
-HNF1A (HGNC:11621),PM5,Supporting,Apply if the previously classified amino acid change is likely pathogenic (rather than pathogenic) or if the previously classified variant is pathogenic but has a greater Grantham distance.,Strength
-HNF1A (HGNC:11621),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-HNF1A (HGNC:11621),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-HNF1A (HGNC:11621),PP1,Strong,"Use thresholds suggested by Jarvik and Browning (PMID: 27236918)
-
-
-
-
-Single Family : ≤ 1/32 (5 meioses) 
-
-
-
-
-1 Family : ≤ 1/16 (4 meioses)","General recommendation,Gene-specific"
-HNF1A (HGNC:11621),PP1,Moderate,"Use thresholds suggested by Jarvik and Browning (PMID: 27236918)
-
-
-
-
-Single Family : ≤ 1/16 (4 meioses)
-
-
-
-
-1 Family : ≤ 1/8 (3 meioses)","General recommendation,Gene-specific"
-HNF1A (HGNC:11621),PP1,Supporting,"Use thresholds suggested by Jarvik and Browning (PMID: 27236918)
-
-
-
-
-Single Family : ≤ 1/8 (3 meioses)          
-
-
-
-
-1 Family : ≤ ¼ (2 meioses)","General recommendation,Gene-specific"
-HNF1A (HGNC:11621),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-HNF1A (HGNC:11621),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-HNF1A (HGNC:11621),PP3,Supporting,Use REVEL score of ≥0.70 as supportive evidence of pathogenicity. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply PP3 when the predicted change is above 0.2 (Wai et al. 2020 PMID: 32123317; Jaganathan et al. 2019 PMID: 30661751).,General recommendation
-HNF1A (HGNC:11621),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-HNF1A (HGNC:11621),PP4,Moderate,"MODY Probability Calculator (MPC) result ≥50% chance of testing positive 
-https://www.diabetesgenes.org/mody-probability-calculator/
-) AND negative HNF4A testing AND presence of at least one additional feature characteristic of HNF1A-MODY:
-
-
-
-
-Antibody negative and/or persistent C-peptide after five years post- T1DM diagnosis
-
-
-Response to low-dose SU (extreme response- hypoglycemia)
-
-
-Low hsCRP in patient with clinical diagnosis of T2DM
-
-
-Biochemical/Molecular phenotypic evidence from patient cell lines
-
-
-Hepatocellular adenomas",Gene-specific
-HNF1A (HGNC:11621),PP4,Supporting,"MODY Probability Calculator (MPC) result ≥50% chance of testing positive 
-https://www.diabetesgenes.org/mody-probability-calculator/
-) AND negative HNF4A testing",Gene-specific
-HNF1A (HGNC:11621),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-HNF1A (HGNC:11621),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-HNF1A (HGNC:11621),BA1,Stand Alone,"MAF ≥ 1:10,000 (≥ 0.01% or 0.0001) in gnomAD Popmax Filtering AF.",Gene-specific
-HNF1A (HGNC:11621),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-HNF1A (HGNC:11621),BS1,Strong,"MAF ≥ 1:30,000 (≥0.0033% or 0.000033) in gnomAD Popmax Filtering AF.",Gene-specific
-HNF1A (HGNC:11621),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-HNF1A (HGNC:11621),BS2,Strong,"Apply to normoglycemic individuals age 70 or older (i.e., genotype positive, phenotype negative)",Gene-specific
-HNF1A (HGNC:11621),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-HNF1A (HGNC:11621),BS3,Strong,Applicable to non-canonical splice site variants that have RNA and in silico evidence of normal splicing.,Gene-specific
-HNF1A (HGNC:11621),BS3,Supporting,"See HNF1A rules for full list of approved functional studies and guidelines for interpretation of data. 
-(1) Luciferase assays for transactivation - ""No functional impact"" is defined as ≥ 75% activity of wildtype
-(2) EMSA for DNA binding - ""No functional impact"" is defined as ≥ 75% activity of wildtype.
-(3) Western blotting and indirect immunoflorescence for protein expression and localization - Determining appropriate thresholds for protein expression is more difficult due to variability in results between different experimental protocols. Altered protein expression can be indirectly captured through the read-out from a transactivation assay and reduced protein expression can provide an explanation for reduced transactivation.",Gene-specific
-HNF1A (HGNC:11621),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-HNF1A (HGNC:11621),BS4,Strong,"Applicable to family members without variant who have MPC score >50% (i.e., genotype negative, phenotype positive).",Gene-specific
-HNF1A (HGNC:11621),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-HNF1A (HGNC:11621),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-HNF1A (HGNC:11621),BP2,Supporting,Also applicable when in cis or trans with a likely pathogenic variant.,General recommendation
-HNF1A (HGNC:11621),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-HNF1A (HGNC:11621),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-HNF1A (HGNC:11621),BP4,Supporting,Use a REVEL score of ≤0.15 as supportive evidence of no predicted impact on the gene or gene product. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply BP4 when the predicted change is below 0.2 (Wai et al. 2020 PMID: 32123317; Jaganathan et al. 2019 PMID: 30661751).,General recommendation
-HNF1A (HGNC:11621),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-HNF1A (HGNC:11621),BP5,Supporting,A variant in other monogenic diabetes gene is P/LP.,General recommendation
-HNF1A (HGNC:11621),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-HNF1A (HGNC:11621),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-HNF1A (HGNC:11621),BP7,Supporting,Apply BP7 when the predicted change from SpliceAI is below 0.2 AND phyloP100 way < 2.0.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF1AVersion2.1.0_version=2.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF1AVersion2.1.0_version=2.1.0.csv
deleted file mode 100644
index c206e4d05e2367e2bc5e11f55238c0f484603e2f..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF1AVersion2.1.0_version=2.1.0.csv
+++ /dev/null
@@ -1,259 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-HNF1A (HGNC:11621),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-HNF1A (HGNC:11621),PVS1,Very Strong,"Use HNF1A PVS1 decision tree.
-
-
-
-
-Variants generating PTCs 3’ of c.1714 of NM_000545.8, which includes the last 55 nucleotides of exon 9 and all of exon 10, are not expected to cause NMD (PMID: 24274751). The transactivation domain (TAD) of the protein overlaps with this region. The last 55 nucleotides of exon 9 (c.1714-1768) is enriched for disease-causing variants and loss-of function variants in this region have been found in patients/families with a MODY phenotype. Therefore, a “very strong” level of evidence will be used for loss-of-function variants 5’ of c.1768 regardless of where the premature termination codon occurs.
-
-
-PVS1_Strong will be applied to nonsense variants at c.1803 (p.601) and 5’ and frameshift variants at c.1854 (p.618) and 5’. The distinction of nonsense and frameshift variants was made following a careful review of the phenotypes of individuals with loss-of-function variants in exon 10, which lead to our prediction that the addition of new amino acids from a frameshift will disrupt the TAD and cause a MODY phenotype more so than the deletion of a small part of the end of the TAD. Moderate phenotypic evidence was applied to the c.1802del (p.601Ter) variant, but the individual with the next nonsense variant (p.Gln625Ter) was unaffected. Frameshift variants at p.Ile618 and 5’ have been identified in patients with a phenotype consistent with MODY.
-
-
-
-
-
-
-“Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame”
-
-
-Deletions of exon 1 would lead at least to loss of the initiation codon (see below for recommendations for initiation codon variants). Deletions of single exons 2, 3, 4, 5, 6, 8 or 9 all cause frameshift, and thus PVS1 would be used. In HNF1A, only exon 7 (LRG_522t1) is surrounded by introns of the same phase. Skipping or deletion of exon 7 would remove 64 amino acids in the TAD, which is >10% of the protein and 18% of the TAD. Given the significance of the TAD, we support still using PVS1 instead of PVS1_Strong in this situation. A deletion of exon 10 would remove part of the TAD but less than 10% of the protein. Since the TAD is critical to protein function, and variants that disrupt all of exon 10 have been found in patients with a MODY phenotype, we will use PVS1_Strong for deletions of exon 10 and splicing variants that would predict the skipping of exon 10. This specification is in accordance with Tayoun’s recommendation to use PVS1_Strong in cases in which the truncated region is critical to protein function.
-
-
-
-
-
-
-Apply PVS1 to initiation codon variants. Four initiation codon variants have been identified in patients with a MODY phenotype. The closest potential in-frame start codon is p.Met118. Starting the protein at p.Met118 would remove 18% of the protein, including the entire dimerization domain. There are many P/LP variants upstream of p.Met118.
-
-
-Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.",Strength
-HNF1A (HGNC:11621),PVS1,Strong,"Use HNF1A PVS1 decision tree.
-
-
-
-
-Variants generating PTCs 3’ of c.1714 of NM_000545.8, which includes the last 55 nucleotides of exon 9 and all of exon 10, are not expected to cause NMD (PMID: 24274751). The transactivation domain (TAD) of the protein overlaps with this region. The last 55 nucleotides of exon 9 (c.1714-1768) is enriched for disease-causing variants and loss-of function variants in this region have been found in patients/families with a MODY phenotype. Therefore, a “very strong” level of evidence will be used for loss-of-function variants 5’ of c.1768 regardless of where the premature termination codon occurs.
-
-
-PVS1_Strong will be applied to nonsense variants at c.1803 (p.601) and 5’ and frameshift variants at c.1854 (p.618) and 5’. The distinction of nonsense and frameshift variants was made following a careful review of the phenotypes of individuals with loss-of-function variants in exon 10, which lead to our prediction that the addition of new amino acids from a frameshift will disrupt the TAD and cause a MODY phenotype more so than the deletion of a small part of the end of the TAD. Moderate phenotypic evidence was applied to the c.1802del (p.601Ter) variant, but the individual with the next nonsense variant (p.Gln625Ter) was unaffected. Frameshift variants at p.Ile618 and 5’ have been identified in patients with a phenotype consistent with MODY.
-
-
-
-
-
-
-“Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame”
-
-
-Deletions of exon 1 would lead at least to loss of the initiation codon (see below for recommendations for initiation codon variants). Deletions of single exons 2, 3, 4, 5, 6, 8 or 9 all cause frameshift, and thus PVS1 would be used. In HNF1A, only exon 7 (LRG_522t1) is surrounded by introns of the same phase. Skipping or deletion of exon 7 would remove 64 amino acids in the TAD, which is >10% of the protein and 18% of the TAD. Given the significance of the TAD, we support still using PVS1 instead of PVS1_Strong in this situation. A deletion of exon 10 would remove part of the TAD but less than 10% of the protein. Since the TAD is critical to protein function, and variants that disrupt all of exon 10 have been found in patients with a MODY phenotype, we will use PVS1_Strong for deletions of exon 10 and splicing variants that would predict the skipping of exon 10. This specification is in accordance with Tayoun’s recommendation to use PVS1_Strong in cases in which the truncated region is critical to protein function.
-
-
-
-
-
-
-Apply PVS1 to initiation codon variants. Four initiation codon variants have been identified in patients with a MODY phenotype. The closest potential in-frame start codon is p.Met118. Starting the protein at p.Met118 would remove 18% of the protein, including the entire dimerization domain. There are many P/LP variants upstream of p.Met118.
-
-
-Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.",Strength
-HNF1A (HGNC:11621),PVS1,Supporting,"Use HNF1A PVS1 decision tree.
-
-
-
-
-Variants generating PTCs 3’ of c.1714 of NM_000545.8, which includes the last 55 nucleotides of exon 9 and all of exon 10, are not expected to cause NMD (PMID: 24274751). The transactivation domain (TAD) of the protein overlaps with this region. The last 55 nucleotides of exon 9 (c.1714-1768) is enriched for disease-causing variants and loss-of function variants in this region have been found in patients/families with a MODY phenotype. Therefore, a “very strong” level of evidence will be used for loss-of-function variants 5’ of c.1768 regardless of where the premature termination codon occurs.
-
-
-PVS1_Strong will be applied to nonsense variants at c.1803 (p.601) and 5’ and frameshift variants at c.1854 (p.618) and 5’. The distinction of nonsense and frameshift variants was made following a careful review of the phenotypes of individuals with loss-of-function variants in exon 10, which lead to our prediction that the addition of new amino acids from a frameshift will disrupt the TAD and cause a MODY phenotype more so than the deletion of a small part of the end of the TAD. Moderate phenotypic evidence was applied to the c.1802del (p.601Ter) variant, but the individual with the next nonsense variant (p.Gln625Ter) was unaffected. Frameshift variants at p.Ile618 and 5’ have been identified in patients with a phenotype consistent with MODY.
-
-
-
-
-
-
-“Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame”
-
-
-Deletions of exon 1 would lead at least to loss of the initiation codon (see below for recommendations for initiation codon variants). Deletions of single exons 2, 3, 4, 5, 6, 8 or 9 all cause frameshift, and thus PVS1 would be used. In HNF1A, only exon 7 (LRG_522t1) is surrounded by introns of the same phase. Skipping or deletion of exon 7 would remove 64 amino acids in the TAD, which is >10% of the protein and 18% of the TAD. Given the significance of the TAD, we support still using PVS1 instead of PVS1_Strong in this situation. A deletion of exon 10 would remove part of the TAD but less than 10% of the protein. Since the TAD is critical to protein function, and variants that disrupt all of exon 10 have been found in patients with a MODY phenotype, we will use PVS1_Strong for deletions of exon 10 and splicing variants that would predict the skipping of exon 10. This specification is in accordance with Tayoun’s recommendation to use PVS1_Strong in cases in which the truncated region is critical to protein function.
-
-
-
-
-
-
-Apply PVS1 to initiation codon variants. Four initiation codon variants have been identified in patients with a MODY phenotype. The closest potential in-frame start codon is p.Met118. Starting the protein at p.Met118 would remove 18% of the protein, including the entire dimerization domain. There are many P/LP variants upstream of p.Met118.
-
-
-Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1.",Strength
-HNF1A (HGNC:11621),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-HNF1A (HGNC:11621),PS1,Strong,No change,No change
-HNF1A (HGNC:11621),PS1,Supporting,PS1 may also be used at a supporting level for canonical and non-canonical splicing variants when a different variant at the same nucleotide has been previously classified as pathogenic and the variant being assessed is predicted by SpliceAI to have a similar (SpliceAI score within 10% of the original variant) or greater deleterious impact.,Strength
-HNF1A (HGNC:11621),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-HNF1A (HGNC:11621),PS2,Very Strong,Use SVI recommended point-based system with specifications for “Phenotype Consistency” described in PP4 specifications.,"Gene-specific,Strength"
-HNF1A (HGNC:11621),PS2,Strong,Use SVI recommended point-based system with specifications for “Phenotype Consistency” described in PP4 specifications.,"Gene-specific,Strength"
-HNF1A (HGNC:11621),PS2,Moderate,Use SVI recommended point-based system with specifications for “Phenotype Consistency” described in PP4 specifications.,"Gene-specific,Strength"
-HNF1A (HGNC:11621),PS2,Supporting,Use SVI recommended point-based system with specifications for “Phenotype Consistency” described in PP4 specifications.,"Gene-specific,Strength"
-HNF1A (HGNC:11621),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-HNF1A (HGNC:11621),PS3,Strong,Applicable to non-canonical splice site variants that have RNA and in silico evidence of aberrant splicing.,"Gene-specific,Strength"
-HNF1A (HGNC:11621),PS3,Moderate,"Applicable for variants with luciferase assay data (evidence of decreased transactivation (<=40% of wild type) by the Gloyn/Oxford group (Althari et al 2020 
-https://pubmed.ncbi.nlm.nih.gov/32910913/
-)","Gene-specific,Strength"
-HNF1A (HGNC:11621),PS3,Supporting,"See list of approved functional studies and guidelines for interpretation of data (below).
-(1) Luciferase assays for transactivation - ""Decreased function"" is defined as activity less than 40% of wildtype. Assays should include controls for WT, T2DM-risk, and known MODY variants. For additional specifications and recommendations, please see the HNF1A rules.
-(2) EMSA for DNA binding - ""Decreased function"" is defined as activity lesss than 405 of wildtype. We recommend that at least two of the following variants be used as positive controls for reduced DNA binding activity: c.335C>T (p.Pro112Leu), c.608G>A (p.Arg203His), c.787C>T (p.Arg263Cys) and c.686G>A (p.Arg229Gln) (PMID: 11162430, 12574234, 24915262). For additional specifications and recommendations, please see the HNF1A rules.
-(3) Western blotting and indirect immunoflorescence for protein expression and localization - Determining appropriate thresholds for protein expression is more difficult due to variability in results between experimental protocols. Altered protein expression can be indirectly captured through the read-out frame from transactivation assay, and reduced protein expression can provide an explanation for reduced transactivation. When exploring protein mis-localization, we recommend that the c.589_615del (p.Lys197_Lys205del) variant is included as a positive control for impaired nuclear localization (cytosolic retention).","Gene-specific,Strength"
-HNF1A (HGNC:11621),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-HNF1A (HGNC:11621),PS4,Strong,"Seven or more= Strong. Variant should meet PM2_Supporting in order to use PS4 at any level (careful review of gnomAD QC data may be necessary to assess whether variant is real or an artifact, especially if variant is in a polyC region). Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology (see below).","Gene-specific,Strength"
-HNF1A (HGNC:11621),PS4,Moderate,4-6 unrelated occurrences = Moderate.,"Gene-specific,Strength"
-HNF1A (HGNC:11621),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-HNF1A (HGNC:11621),PM1,Moderate,"This criterion can be used for variants in residues that directly bind DNA:   Gln130, Arg131, Glu132, His143, Leu144, Ser145, Gln146, His147, Leu148, Asn149, Lys155, Thr156, Gln157, Lys158, Arg203, Phe204, Lys205, Trp206, Arg263, Val264, Tyr265, Asn270, Arg271, Arg272, Lys273","Gene-specific,Strength"
-HNF1A (HGNC:11621),PM1,Supporting,"Use for defined regions in the DNA binding and dimerization domains. 
-
-
-
-
-Dimerization: codons 1-32, NM_000545.8 
-
-
-Subset of DNA binding domains: codons 107-174 and 201-280, NM_000545.8 
-It can also be used for variants within certain transcription factor binding sites of the promoter.  
-
-
-–c.-187 to c.-195 (AP1 binding site) 
-
-
-–c.-209 to c.-227 (Overlapping HNF3 & NF-Y sites) 
-
-
-–c.-238 to c.-259 (HNF1A binding site) 
-
-
-–c.-276 to c.-288 (HNF4A binding site)","Gene-specific,Strength"
-HNF1A (HGNC:11621),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-HNF1A (HGNC:11621),PM2,Supporting,"gnomAD 2.1.1* Popmax FAF ≤ 1:333,000 (≤ 0.000003 or 0.0003%) in gnomAD European Non-Finnish population AND ≤ 2 copies observed in ENF AND ≤ 1 copy in any other founder or non-founder population.  
-
-
-*Use gnomAD 2.1.1 exome data unless the region is not covered in the exome, in which case gnomAD 3.1.2 genome data should be used.","General recommendation,Gene-specific"
-HNF1A (HGNC:11621),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-HNF1A (HGNC:11621),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-HNF1A (HGNC:11621),PM4,Moderate,"For single amino acid deletions, use as supporting level of evidence.",Strength
-HNF1A (HGNC:11621),PM4,Supporting,"For single amino acid deletions/insertions, use as supporting level of evidence",Strength
-HNF1A (HGNC:11621),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-HNF1A (HGNC:11621),PM5,Strong,Applicable once two amino acid changes have been classified as pathogenic at the same amino acid residue,Strength
-HNF1A (HGNC:11621),PM5,Moderate,The novel amino acid change must have a Grantham distance greater than or equal to the previously classified pathogenic variant.,Strength
-HNF1A (HGNC:11621),PM5,Supporting,Apply if the previously classified amino acid change is likely pathogenic (rather than pathogenic) or if the previously classified variant is pathogenic but has a greater Grantham distance.,Strength
-HNF1A (HGNC:11621),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-HNF1A (HGNC:11621),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-HNF1A (HGNC:11621),PP1,Strong,"Use thresholds suggested by Jarvik and Browning (PMID: 27236918)
-
-
-
-
-Single Family : ≤ 1/32 (5 meioses) 
-
-
-
-
-1 Family : ≤ 1/16 (4 meioses)","General recommendation,Gene-specific"
-HNF1A (HGNC:11621),PP1,Moderate,"Use thresholds suggested by Jarvik and Browning (PMID: 27236918)
-
-
-
-
-Single Family : ≤ 1/16 (4 meioses)
-
-
-
-
-1 Family : ≤ 1/8 (3 meioses)","General recommendation,Gene-specific"
-HNF1A (HGNC:11621),PP1,Supporting,"Use thresholds suggested by Jarvik and Browning (PMID: 27236918)
-
-
-
-
-Single Family : ≤ 1/8 (3 meioses)          
-
-
-
-
-1 Family : ≤ ¼ (2 meioses)","General recommendation,Gene-specific"
-HNF1A (HGNC:11621),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-HNF1A (HGNC:11621),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-HNF1A (HGNC:11621),PP3,Supporting,Use REVEL score of ≥0.70 as supportive evidence of pathogenicity. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply PP3 when the predicted change is above 0.2 (Wai et al. 2020 PMID: 32123317; Jaganathan et al. 2019 PMID: 30661751).,General recommendation
-HNF1A (HGNC:11621),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-HNF1A (HGNC:11621),PP4,Moderate,"MODY Probability Calculator (MPC) result ≥50% chance of testing positive 
-https://www.diabetesgenes.org/mody-probability-calculator/
-) AND negative HNF4A testing AND presence of at least one additional feature characteristic of HNF1A-MODY:
-
-
-
-
-Antibody negative and/or persistent C-peptide after five years post- T1DM diagnosis
-
-
-Response to low-dose SU (extreme response- hypoglycemia)
-
-
-Low hsCRP in patient with clinical diagnosis of T2DM
-
-
-Biochemical/Molecular phenotypic evidence from patient cell lines
-
-
-Hepatocellular adenomas",Gene-specific
-HNF1A (HGNC:11621),PP4,Supporting,"MODY Probability Calculator (MPC) result ≥50% chance of testing positive 
-https://www.diabetesgenes.org/mody-probability-calculator/
-) AND negative HNF4A testing",Gene-specific
-HNF1A (HGNC:11621),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-HNF1A (HGNC:11621),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-HNF1A (HGNC:11621),BA1,Stand Alone,"MAF ≥ 1:10,000 (≥ 0.01% or 0.0001) in gnomAD 2.1.1* Popmax Filtering AF.
-
-
-*Use gnomAD 2.1.1 exome data unless the region is not covered in the exome, in which case gnomAD 3.1.2 genome data should be used.",Gene-specific
-HNF1A (HGNC:11621),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-HNF1A (HGNC:11621),BS1,Strong,"MAF ≥ 1:30,000 (≥0.0033% or 0.000033) in gnomAD 2.1.1* Popmax Filtering AF.
-
-
-*Use gnomAD 2.1.1 exome data unless the region is not covered in the exome, in which case gnomAD 3.1.2 genome data should be used.",Gene-specific
-HNF1A (HGNC:11621),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-HNF1A (HGNC:11621),BS2,Strong,"Apply to normoglycemic individuals age 70 or older (i.e., genotype positive, phenotype negative)",Gene-specific
-HNF1A (HGNC:11621),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-HNF1A (HGNC:11621),BS3,Strong,Applicable to non-canonical splice site variants that have RNA and in silico evidence of normal splicing.,Gene-specific
-HNF1A (HGNC:11621),BS3,Supporting,"See HNF1A rules for full list of approved functional studies and guidelines for interpretation of data. 
-(1) Luciferase assays for transactivation - ""No functional impact"" is defined as ≥ 75% activity of wildtype
-(2) EMSA for DNA binding - ""No functional impact"" is defined as ≥ 75% activity of wildtype.
-(3) Western blotting and indirect immunoflorescence for protein expression and localization - Determining appropriate thresholds for protein expression is more difficult due to variability in results between different experimental protocols. Altered protein expression can be indirectly captured through the read-out from a transactivation assay and reduced protein expression can provide an explanation for reduced transactivation.",Gene-specific
-HNF1A (HGNC:11621),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-HNF1A (HGNC:11621),BS4,Strong,"Applicable to family members without variant who have MPC score >50% (i.e., genotype negative, phenotype positive).",Gene-specific
-HNF1A (HGNC:11621),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-HNF1A (HGNC:11621),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-HNF1A (HGNC:11621),BP2,Supporting,Also applicable when in cis or trans with a likely pathogenic variant.,General recommendation
-HNF1A (HGNC:11621),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-HNF1A (HGNC:11621),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-HNF1A (HGNC:11621),BP4,Supporting,Use a REVEL score of ≤0.15 as supportive evidence of no predicted impact on the gene or gene product. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply BP4 when the predicted change is below 0.2 (Wai et al. 2020 PMID: 32123317; Jaganathan et al. 2019 PMID: 30661751).,General recommendation
-HNF1A (HGNC:11621),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-HNF1A (HGNC:11621),BP5,Supporting,A variant in other monogenic diabetes gene is P/LP.,General recommendation
-HNF1A (HGNC:11621),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-HNF1A (HGNC:11621),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-HNF1A (HGNC:11621),BP7,Supporting,Apply BP7 when the predicted change from SpliceAI is below 0.2 AND phyloP100 way < 2.0.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF4AVersion1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF4AVersion1.0.0_version=1.0.0.csv
deleted file mode 100644
index 79f02c4b9c531c6c94de06f178c5d2f7adb1a430..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF4AVersion1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,376 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-HNF4A (HGNC:5024),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-HNF4A (HGNC:5024),PVS1,Very Strong,"Use 
-HNF4A
- PVS1 decision tree.
-
-
-
-
-Variants generating PTCs in exon 10 and last 55 nucleotides of exon 9 (c.1162-1216) are not expected to cause NMD
-1
-
-
-The most 3’ nonsense or frameshift variant is c.1256C>G, p.S419X in the last exon. This variant has been classified as Pathogenic by the MDEP.  There are six other nonsense and frameshift variants in exon 10, none of which have case information and are all currently classified as VUS. The collective evidence supports applying PVS1 for variants at codon 419 (c.1257) and 5’ and PVS1_Supporting for variants at c.1258 (G)/p.Gly420 and 3’.
-
-
-
-
-
-
-“Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame”
-
-
-Exons 1, 2 (LRG 4), 3 (LRG 5), 4 (LRG 6), 6 (LRG 8): deletion or skipping causes frameshift: PVS1 
-
-
-Exons 5 (LRG 7), 7 (LRG 9), 8 (LRG 10), 9 (LRG 11) - deletion or skipping causes in-frame deletion, 52/52/79/51-79 AA deleted, that is >10 % of the protein in each case - PVS1_Strong  
-
-
-Exon 10 (LRG 12) - 46 AA, contains the transactivation domain, includes stop loss - PVS1_Strong",Strength
-HNF4A (HGNC:5024),PVS1,Strong,"Use 
-HNF4A
- PVS1 decision tree.
-
-
-
-
-“Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame” 
-
-
-Exons 5 (LRG 7), 7 (LRG 9), 8 (LRG 10), 9 (LRG 11) - deletion or skipping causes in-frame deletion, 52/52/79/51-79 AA deleted, that is >10 % of the protein in each case - PVS1_Strong  
-
-
-Exon 10 (LRG 12) - 46 AA, contains the transactivation domain, includes stop loss - PVS1_Strong",Strength
-HNF4A (HGNC:5024),PVS1,Moderate,"Use 
-HNF4A
- PVS1 decision tree.
-
-
-Apply PVS1_Moderate to initiation codon variants.  MDEP has classified two start codon variants as likely pathogenic (c.3G>A: PM2_Supporting + PP4_Moderate + PP1_Strong + PVS1_Moderate (c.1delA); c.1delA: PM2_Supporting + PP1 + PP4_Moderate + PVS1_Moderate) and there are multiple P/LP variants before the next methionine, p.Met71.",Strength
-HNF4A (HGNC:5024),PVS1,Supporting,"Use 
-HNF4A
- PVS1 decision tree.
-
-
-Apply PVS1_Supporting to nonsense or frameshift variants at c.1258 (G)/p.Gly420 and 3’.",Strength
-HNF4A (HGNC:5024),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-HNF4A (HGNC:5024),PS1,Strong,No change,No change
-HNF4A (HGNC:5024),PS1,Supporting,PS1 may also be used at a supporting level for canonical and non-canonical splicing variants when a different variant at the same nucleotide has been previously classified as pathogenic and the variant being assessed is predicted by SpliceAI to have a similar (SpliceAI score within 10% of the original variant) or greater deleterious impact.,Strength
-HNF4A (HGNC:5024),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-HNF4A (HGNC:5024),PS2,Very Strong,Use SVI recommended point-based system with specifications for “Phenotype Consistency” per instructions.,"Gene-specific,Strength"
-HNF4A (HGNC:5024),PS2,Strong,Use SVI recommended point-based system with specifications for “Phenotype Consistency” per instructions.,"Gene-specific,Strength"
-HNF4A (HGNC:5024),PS2,Moderate,Use SVI recommended point-based system with specifications for “Phenotype Consistency” per instructions.,"Gene-specific,Strength"
-HNF4A (HGNC:5024),PS2,Supporting,Use SVI recommended point-based system with specifications for “Phenotype Consistency” per instructions.,"Gene-specific,Strength"
-HNF4A (HGNC:5024),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-HNF4A (HGNC:5024),PS3,Strong,Applicable to non-canonical splice site variants that have RNA and in silico evidence of aberrant splicing.,"Gene-specific,Strength"
-HNF4A (HGNC:5024),PS3,Supporting,"List of approved functional studies and guidelines for interpretation:
-
-
-
-
-EMSA for DNA binding
-
-
-“Decreased function” is defined as activity less than 60% of wildtype 
-
-
-Note: the effect of the variant on DNA binding will be highly dependent on whether the variant is located within the DNA binding domain.
-
-
-
-
-
-
-Luciferase assays for transactivation 
-
-
-“Decreased function” is defined as activity less than 60% of wildtype  
-
-
-Note: this threshold is not 100% specific for transactivation (TA) activity and is complicated by the fact that TA activity will vary depend on many factors, for instance cell line that is used (HeLa, INS, MIN6 etc).
-
-
-
-
-
-
-Western blotting and indirect immunofluorescence for protein expression (specifically levels and nuclear and cytoplasmic localization, respectively).
-
-
-Determining appropriate thresholds for protein expression is more difficult due to variability in results due to the complexity of the technique.  Sample preparations, gel loading, transfer efficiency, specificity of the antibody, choice of internal control and inaccurate detection and quantification are some of the factors that can contribute to varying and inconsistent results. If a reduction in protein expression is seen by immunoblotting, then further testing by quantitative PCR (qPCR) is recommended in order to measure the mRNA level and assess whether a reduction in amount of protein is due to a reduced mRNA level.
-
-
-
-
-
-
-To use PS3_Supporting, functional study must have been performed on a transfected variant.  If a study was performed on a cell line generated from a patient sample (and therefore contains the variant plus wild-type allele) does not count as PS3_Supporting.","Gene-specific,Strength"
-HNF4A (HGNC:5024),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-HNF4A (HGNC:5024),PS4,Strong,"7 (seven) or more unrelated occurrences = Strong. Variant should meet PM2_Supporting in order to use PS4 at any level (careful review of gnomAD QC data may be necessary to assess whether variant is real or an artifact, especially if variant is in a polyC region).  Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology.
-
-
-
-
-One or more positive diabetes autoantibodies (IA-2A, ZnT8A+, GAD)
-7
-,
-8
-,
-9
-,
-10
- 
-
-
-Very low or negative C-peptide, defined as either fasting or non-fasting random C-peptide (<200pmol/L or 0.6ng/mL)
-11
-,
-12
- or urinary C-peptide/creatinine ratio <0.2 nmol/mmol
-8
-,
-9","Gene-specific,Strength"
-HNF4A (HGNC:5024),PS4,Moderate,"4-6 unrelated occurrences = Moderate. Variant should meet PM2_Supporting in order to use PS4 at any level. Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology.
-
-
-
-
-One or more positive diabetes autoantibodies (IA-2A, ZnT8A+, GAD)
-7
-,
-8
-,
-9
-,
-10
-
-
-Very low or negative C-peptide, defined as either fasting or non-fasting random C-peptide (<200pmol/L or 0.6ng/mL)
-11
-,
-12
- or urinary C-peptide/creatinine ratio <0.2 nmol/mmol
-8
-,
-9","Gene-specific,Strength"
-HNF4A (HGNC:5024),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-HNF4A (HGNC:5024),PM1,Moderate,"Applicable to amino acids that directly bind DNA and are necessary for Zinc-finger or homodimer formation
-2
- 
-
-
-
-
-Directly bind DNA: Asp43, His49, Tyr 50, Gly51, Asp56, Gly57, Lys59, Arg63, Arg64, Arg67, His70, Tyr72, Arg87, Asn88, Arg91, Arg94, Gln109, Arg112   
-
-
-Homodimer: Arg75, Gln89, Glu111, Asp113 
-
-
-Zinc finger: Cys38, Cys41, Cys55, Cys58, Cys74, Cys80, Cys90, Cys93","Gene-specific,Strength"
-HNF4A (HGNC:5024),PM1,Supporting,"This criterion can be used for missense variants in well-conserved regions within the DNA and ligand-binding domains. It can also be used for variants within certain transcription factor binding sites in the promoter (see below for details).
-
-
-
-
-Promoter region: 
-
-
-c.-132 to c.-151 (HNF6/OC2 and IPF1 binding sites) 
-
-
-c.-169 to c.-181 (HNF1A/HNF1B binding sites)
-
-
-
-
-
-
-DNA binding: 
-
-
-codons 37-113 (NM_175914.4:c.175C-339C p.Leu37-Asp113) (While the paper describing the crystal structure of 
-HNF4A
-2
- shows the sequence as amino acids 33-113, amino acids 33-36 do not bind DNA and the conserved sequence starts as Leu37.)
-
-
-
-
-
-
-Ligand binding: 
-
-
-codons 180-220 and 300-350  
-
-
-(NM_175914.4:c.538G-658G p.Ala180-Val220) 
-
-
-(NM_175914.4:c.898T-1048G p.Tyr300-Glu350)","Gene-specific,Strength"
-HNF4A (HGNC:5024),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-HNF4A (HGNC:5024),PM2,Supporting,"gnomAD 2.1.1 Popmax FAF ≤ 1:333,000 (≤ 0.000003 or 0.0003%) in gnomAD European Non-Finnish population AND ≤ 2 copies observed in ENF AND ≤ 1 copy in any other founder or non-founder population.","General recommendation,Gene-specific"
-HNF4A (HGNC:5024),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-HNF4A (HGNC:5024),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-HNF4A (HGNC:5024),PM4,Moderate,"For single amino acid deletions, use as supporting level of evidence.",Strength
-HNF4A (HGNC:5024),PM4,Supporting,"For single amino acid deletions/insertions, use as supporting level of evidence",Strength
-HNF4A (HGNC:5024),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-HNF4A (HGNC:5024),PM5,Strong,Applicable once two amino acid changes have been classified as pathogenic at the same amino acid residue.,Strength
-HNF4A (HGNC:5024),PM5,Moderate,The novel amino acid change must have a Grantham distance greater than or equal to the previously classified pathogenic variant.,Strength
-HNF4A (HGNC:5024),PM5,Supporting,Apply if the previously classified amino acid change is likely pathogenic (rather than pathogenic) or if the previously classified variant is pathogenic but has a greater Grantham distance than the novel variant.,Strength
-HNF4A (HGNC:5024),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-HNF4A (HGNC:5024),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-HNF4A (HGNC:5024),PP1,Strong,"Use thresholds suggested by Jarvik and Browning
-5
-
-
-
-
-Single Family : ≤ 1/32 (5 meioses)
-
-
-> 1 Family : ≤ 1/16 (4 meioses)","General recommendation,Gene-specific"
-HNF4A (HGNC:5024),PP1,Moderate,"Use thresholds suggested by Jarvik and Browning
-5
-
-
-
-
-Single Family : ≤ 1/16 (4 meioses)
-
-
-> 1 Family : ≤ 1/8 (3 meioses)","General recommendation,Gene-specific"
-HNF4A (HGNC:5024),PP1,Supporting,"Use thresholds suggested by Jarvik and Browning
-5
-
-
-
-
-Single Family : ≤ 1/8 (3 meioses)
-
-
-> 1 Family : ≤ ¼ (2 meioses)","General recommendation,Gene-specific"
-HNF4A (HGNC:5024),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-HNF4A (HGNC:5024),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-HNF4A (HGNC:5024),PP3,Supporting,"Use REVEL score of ≥0.70 as supportive evidence of pathogenicity. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply PP3 when the predicted change is at least 0.2 
-4
-,
-3
-.",General recommendation
-HNF4A (HGNC:5024),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-HNF4A (HGNC:5024),PP4,Moderate,"Phenotype: MODY Probability Calculator result ≥50% chance of testing positive
-6
- AND negative 
-HNF1A
- testing AND presence of at least one additional feature characteristic of _
-HNF4A
-_-MODY:   
-
-
-
-
-Antibody negative and/or persistent C-peptide after five years following T1DM diagnosis  
-
-
-Personal or family history of persistent neonatal hypoglycemia  
-
-
-Personal or family history of large for gestational age (LGA) infants or macrosomia in the absence of sufficient maternal hyperglycemia 
-
-
-Response to low-dose SU (extreme response- hypoglycemia) 
-
-
-Biochemical/Molecular phenotypic evidence from patient cell lines 
-
-
-Fanconi phenotype in conjunction with c.187C>T p.R63W",Gene-specific
-HNF4A (HGNC:5024),PP4,Supporting,"MODY Probability Calculator (MPC)
-6
- result ≥50% chance of testing positive AND negative 
-HNF1A
- testing",Gene-specific
-HNF4A (HGNC:5024),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-HNF4A (HGNC:5024),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-HNF4A (HGNC:5024),BA1,Stand Alone,"gnomAD 2.1.1 Popmax Filtering AF ≥ 1:10,000 (≥ 0.01% or 0.0001).",Gene-specific
-HNF4A (HGNC:5024),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-HNF4A (HGNC:5024),BS1,Strong,"gnomAD 2.1.1 Popmax Filtering AF  ≥ 1:30,000 (≥0.0033% or 0.000033).",Gene-specific
-HNF4A (HGNC:5024),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-HNF4A (HGNC:5024),BS2,Strong,"Apply to normoglycemic individuals age 70 or older (i.e., genotype positive, phenotype negative)",Gene-specific
-HNF4A (HGNC:5024),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-HNF4A (HGNC:5024),BS3,Strong,Applicable to non-canonical splice site variants that have RNA and in silico evidence of normal splicing.,Gene-specific
-HNF4A (HGNC:5024),BS3,Supporting,"List of approved functional studies and guidelines for interpretation of data.
-
-
-
-
-EMSA for DNA binding 
-
-
-“No functional impact” is defined as ≥75% activity of wildtype 
-
-
-Note: the effect of the variant on DNA binding will be highly dependent on whether the variant is located within the DNA binding domain.
-
-
-
-
-
-
-Luciferase assays for transactivation 
-
-
-“No functional impact” is defined as ≥75% activity of wildtype 
-
-
-Note: this threshold is not 100% specific for transactivation (TA) activity and is complicated by the fact that TA activity will vary depend on many factors, for instance cell line that is used (HeLa, INS, MIN6 etc). Assays should include controls for WT, T2DM and known MODY variants.
-
-
-
-
-
-
-Western blotting and indirect immunofluorescence for protein expression (specifically levels and nuclear and cytoplasmic localization, respectively).   
-
-
-Determining appropriate thresholds for protein expression is more difficult due to variability in results due to the complexity of the technique.  Sample preparations, gel loading, transfer efficiency, specificity of the antibody, choice of internal control and inaccurate detection and quantification are some of the factors that can contribute to varying and inconsistent results. If a difference in protein expression compared to WT is seen by immunoblotting, then further testing by quantitative PCR (qPCR) is recommended in order to measure the mRNA level and assess whether the difference in amount of protein is due to a reduced mRNA level.",Gene-specific
-HNF4A (HGNC:5024),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-HNF4A (HGNC:5024),BS4,Strong,"Applicable to family members without variant who have MPC
-6
- score ≥50% (i.e., genotype negative, phenotype positive).","General recommendation,Gene-specific"
-HNF4A (HGNC:5024),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-HNF4A (HGNC:5024),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-HNF4A (HGNC:5024),BP2,Supporting,Also applicable when in cis or trans with a likely pathogenic variant.,General recommendation
-HNF4A (HGNC:5024),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-HNF4A (HGNC:5024),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-HNF4A (HGNC:5024),BP4,Supporting,"Use a REVEL score of ≤0.15 as supportive evidence of no predicted impact on the gene or gene product. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply BP4 when the predicted change is below 0.2
-3
-,
-4
-.",General recommendation
-HNF4A (HGNC:5024),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-HNF4A (HGNC:5024),BP5,Supporting,A variant in another monogenic diabetes gene is Pathogenic/Likely Pathogenic.,General recommendation
-HNF4A (HGNC:5024),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-HNF4A (HGNC:5024),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-HNF4A (HGNC:5024),BP7,Supporting,Apply BP7 when the predicted change from SpliceAI is below 0.2 AND phyloP100 way < 2.0.,Gene-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF4AVersion1.1.0_version=1.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF4AVersion1.1.0_version=1.1.0.csv
deleted file mode 100644
index b1b1c7359c7d952e7fc66883ceeea217a9025379..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF4AVersion1.1.0_version=1.1.0.csv
+++ /dev/null
@@ -1,385 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-HNF4A (HGNC:5024),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-HNF4A (HGNC:5024),PVS1,Very Strong,"Use 
-HNF4A
- PVS1 decision tree.
-
-
-
-
-Variants generating PTCs in exon 10 and last 55 nucleotides of exon 9 (c.1162-1216) are not expected to cause NMD
-1
-
-
-The most 3’ nonsense or frameshift variant is c.1256C>G, p.S419X in the last exon. This variant has been classified as Pathogenic by the MDEP.  There are six other nonsense and frameshift variants in exon 10, none of which have case information and are all currently classified as VUS. The collective evidence supports applying PVS1 for variants at codon 419 (c.1257) and 5’ and PVS1_Supporting for variants at c.1258 (G)/p.Gly420 and 3’.
-
-
-
-
-
-
-“Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame”
-
-
-Exons 1, 2 (LRG 4), 3 (LRG 5), 4 (LRG 6), 6 (LRG 8): deletion or skipping causes frameshift: PVS1 
-
-
-Exons 5 (LRG 7), 7 (LRG 9), 8 (LRG 10), 9 (LRG 11) - deletion or skipping causes in-frame deletion, 52/52/79/51-79 AA deleted, that is >10 % of the protein in each case - PVS1_Strong  
-
-
-Exon 10 (LRG 12) - 46 AA, contains the transactivation domain, includes stop loss - PVS1_Strong",Strength
-HNF4A (HGNC:5024),PVS1,Strong,"Use 
-HNF4A
- PVS1 decision tree.
-
-
-
-
-“Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame” 
-
-
-Exons 5 (LRG 7), 7 (LRG 9), 8 (LRG 10), 9 (LRG 11) - deletion or skipping causes in-frame deletion, 52/52/79/51-79 AA deleted, that is >10 % of the protein in each case - PVS1_Strong  
-
-
-Exon 10 (LRG 12) - 46 AA, contains the transactivation domain, includes stop loss - PVS1_Strong",Strength
-HNF4A (HGNC:5024),PVS1,Moderate,"Use 
-HNF4A
- PVS1 decision tree.
-
-
-Apply PVS1_Moderate to initiation codon variants.  MDEP has classified two start codon variants as likely pathogenic (c.3G>A: PM2_Supporting + PP4_Moderate + PP1_Strong + PVS1_Moderate (c.1delA); c.1delA: PM2_Supporting + PP1 + PP4_Moderate + PVS1_Moderate) and there are multiple P/LP variants before the next methionine, p.Met71.",Strength
-HNF4A (HGNC:5024),PVS1,Supporting,"Use 
-HNF4A
- PVS1 decision tree.
-
-
-Apply PVS1_Supporting to nonsense or frameshift variants at c.1258 (G)/p.Gly420 and 3’.",Strength
-HNF4A (HGNC:5024),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-HNF4A (HGNC:5024),PS1,Strong,No change,No change
-HNF4A (HGNC:5024),PS1,Supporting,PS1 may also be used at a supporting level for canonical and non-canonical splicing variants when a different variant at the same nucleotide has been previously classified as pathogenic and the variant being assessed is predicted by SpliceAI to have a similar (SpliceAI score within 10% of the original variant) or greater deleterious impact.,Strength
-HNF4A (HGNC:5024),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-HNF4A (HGNC:5024),PS2,Very Strong,Use SVI recommended point-based system with specifications for “Phenotype Consistency” per instructions.,"Gene-specific,Strength"
-HNF4A (HGNC:5024),PS2,Strong,Use SVI recommended point-based system with specifications for “Phenotype Consistency” per instructions.,"Gene-specific,Strength"
-HNF4A (HGNC:5024),PS2,Moderate,Use SVI recommended point-based system with specifications for “Phenotype Consistency” per instructions.,"Gene-specific,Strength"
-HNF4A (HGNC:5024),PS2,Supporting,Use SVI recommended point-based system with specifications for “Phenotype Consistency” per instructions.,"Gene-specific,Strength"
-HNF4A (HGNC:5024),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-HNF4A (HGNC:5024),PS3,Strong,Applicable to non-canonical splice site variants that have RNA and in silico evidence of aberrant splicing.,"Gene-specific,Strength"
-HNF4A (HGNC:5024),PS3,Supporting,"List of approved functional studies and guidelines for interpretation:
-
-
-
-
-EMSA for DNA binding
-
-
-“Decreased function” is defined as activity less than 60% of wildtype 
-
-
-Note: the effect of the variant on DNA binding will be highly dependent on whether the variant is located within the DNA binding domain.
-
-
-
-
-
-
-Luciferase assays for transactivation 
-
-
-“Decreased function” is defined as activity less than 60% of wildtype  
-
-
-Note: this threshold is not 100% specific for transactivation (TA) activity and is complicated by the fact that TA activity will vary depend on many factors, for instance cell line that is used (HeLa, INS, MIN6 etc).
-
-
-
-
-
-
-Western blotting and indirect immunofluorescence for protein expression (specifically levels and nuclear and cytoplasmic localization, respectively).
-
-
-Determining appropriate thresholds for protein expression is more difficult due to variability in results due to the complexity of the technique.  Sample preparations, gel loading, transfer efficiency, specificity of the antibody, choice of internal control and inaccurate detection and quantification are some of the factors that can contribute to varying and inconsistent results. If a reduction in protein expression is seen by immunoblotting, then further testing by quantitative PCR (qPCR) is recommended in order to measure the mRNA level and assess whether a reduction in amount of protein is due to a reduced mRNA level.
-
-
-
-
-
-
-To use PS3_Supporting, functional study must have been performed on a transfected variant.  If a study was performed on a cell line generated from a patient sample (and therefore contains the variant plus wild-type allele) does not count as PS3_Supporting.","Gene-specific,Strength"
-HNF4A (HGNC:5024),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-HNF4A (HGNC:5024),PS4,Strong,"7 (seven) or more unrelated occurrences = Strong. Variant should meet PM2_Supporting in order to use PS4 at any level (careful review of gnomAD QC data may be necessary to assess whether variant is real or an artifact, especially if variant is in a polyC region).  Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology.
-
-
-
-
-One or more positive diabetes autoantibodies (IA-2A, ZnT8A+, GAD)
-7
-,
-8
-,
-9
-,
-10
- 
-
-
-Very low or negative C-peptide, defined as either fasting or non-fasting random C-peptide (<200pmol/L or 0.6ng/mL)
-11
-,
-12
- or urinary C-peptide/creatinine ratio <0.2 nmol/mmol
-8
-,
-9","Gene-specific,Strength"
-HNF4A (HGNC:5024),PS4,Moderate,"4-6 unrelated occurrences = Moderate. Variant should meet PM2_Supporting in order to use PS4 at any level. Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology.
-
-
-
-
-One or more positive diabetes autoantibodies (IA-2A, ZnT8A+, GAD)
-7
-,
-8
-,
-9
-,
-10
-
-
-Very low or negative C-peptide, defined as either fasting or non-fasting random C-peptide (<200pmol/L or 0.6ng/mL)
-11
-,
-12
- or urinary C-peptide/creatinine ratio <0.2 nmol/mmol
-8
-,
-9","Gene-specific,Strength"
-HNF4A (HGNC:5024),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-HNF4A (HGNC:5024),PM1,Moderate,"Applicable to amino acids that directly bind DNA and are necessary for Zinc-finger or homodimer formation
-2
- 
-
-
-
-
-Directly bind DNA: Asp43, His49, Tyr 50, Gly51, Asp56, Gly57, Lys59, Arg63, Arg64, Arg67, His70, Tyr72, Arg87, Asn88, Arg91, Arg94, Gln109, Arg112   
-
-
-Homodimer: Arg75, Gln89, Glu111, Asp113 
-
-
-Zinc finger: Cys38, Cys41, Cys55, Cys58, Cys74, Cys80, Cys90, Cys93","Gene-specific,Strength"
-HNF4A (HGNC:5024),PM1,Supporting,"This criterion can be used for missense variants in well-conserved regions within the DNA and ligand-binding domains. It can also be used for variants within certain transcription factor binding sites in the promoter (see below for details).
-
-
-
-
-Promoter region: 
-
-
-c.-132 to c.-151 (HNF6/OC2 and IPF1 binding sites) 
-
-
-c.-169 to c.-181 (HNF1A/HNF1B binding sites)
-
-
-
-
-
-
-DNA binding: 
-
-
-codons 37-113 (NM_175914.4:c.175C-339C p.Leu37-Asp113) (While the paper describing the crystal structure of 
-HNF4A
-2
- shows the sequence as amino acids 33-113, amino acids 33-36 do not bind DNA and the conserved sequence starts as Leu37.)
-
-
-
-
-
-
-Ligand binding: 
-
-
-codons 180-220 and 300-350  
-
-
-(NM_175914.4:c.538G-658G p.Ala180-Val220) 
-
-
-(NM_175914.4:c.898T-1048G p.Tyr300-Glu350)","Gene-specific,Strength"
-HNF4A (HGNC:5024),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-HNF4A (HGNC:5024),PM2,Supporting,"gnomAD 2.1.1* Popmax FAF ≤ 1:333,000 (≤ 0.000003 or 0.0003%) in gnomAD European Non-Finnish population AND ≤ 2 copies observed in ENF AND ≤ 1 copy in any other founder or non-founder population.
-
-
-*Use gnomAD 2.1.1 exome data unless the region is not covered in the exome, in which case gnomAD 3.1.2 genome data should be used.","General recommendation,Gene-specific"
-HNF4A (HGNC:5024),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-HNF4A (HGNC:5024),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-HNF4A (HGNC:5024),PM4,Moderate,"For single amino acid deletions, use as supporting level of evidence.",Strength
-HNF4A (HGNC:5024),PM4,Supporting,"For single amino acid deletions/insertions, use as supporting level of evidence",Strength
-HNF4A (HGNC:5024),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-HNF4A (HGNC:5024),PM5,Strong,Applicable once two amino acid changes have been classified as pathogenic at the same amino acid residue.,Strength
-HNF4A (HGNC:5024),PM5,Moderate,The novel amino acid change must have a Grantham distance greater than or equal to the previously classified pathogenic variant.,Strength
-HNF4A (HGNC:5024),PM5,Supporting,Apply if the previously classified amino acid change is likely pathogenic (rather than pathogenic) or if the previously classified variant is pathogenic but has a greater Grantham distance than the novel variant.,Strength
-HNF4A (HGNC:5024),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-HNF4A (HGNC:5024),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-HNF4A (HGNC:5024),PP1,Strong,"Use thresholds suggested by Jarvik and Browning
-5
-
-
-
-
-Single Family : ≤ 1/32 (5 meioses)
-
-
-> 1 Family : ≤ 1/16 (4 meioses)","General recommendation,Gene-specific"
-HNF4A (HGNC:5024),PP1,Moderate,"Use thresholds suggested by Jarvik and Browning
-5
-
-
-
-
-Single Family : ≤ 1/16 (4 meioses)
-
-
-> 1 Family : ≤ 1/8 (3 meioses)","General recommendation,Gene-specific"
-HNF4A (HGNC:5024),PP1,Supporting,"Use thresholds suggested by Jarvik and Browning
-5
-
-
-
-
-Single Family : ≤ 1/8 (3 meioses)
-
-
-> 1 Family : ≤ ¼ (2 meioses)","General recommendation,Gene-specific"
-HNF4A (HGNC:5024),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-HNF4A (HGNC:5024),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-HNF4A (HGNC:5024),PP3,Supporting,"Use REVEL score of ≥0.70 as supportive evidence of pathogenicity. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply PP3 when the predicted change is at least 0.2 
-4
-,
-3
-.",General recommendation
-HNF4A (HGNC:5024),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-HNF4A (HGNC:5024),PP4,Moderate,"Phenotype: MODY Probability Calculator result ≥50% chance of testing positive
-6
- AND negative 
-HNF1A
- testing AND presence of at least one additional feature characteristic of _
-HNF4A
-_-MODY:   
-
-
-
-
-Antibody negative and/or persistent C-peptide after five years following T1DM diagnosis  
-
-
-Personal or family history of persistent neonatal hypoglycemia  
-
-
-Personal or family history of large for gestational age (LGA) infants or macrosomia in the absence of sufficient maternal hyperglycemia 
-
-
-Response to low-dose SU (extreme response- hypoglycemia) 
-
-
-Biochemical/Molecular phenotypic evidence from patient cell lines 
-
-
-Fanconi phenotype in conjunction with c.187C>T p.R63W",Gene-specific
-HNF4A (HGNC:5024),PP4,Supporting,"MODY Probability Calculator (MPC)
-6
- result ≥50% chance of testing positive AND negative 
-HNF1A
- testing",Gene-specific
-HNF4A (HGNC:5024),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-HNF4A (HGNC:5024),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-HNF4A (HGNC:5024),BA1,Stand Alone,"gnomAD 2.1.1* Popmax Filtering AF ≥ 1:10,000 (≥ 0.01% or 0.0001).
-
-
-*Use gnomAD 2.1.1 exome data unless the region is not covered in the exome, in which case gnomAD 3.1.2 genome data should be used.",Gene-specific
-HNF4A (HGNC:5024),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-HNF4A (HGNC:5024),BS1,Strong,"gnomAD 2.1.1* Popmax Filtering AF  ≥ 1:30,000 (≥0.0033% or 0.000033).
-
-
-*Use gnomAD 2.1.1 exome data unless the region is not covered in the exome, in which case gnomAD 3.1.2 genome data should be used.",Gene-specific
-HNF4A (HGNC:5024),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-HNF4A (HGNC:5024),BS2,Strong,"Apply to normoglycemic individuals age 70 or older (i.e., genotype positive, phenotype negative)",Gene-specific
-HNF4A (HGNC:5024),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-HNF4A (HGNC:5024),BS3,Strong,Applicable to non-canonical splice site variants that have RNA and in silico evidence of normal splicing.,Gene-specific
-HNF4A (HGNC:5024),BS3,Supporting,"List of approved functional studies and guidelines for interpretation of data.
-
-
-
-
-EMSA for DNA binding 
-
-
-“No functional impact” is defined as ≥75% activity of wildtype 
-
-
-Note: the effect of the variant on DNA binding will be highly dependent on whether the variant is located within the DNA binding domain.
-
-
-
-
-
-
-Luciferase assays for transactivation 
-
-
-“No functional impact” is defined as ≥75% activity of wildtype 
-
-
-Note: this threshold is not 100% specific for transactivation (TA) activity and is complicated by the fact that TA activity will vary depend on many factors, for instance cell line that is used (HeLa, INS, MIN6 etc). Assays should include controls for WT, T2DM and known MODY variants.
-
-
-
-
-
-
-Western blotting and indirect immunofluorescence for protein expression (specifically levels and nuclear and cytoplasmic localization, respectively).   
-
-
-Determining appropriate thresholds for protein expression is more difficult due to variability in results due to the complexity of the technique.  Sample preparations, gel loading, transfer efficiency, specificity of the antibody, choice of internal control and inaccurate detection and quantification are some of the factors that can contribute to varying and inconsistent results. If a difference in protein expression compared to WT is seen by immunoblotting, then further testing by quantitative PCR (qPCR) is recommended in order to measure the mRNA level and assess whether the difference in amount of protein is due to a reduced mRNA level.",Gene-specific
-HNF4A (HGNC:5024),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-HNF4A (HGNC:5024),BS4,Strong,"Applicable to family members without variant who have MPC
-6
- score ≥50% (i.e., genotype negative, phenotype positive).","General recommendation,Gene-specific"
-HNF4A (HGNC:5024),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-HNF4A (HGNC:5024),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-HNF4A (HGNC:5024),BP2,Supporting,Also applicable when in cis or trans with a likely pathogenic variant.,General recommendation
-HNF4A (HGNC:5024),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-HNF4A (HGNC:5024),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-HNF4A (HGNC:5024),BP4,Supporting,"Use a REVEL score of ≤0.15 as supportive evidence of no predicted impact on the gene or gene product. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply BP4 when the predicted change is below 0.2
-3
-,
-4
-.",General recommendation
-HNF4A (HGNC:5024),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-HNF4A (HGNC:5024),BP5,Supporting,A variant in another monogenic diabetes gene is Pathogenic/Likely Pathogenic.,General recommendation
-HNF4A (HGNC:5024),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-HNF4A (HGNC:5024),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-HNF4A (HGNC:5024),BP7,Supporting,Apply BP7 when the predicted change from SpliceAI is below 0.2 AND phyloP100 way < 2.0.,Gene-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF4AVersion2.0.0_version=2.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF4AVersion2.0.0_version=2.0.0.csv
deleted file mode 100644
index d3c38e0d7b9075e9cef94a7609b9e017182e899c..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF4AVersion2.0.0_version=2.0.0.csv
+++ /dev/null
@@ -1,386 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-HNF4A (HGNC:5024),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-HNF4A (HGNC:5024),PVS1,Very Strong,"Use 
-HNF4A
- PVS1 decision tree.
-
-
-
-
-Variants generating PTCs in exon 10 and last 55 nucleotides of exon 9 (c.1162-1216) are not expected to cause NMD
-1
-
-
-The most 3’ nonsense or frameshift variant is c.1256C>G, p.S419X in the last exon. This variant has been classified as Pathogenic by the MDEP.  There are six other nonsense and frameshift variants in exon 10, none of which have case information and are all currently classified as VUS. The collective evidence supports applying PVS1 for variants at codon 419 (c.1257) and 5’ and PVS1_Supporting for variants at c.1258 (G)/p.Gly420 and 3’.
-
-
-
-
-
-
-“Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame”
-
-
-Exons 1, 2 (LRG 4), 3 (LRG 5), 4 (LRG 6), 6 (LRG 8): deletion or skipping causes frameshift: PVS1 
-
-
-Exons 5 (LRG 7), 7 (LRG 9), 8 (LRG 10), 9 (LRG 11) - deletion or skipping causes in-frame deletion, 52/52/79/51-79 AA deleted, that is >10 % of the protein in each case - PVS1_Strong  
-
-
-Exon 10 (LRG 12) - 46 AA, contains the transactivation domain, includes stop loss - PVS1_Strong",Strength
-HNF4A (HGNC:5024),PVS1,Strong,"Use 
-HNF4A
- PVS1 decision tree.
-
-
-
-
-“Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame” 
-
-
-Exons 5 (LRG 7), 7 (LRG 9), 8 (LRG 10), 9 (LRG 11) - deletion or skipping causes in-frame deletion, 52/52/79/51-79 AA deleted, that is >10 % of the protein in each case - PVS1_Strong  
-
-
-Exon 10 (LRG 12) - 46 AA, contains the transactivation domain, includes stop loss - PVS1_Strong
-
-
-
-
-
-
-Apply PVS1_Strong to initiation codon variants.  MDEP has classified two start codon variants as likely pathogenic (c.3G>A: PM2_Supporting + PP4_Moderate + PP1_Strong + PVS1_Moderate (c.1delA); c.1delA: PM2_Supporting + PP1 + PP4_Moderate + PVS1_Moderate) and there are multiple P/LP variants before the next methionine, p.Met71.",Strength
-HNF4A (HGNC:5024),PVS1,Supporting,"Use 
-HNF4A
- PVS1 decision tree.
-
-
-Apply PVS1_Supporting to nonsense or frameshift variants at c.1258 (G)/p.Gly420 and 3’.",Strength
-HNF4A (HGNC:5024),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-HNF4A (HGNC:5024),PS1,Strong,No change,No change
-HNF4A (HGNC:5024),PS1,Supporting,PS1 may also be used at a supporting level for canonical and non-canonical splicing variants when a different variant at the same nucleotide has been previously classified as pathogenic and the variant being assessed is predicted by SpliceAI to have a similar (SpliceAI score within 10% of the original variant) or greater deleterious impact.,Strength
-HNF4A (HGNC:5024),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-HNF4A (HGNC:5024),PS2,Very Strong,Use SVI recommended point-based system with specifications for “Phenotype Consistency” per instructions.,"Gene-specific,Strength"
-HNF4A (HGNC:5024),PS2,Strong,Use SVI recommended point-based system with specifications for “Phenotype Consistency” per instructions.,"Gene-specific,Strength"
-HNF4A (HGNC:5024),PS2,Moderate,Use SVI recommended point-based system with specifications for “Phenotype Consistency” per instructions.,"Gene-specific,Strength"
-HNF4A (HGNC:5024),PS2,Supporting,Use SVI recommended point-based system with specifications for “Phenotype Consistency” per instructions.,"Gene-specific,Strength"
-HNF4A (HGNC:5024),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-HNF4A (HGNC:5024),PS3,Strong,Applicable to non-canonical splice site variants that have RNA and in silico evidence of aberrant splicing.,"Gene-specific,Strength"
-HNF4A (HGNC:5024),PS3,Supporting,"List of approved functional studies and guidelines for interpretation:
-
-
-
-
-EMSA for DNA binding
-
-
-“Decreased function” is defined as activity less than 60% of wildtype 
-
-
-Note: the effect of the variant on DNA binding will be highly dependent on whether the variant is located within the DNA binding domain.
-
-
-
-
-
-
-Luciferase assays for transactivation 
-
-
-“Decreased function” is defined as activity less than 60% of wildtype  
-
-
-Note: this threshold is not 100% specific for transactivation (TA) activity and is complicated by the fact that TA activity will vary depend on many factors, for instance cell line that is used (HeLa, INS, MIN6 etc).
-
-
-
-
-
-
-Western blotting and indirect immunofluorescence for protein expression (specifically levels and nuclear and cytoplasmic localization, respectively).
-
-
-Determining appropriate thresholds for protein expression is more difficult due to variability in results due to the complexity of the technique.  Sample preparations, gel loading, transfer efficiency, specificity of the antibody, choice of internal control and inaccurate detection and quantification are some of the factors that can contribute to varying and inconsistent results. If a reduction in protein expression is seen by immunoblotting, then further testing by quantitative PCR (qPCR) is recommended in order to measure the mRNA level and assess whether a reduction in amount of protein is due to a reduced mRNA level.
-
-
-
-
-
-
-To use PS3_Supporting, functional study must have been performed on a transfected variant.  If a study was performed on a cell line generated from a patient sample (and therefore contains the variant plus wild-type allele) does not count as PS3_Supporting.","Gene-specific,Strength"
-HNF4A (HGNC:5024),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-HNF4A (HGNC:5024),PS4,Strong,"7 (seven) or more unrelated occurrences = Strong. Variant should meet PM2_Supporting in order to use PS4 at any level (careful review of gnomAD QC data may be necessary to assess whether variant is real or an artifact, especially if variant is in a polyC region).  Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology.
-
-
-
-
-One or more positive diabetes autoantibodies (IA-2A, ZnT8A+, GAD)
-7
-,
-8
-,
-9
-,
-10
- 
-
-
-Very low or negative C-peptide, defined as either fasting or non-fasting random C-peptide (<200pmol/L or 0.6ng/mL)
-11
-,
-12
- or urinary C-peptide/creatinine ratio <0.2 nmol/mmol
-8
-,
-9","Gene-specific,Strength"
-HNF4A (HGNC:5024),PS4,Moderate,"4-6 unrelated occurrences = Moderate. Variant should meet PM2_Supporting in order to use PS4 at any level. Phenotype of affected individuals must include diabetes, without clear evidence of an autoimmune etiology.
-
-
-
-
-One or more positive diabetes autoantibodies (IA-2A, ZnT8A+, GAD)
-7
-,
-8
-,
-9
-,
-10
-
-
-Very low or negative C-peptide, defined as either fasting or non-fasting random C-peptide (<200pmol/L or 0.6ng/mL)
-11
-,
-12
- or urinary C-peptide/creatinine ratio <0.2 nmol/mmol
-8
-,
-9","Gene-specific,Strength"
-HNF4A (HGNC:5024),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-HNF4A (HGNC:5024),PM1,Moderate,"Applicable to amino acids that directly bind DNA and are necessary for Zinc-finger or homodimer formation
-2
- 
-
-
-
-
-Directly bind DNA: Asp43, His49, Tyr 50, Gly51, Asp56, Gly57, Lys59, Arg63, Arg64, Arg67, His70, Tyr72, Arg87, Asn88, Arg91, Arg94, Gln109, Arg112   
-
-
-Homodimer: Arg75, Gln89, Glu111, Asp113 
-
-
-Zinc finger: Cys38, Cys41, Cys55, Cys58, Cys74, Cys80, Cys90, Cys93","Gene-specific,Strength"
-HNF4A (HGNC:5024),PM1,Supporting,"This criterion can be used for missense variants in well-conserved regions within the DNA and ligand-binding domains. It can also be used for variants within certain transcription factor binding sites in the promoter (see below for details).
-
-
-
-
-Promoter region: 
-
-
-c.-132 to c.-151 (HNF6/OC2 and IPF1 binding sites) 
-
-
-c.-169 to c.-181 (HNF1A/HNF1B binding sites)
-
-
-
-
-
-
-DNA binding: 
-
-
-codons 37-113 (NM_175914.4:c.175C-339C p.Leu37-Asp113) (While the paper describing the crystal structure of 
-HNF4A
-2
- shows the sequence as amino acids 33-113, amino acids 33-36 do not bind DNA and the conserved sequence starts as Leu37.)
-
-
-
-
-
-
-Ligand binding: 
-
-
-codons 180-220 and 300-350  
-
-
-(NM_175914.4:c.538G-658G p.Ala180-Val220) 
-
-
-(NM_175914.4:c.898T-1048G p.Tyr300-Glu350)","Gene-specific,Strength"
-HNF4A (HGNC:5024),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-HNF4A (HGNC:5024),PM2,Supporting,"gnomAD 2.1.1* Popmax FAF ≤ 1:333,000 (≤ 0.000003 or 0.0003%) in gnomAD European Non-Finnish population AND ≤ 2 copies observed in ENF AND ≤ 1 copy in any other founder or non-founder population.
-
-
-*Use gnomAD 2.1.1 exome data unless the region is not covered in the exome, in which case gnomAD 3.1.2 genome data should be used.","General recommendation,Gene-specific"
-HNF4A (HGNC:5024),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-HNF4A (HGNC:5024),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-HNF4A (HGNC:5024),PM4,Moderate,"For single amino acid deletions, use as supporting level of evidence.",Strength
-HNF4A (HGNC:5024),PM4,Supporting,"For single amino acid deletions/insertions, use as supporting level of evidence",Strength
-HNF4A (HGNC:5024),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-HNF4A (HGNC:5024),PM5,Strong,Applicable once two amino acid changes have been classified as pathogenic at the same amino acid residue.,Strength
-HNF4A (HGNC:5024),PM5,Moderate,The novel amino acid change must have a Grantham distance greater than or equal to the previously classified pathogenic variant.,Strength
-HNF4A (HGNC:5024),PM5,Supporting,Apply if the previously classified amino acid change is likely pathogenic (rather than pathogenic) or if the previously classified variant is pathogenic but has a greater Grantham distance than the novel variant.,Strength
-HNF4A (HGNC:5024),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-HNF4A (HGNC:5024),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-HNF4A (HGNC:5024),PP1,Strong,"Use thresholds suggested by Jarvik and Browning
-5
-
-
-
-
-Single Family : ≤ 1/32 (5 meioses)
-
-
-> 1 Family : ≤ 1/16 (4 meioses)","General recommendation,Gene-specific"
-HNF4A (HGNC:5024),PP1,Moderate,"Use thresholds suggested by Jarvik and Browning
-5
-
-
-
-
-Single Family : ≤ 1/16 (4 meioses)
-
-
-> 1 Family : ≤ 1/8 (3 meioses)","General recommendation,Gene-specific"
-HNF4A (HGNC:5024),PP1,Supporting,"Use thresholds suggested by Jarvik and Browning
-5
-
-
-
-
-Single Family : ≤ 1/8 (3 meioses)
-
-
-> 1 Family : ≤ ¼ (2 meioses)","General recommendation,Gene-specific"
-HNF4A (HGNC:5024),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-HNF4A (HGNC:5024),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-HNF4A (HGNC:5024),PP3,Supporting,"Use REVEL score of ≥0.70 as supportive evidence of pathogenicity. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply PP3 when the predicted change is at least 0.2 
-4
-,
-3
-.",General recommendation
-HNF4A (HGNC:5024),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-HNF4A (HGNC:5024),PP4,Moderate,"Phenotype: MODY Probability Calculator result ≥50% chance of testing positive
-6
- AND negative 
-HNF1A
- testing AND presence of at least one additional feature characteristic of _
-HNF4A
-_-MODY:   
-
-
-
-
-Antibody negative and/or persistent C-peptide after five years following T1DM diagnosis  
-
-
-Personal or family history of persistent neonatal hypoglycemia  
-
-
-Personal or family history of large for gestational age (LGA) infants or macrosomia in the absence of sufficient maternal hyperglycemia 
-
-
-Response to low-dose SU (extreme response- hypoglycemia) 
-
-
-Biochemical/Molecular phenotypic evidence from patient cell lines 
-
-
-Fanconi phenotype in conjunction with c.187C>T p.R63W",Gene-specific
-HNF4A (HGNC:5024),PP4,Supporting,"MODY Probability Calculator (MPC)
-6
- result ≥50% chance of testing positive AND negative 
-HNF1A
- testing",Gene-specific
-HNF4A (HGNC:5024),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-HNF4A (HGNC:5024),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-HNF4A (HGNC:5024),BA1,Stand Alone,"gnomAD 2.1.1* Popmax Filtering AF ≥ 1:10,000 (≥ 0.01% or 0.0001).
-
-
-*Use gnomAD 2.1.1 exome data unless the region is not covered in the exome, in which case gnomAD 3.1.2 genome data should be used.",Gene-specific
-HNF4A (HGNC:5024),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-HNF4A (HGNC:5024),BS1,Strong,"gnomAD 2.1.1* Popmax Filtering AF  ≥ 1:30,000 (≥0.0033% or 0.000033).
-
-
-*Use gnomAD 2.1.1 exome data unless the region is not covered in the exome, in which case gnomAD 3.1.2 genome data should be used.",Gene-specific
-HNF4A (HGNC:5024),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-HNF4A (HGNC:5024),BS2,Strong,"Apply to normoglycemic individuals age 70 or older (i.e., genotype positive, phenotype negative)",Gene-specific
-HNF4A (HGNC:5024),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-HNF4A (HGNC:5024),BS3,Strong,Applicable to non-canonical splice site variants that have RNA and in silico evidence of normal splicing.,Gene-specific
-HNF4A (HGNC:5024),BS3,Supporting,"List of approved functional studies and guidelines for interpretation of data.
-
-
-
-
-EMSA for DNA binding 
-
-
-“No functional impact” is defined as ≥75% activity of wildtype 
-
-
-Note: the effect of the variant on DNA binding will be highly dependent on whether the variant is located within the DNA binding domain.
-
-
-
-
-
-
-Luciferase assays for transactivation 
-
-
-“No functional impact” is defined as ≥75% activity of wildtype 
-
-
-Note: this threshold is not 100% specific for transactivation (TA) activity and is complicated by the fact that TA activity will vary depend on many factors, for instance cell line that is used (HeLa, INS, MIN6 etc). Assays should include controls for WT, T2DM and known MODY variants.
-
-
-
-
-
-
-Western blotting and indirect immunofluorescence for protein expression (specifically levels and nuclear and cytoplasmic localization, respectively).   
-
-
-Determining appropriate thresholds for protein expression is more difficult due to variability in results due to the complexity of the technique.  Sample preparations, gel loading, transfer efficiency, specificity of the antibody, choice of internal control and inaccurate detection and quantification are some of the factors that can contribute to varying and inconsistent results. If a difference in protein expression compared to WT is seen by immunoblotting, then further testing by quantitative PCR (qPCR) is recommended in order to measure the mRNA level and assess whether the difference in amount of protein is due to a reduced mRNA level.",Gene-specific
-HNF4A (HGNC:5024),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-HNF4A (HGNC:5024),BS4,Strong,"Applicable to family members without variant who have MPC
-6
- score ≥50% (i.e., genotype negative, phenotype positive).","General recommendation,Gene-specific"
-HNF4A (HGNC:5024),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-HNF4A (HGNC:5024),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-HNF4A (HGNC:5024),BP2,Supporting,Also applicable when in cis or trans with a likely pathogenic variant.,General recommendation
-HNF4A (HGNC:5024),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-HNF4A (HGNC:5024),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-HNF4A (HGNC:5024),BP4,Supporting,"Use a REVEL score of ≤0.15 as supportive evidence of no predicted impact on the gene or gene product. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply BP4 when the predicted change is below 0.2
-3
-,
-4
-.",General recommendation
-HNF4A (HGNC:5024),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-HNF4A (HGNC:5024),BP5,Supporting,A variant in another monogenic diabetes gene is Pathogenic/Likely Pathogenic.,General recommendation
-HNF4A (HGNC:5024),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-HNF4A (HGNC:5024),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-HNF4A (HGNC:5024),BP7,Supporting,Apply BP7 when the predicted change from SpliceAI is below 0.2 AND phyloP100 way < 2.0.,Gene-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
deleted file mode 100644
index 7a2bbcb206a8a273bbce6c1df6c76eb20bc0c74b..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
+++ /dev/null
@@ -1,423 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-RUNX1 (HGNC:10471),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7)
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact
- • Use caution in the presence of multiple transcripts",
-RUNX1 (HGNC:10471),PVS1,Very Strong,"Null variant in a gene where LOF is a known mechanism of disease.
-
-
-Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects.
-
-
-Comments:
-
-
-RUNX1 LOF variants are a common mechanism of disease in FPD/AML. Three major isoforms (A, B, C) are expressed by use of two promotors and alternative splicing. C-terminal variants not predicted to undergo NMD are classified as PVS1_strong, deletions of exons 2 and 3, presumably only affecting RUNX1 isoform 1C,  meet PVS1_moderate.",
-RUNX1 (HGNC:10471),PVS1,Strong,"Null variant in a gene where LOF is a known mechanism of disease.
-
-
-Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects.
-
-
-Comments:
-
-
-RUNX1 LOF variants are a common mechanism of disease in FPD/AML. Three major isoforms (A, B, C) are expressed by use of two promotors and alternative splicing. C-terminal variants not predicted to undergo NMD are classified as PVS1_strong, deletions of exons 2 and 3, presumably only affecting RUNX1 isoform 1C,  meet PVS1_moderate.",
-RUNX1 (HGNC:10471),PVS1,Moderate,"Null variant in a gene where LOF is a known mechanism of disease.
-
-
-Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects.
-
-
-Comments:
-
-
-RUNX1 LOF variants are a common mechanism of disease in FPD/AML. Three major isoforms (A, B, C) are expressed by use of two promotors and alternative splicing. C-terminal variants not predicted to undergo NMD are classified as PVS1_strong, deletions of exons 2 and 3, presumably only affecting RUNX1 isoform 1C,  meet PVS1_moderate.",
-RUNX1 (HGNC:10471),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level",
-RUNX1 (HGNC:10471),PS1,Strong,"Same AA change as a previously established pathogenic variant regardless of nucleotide change.
-
-
-Comments:
-
-
-RNA data or agreement in splicing predictors show no splicing effects (SSF and MES predict either increase in canonical splice site score or decrease of  canonical splice score by no more than 10% and no putative splice site are created).
-
-
-The previously established PATH/LPATH variant must be asserted pathogenic/likely pathogenic based on MM-VCEP rules for RUNX1 before this rule can be applied",
-RUNX1 (HGNC:10471),PS1,Moderate,"Same AA change as a previously established likely pathogenic variant regardless of nucleotide change.
-
-
-Comments:
-
-
-RNA data or agreement in splicing predictors show no splicing effects (SSF and MES predict either increase in canonical splice site score or decrease of  canonical splice score by no more than 10% and no putative splice site are created).
-
-
-The previously established PATH/LPATH variant must be asserted pathogenic/likely pathogenic based on MM-VCEP rules for RUNX1 before this rule can be applied",
-RUNX1 (HGNC:10471),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity",
-RUNX1 (HGNC:10471),PS2,Moderate,"≥ 2 proven de novo occurrences (maternity and paternity confirmed) in patients with the RUNX1-phenotype.
-
-
-Comments:
-
-
-No family history is defined as: absence of the variant and any of the RUNX1-phenotypic criteria in first- or second degree relatives.
-
-
-The proband must exhibit at least one phenotypic FPD/AML criterion. (3) The maximum allowable strength by combining PS2 and PM6 criteria is to apply one moderate or two supporting rules.",
-RUNX1 (HGNC:10471),PS2,Supporting,"1 proven de novo occurrence (maternity and paternity confirmed) in a patient with the RUNX1-phenotype.
-
-
-Comments:
-
-
-No family history is defined as: absence of the variant and any of the RUNX1-phenotypic criteria in first- or second degree relatives.
-
-
-The proband must exhibit at least one phenotypic FPD/AML criterion. (3) The maximum allowable strength by combining PS2 and PM6 criteria is to apply one moderate or two supporting rules.",
-RUNX1 (HGNC:10471),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established",
-RUNX1 (HGNC:10471),PS3,Strong,"Transactivation assays demonstrating altered transactivation (<20% of wt, and/or reduced to levels similar to well-established pathogenic variants such as R201Q or R166Q) AND data from a secondary assay demonstrating altered function.
-
-
-PS3 cannot be applied if the variant meets PVS1. If the variant meets criteria for PVS1_strong and PS3, we recommend applying either PS3_moderate or upgrading PVS1_strong to PVS1 without applying PS3 .
- Comments:
-
-
-Transactivation assays should include wt and known pathogenic controls, as well as co-expression with CBFβ. Promoter sequences of CSF1R (M-CSF-R), PF4, C-FMS and GZMB, containing consensus RUNX1 binding sites have been used for transactivation assays.
-
-
-The following secondary assays have been performed: EMSA and yeast hybrid assays (decreased DNA-binding affinity), co-IP, FRET and affinity assays (diminished heterodimerization ability with CBFβ), IF and WB with cell fractionation (abnormal cellular localization), colony forming assays (reduced colony-forming potential), xenotransplantation experiments (abnormal function of mutant RUNX1 in vivo).
-
-
-PS3 can also be applied for evidence of very low or abnormal mRNA/protein expression of the variant allele as a functional consequence of a null variant or incorrect mRNA/protein products",
-RUNX1 (HGNC:10471),PS3,Moderate,"Transactivation assays demonstrating altered transactivation (<20% of wt, and/or reduced to levels similar to well-established pathogenic variants such as R201Q or R166Q) OR ≥ 2 secondary assays demonstrating altered function.
-
-
-Comments:
-
-
-Transactivation assays should include wt and known pathogenic controls, as well as co-expression with CBFβ. Promoter sequences of CSF1R (M-CSF-R), PF4, C-FMS and GZMB, containing consensus RUNX1 binding sites have been used for transactivation assays.
-
-
-The following secondary assays have been performed: EMSA and yeast hybrid assays (decreased DNA-binding affinity), co-IP, FRET and affinity assays (diminished heterodimerization ability with CBFβ), IF and WB with cell fractionation (abnormal cellular localization), colony forming assays (reduced colony-forming potential), xenotransplantation experiments (abnormal function of mutant RUNX1 in vivo).
-
-
-PS3 can also be applied for evidence of very low or abnormal mRNA/protein expression of the variant allele as a functional consequence of a null variant or incorrect mRNA/protein products",
-RUNX1 (HGNC:10471),PS3,Supporting,"Transactivation assays demonstrating enhanced transactivation (>115% of wt).
-
-
-Comments:
-
-
-Transactivation assays should include wt and known pathogenic controls, as well as co-expression with CBFβ. Promoter sequences of CSF1R (M-CSF-R), PF4, C-FMS and GZMB, containing consensus RUNX1 binding sites have been used for transactivation assays.
-
-
-The following secondary assays have been performed: EMSA and yeast hybrid assays (decreased DNA-binding affinity), co-IP, FRET and affinity assays (diminished heterodimerization ability with CBFβ), IF and WB with cell fractionation (abnormal cellular localization), colony forming assays (reduced colony-forming potential), xenotransplantation experiments (abnormal function of mutant RUNX1 in vivo).
-
-
-PS3 can also be applied for evidence of very low or abnormal mRNA/protein expression of the variant allele as a functional consequence of a null variant or incorrect mRNA/protein products",
-RUNX1 (HGNC:10471),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-RUNX1 (HGNC:10471),PS4,Strong,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-
-
-≥ 4 probands meeting RUNX1-phenotypic criteria.
-
-
-Comments:
-
-
-The affected individual has to fit at least one of the RUNX1-phenotypic criteria AND variant has to be either absent from gnomAD (overall population) or only present once.",
-RUNX1 (HGNC:10471),PS4,Moderate,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-
-
-2-3 probands meeting RUNX1-phenotypic criteria.
-
-
-Comments:
-
-
-The affected individual has to fit at least one of the RUNX1-phenotypic criteria AND variant has to be either absent from gnomAD (overall population) or only present once.",
-RUNX1 (HGNC:10471),PS4,Supporting,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-
-
-1 proband meeting RUNX1-phenotypic criteria.
-
-
-Comments:
-
-
-The affected individual has to fit at least one of the RUNX1-phenotypic criteria AND variant has to be either absent from gnomAD (overall population) or only present once.",
-RUNX1 (HGNC:10471),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation,
-RUNX1 (HGNC:10471),PM1,Moderate,"Located in a mutational hot spot and/or critical and well-established functional domain without benign variation.
-
-
-Variant affecting one of the following 13 hotspot residues: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204.
-
-
-Comments:
-
-
-The RHD (AA 77-204) has been established as highly conserved DNA-binding domain without any benign variation in ClinVar. Residues in the region (AA 77-104) are also in the RHD, but no germline variants have been reported to date. The AA range under PM1_supporting may be expanded in the future to other parts of the protein if more evidence emerges.",
-RUNX1 (HGNC:10471),PM1,Supporting,"Located in a mutational hot spot and/or critical and well-established functional domain without benign variation.
-
-
-Variant affecting one of the other AA residues 105-204 within the RHD.
-
-
-Comments:
-
-
-The RHD (AA 77-204) has been established as highly conserved DNA-binding domain without any benign variation in ClinVar. Residues in the region (AA 77-104) are also in the RHD, but no germline variants have been reported to date. The AA range under PM1_supporting may be expanded in the future to other parts of the protein if more evidence emerges.",
-RUNX1 (HGNC:10471),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium
-Caveat: Population data for indels may be poorly called by next generation sequencing",
-RUNX1 (HGNC:10471),PM2,Moderate,"Absent from controls.
-
-
-Per original ACMG/AMP guidelines.
-
-
-Comments:
-
-
-Variant must be completely absent from all population databases.  The mean coverage of RUNX1 in the population database used should be at least 20x.",
-RUNX1 (HGNC:10471),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase",NA
-RUNX1 (HGNC:10471),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-RUNX1 (HGNC:10471),PM4,Moderate,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-In-frame deletion/insertion impacting at least one of the 13 hotspot residues R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201
-
-
-Comments:
-
-
-See PM1",
-RUNX1 (HGNC:10471),PM4,Supporting,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-Other in-frame deletion/insertion impacting residues 105-204 within the RHD.
-
-
-Comments:
-
-
-See PM1",
-RUNX1 (HGNC:10471),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
-Example: Arg156His is pathogenic; now you observe Arg156Cys
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level",
-RUNX1 (HGNC:10471),PM5,Strong,"Missense change at the same residue where ≥ 2  different missense changes have previoulsy been determined to be pathogenic. PM5_strong cannot be applied together with PM1.
-
-
-Comments:
-
-
-see PS1",
-RUNX1 (HGNC:10471),PM5,Moderate,"Missense change at the same residue where a different missense change has previously been determined to be pathogenic.
-
-
-Comments:
-
-
-see PS1",
-RUNX1 (HGNC:10471),PM5,Supporting,"Missense change at the same residue where a different missense change has previously been determined to be likely pathogenic.
-
-
-Comments:
-
-
-see PS1",
-RUNX1 (HGNC:10471),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity",
-RUNX1 (HGNC:10471),PM6,Moderate,"Assumed de novo (but without confirmation of maternity and paternity) in a patient with the disease and no family history.
-
-
-≥ 4 assumed de novo occurrences (without confirmation of maternity and paternity) in patients with the RUNX1-phenotype.
-
-
-Comments:
-
-
-see PS2",
-RUNX1 (HGNC:10471),PM6,Supporting,"Assumed de novo (but without confirmation of maternity and paternity) in a patient with the disease and no family history.
-
-
-2 or 3 assumed de novo occurrences (without confirmation of maternity and paternity) in patients with the RUNX1-phenotype.
-
-
-Comments:
-
-
-see PS2",
-RUNX1 (HGNC:10471),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease
-Note: May be used as stronger evidence with increasing segregation data",
-RUNX1 (HGNC:10471),PP1,Strong,"Co-segregation with disease in multiple affected family members.
-
-
-≥ 7 meioses observed within one or across multiple families.
-
-
-Comments:
-
-
-Affected individuals show at least one of the RUNX1-specific phenotypic criteria.
-
-
-Only genotype and phenotype positive individuals and obligate carriers are counted.
-
-
-Demonstration of co-segregation in multiple families is not required since many RUNX1 variants are unique and only occur in one family.",
-RUNX1 (HGNC:10471),PP1,Moderate,"Co-segregation with disease in multiple affected family members.
-
-
-5 or 6 meioses observed within one or across multiple families.
-
-
-Comments:
-
-
-Affected individuals show at least one of the RUNX1-specific phenotypic criteria.
-
-
-Only genotype and phenotype positive individuals and obligate carriers are counted.
-
-
-Demonstration of co-segregation in multiple families is not required since many RUNX1 variants are unique and only occur in one family.",
-RUNX1 (HGNC:10471),PP1,Supporting,"Co-segregation with disease in multiple affected family members.
-
-
-3 or 4 meioses observed within one or across multiple families.
-
-
-Comments:
-
-
-Affected individuals show at least one of the RUNX1-specific phenotypic criteria.
-
-
-Only genotype and phenotype positive individuals and obligate carriers are counted.
-
-
-Demonstration of co-segregation in multiple families is not required since many RUNX1 variants are unique and only occur in one family.",
-RUNX1 (HGNC:10471),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease,NA
-RUNX1 (HGNC:10471),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-RUNX1 (HGNC:10471),PP3,Supporting,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product.
-
-
-Comments:
-
-
-PP3 should be applied for missense variants with a REVEL score of >0.75.
-
-
-PP3 should also be applied for missense or synonymous variants if the variant alters the last three bases of an exon preceding a splice donor site or the first three bases of an exon following an acceptor splice site and the predicted decrease in the score of the canonical splice site (measured by both MES and SSF) is at least 75% regardless of the predicted creation/presence of a putative cryptic splice site.
-
-
-PP3 should also be applied for intronic variants (in introns 4-8) located in reference to exons at positions +3 to +5 for donor splice sites or -3 to -5 for acceptor splice sites and the predicted decrease in the score of the canonical splice site is at least 75% (measured by both MES and SSF) regardless of the predicted creation/presence of a putative cryptic splice site.
-
-
-PP3 cannot be applied for canonical splice site variants.",
-RUNX1 (HGNC:10471),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology,NA
-RUNX1 (HGNC:10471),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RUNX1 (HGNC:10471),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium",
-RUNX1 (HGNC:10471),BA1,Stand Alone,"Allele frequency is >5% in ESP, 1000G, or ExAC.
-
-
-Comments:
-
-
-The variant is present in in any general continental population dataset with a minimum number of 2,000 alleles and variant present in ≥ 5 alleles.",
-RUNX1 (HGNC:10471),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-RUNX1 (HGNC:10471),BS1,Strong,"Allele frequency is greater than expected for disorder.
-
-
-MAF between 0.00015 (0.015%) and 0.0015 (0.15%)
-
-
-Comments:
-
-
-The variant is present in any general continental population dataset with a minimum number of 2,000 alleles and variant present in ≥ 5 alleles.
-
-
-Variant can be classified as likely benign based on BS1 alone if there is no contradictory evidence supporting pathogenicity.",
-RUNX1 (HGNC:10471),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age",NA
-RUNX1 (HGNC:10471),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-RUNX1 (HGNC:10471),BS3,Strong,"Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
-
-
-Transactivation assays demonstrating normal transactivation (80-115% of wt) AND
-
-
-data from a secondary assay demonstrating normal function.
-
-
-Comments:
-
-
-see PS3 (1) and (2)",
-RUNX1 (HGNC:10471),BS3,Supporting,"Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
-
-
-Transactivation assays demonstrating normal transactivation (80-115% of wt).
-
-
-Comments:
-
-
-see PS3 (1) and (2)",
-RUNX1 (HGNC:10471),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation",
-RUNX1 (HGNC:10471),BS4,Strong,"Lack of segregation in affected members of a family.
-
-
-Applied when seen in ≥ 2 informative meioses.
-
-
-Comments:
-
-
-This code should only be applied for genotype-positive, phenotype-negative (with sufficient laboratory evidence) family members.",
-RUNX1 (HGNC:10471),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease,NA
-RUNX1 (HGNC:10471),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-RUNX1 (HGNC:10471),BP2,Supporting,"Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
-
-
-Per original ACMG/AMP guidelines.
-
-
-Comments:
-
-
-BP2 can also be applied if the variant is detected in a homozygous state.",
-RUNX1 (HGNC:10471),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-RUNX1 (HGNC:10471),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-RUNX1 (HGNC:10471),BP4,Supporting,"Multiple lines of computational evidence suggest no impact on gene or gene product.
-
-
-Comments:
-
-
-BP4 should be applied for missense variants with a REVEL score < 0.15 as well as synonymous, intronic and non-coding variants for which SSF and MES predict either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created.",
-RUNX1 (HGNC:10471),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-RUNX1 (HGNC:10471),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RUNX1 (HGNC:10471),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-RUNX1 (HGNC:10471),BP7,Supporting,"A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
-
-
-Per original ACMG/AMP guidelines. BP7 can not be applied in combination with PP3.
-
-
-Comments:
-
-
-Also applicable to intronic/non-coding variants at or beyond positions +7/-21 for which (1) SSF and MES predict either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created AND (2) evolutionary conservation prediction algorithms predict the site as not conserved (e.g. PhyloP score < 0.1 or the variant is the reference nucleotide in one primate and/or three mammal species.).",
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
deleted file mode 100644
index 7800f514ba608aa7cd9591835a7d53f4cd5c92ec..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
+++ /dev/null
@@ -1,87 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-RUNX1 (HGNC:10471),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-RUNX1 (HGNC:10471),PVS1,Very Strong,Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects.,Gene-specific
-RUNX1 (HGNC:10471),PVS1,Strong,Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects.,"Gene-specific,Strength"
-RUNX1 (HGNC:10471),PVS1,Moderate,Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects.,"Disease-specific,Strength"
-RUNX1 (HGNC:10471),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RUNX1 (HGNC:10471),PS1,Strong,Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.,None
-RUNX1 (HGNC:10471),PS1,Moderate,Same amino acid change as a previously established likely pathogenic variant regardless of nucleotide change.,Strength
-RUNX1 (HGNC:10471),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-RUNX1 (HGNC:10471),PS2,Moderate,"Phenotypic specificity category: “Phenotype consistent with gene but not highly specific and high genetic heterogeneity”. For each proven de novo case give 0.5 points, for each assumed de novo case give 0.25 point.
-Moderate = 1.0 points total.","Disease-specific,Strength"
-RUNX1 (HGNC:10471),PS2,Supporting,"Phenotypic specificity category: “Phenotype consistent with gene but not highly specific and high genetic heterogeneity”. For each proven de novo case give 0.5 points, for each assumed de novo case give 0.25 point.
-Supporting = 0.5 points total.","Disease-specific,Strength"
-RUNX1 (HGNC:10471),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-RUNX1 (HGNC:10471),PS3,Strong,"Transactivation assays demonstrating altered transactivation (<20% of wt, and/or reduced to levels similar to well established pathogenic variants such as R201Q or R166Q) AND data from a secondary assay demonstrating altered function. Not applicable if variant meets PVS1. If variant meets PVS1_strong, either apply PS3_moderate or upgrade to PVS1.",Gene-specific
-RUNX1 (HGNC:10471),PS3,Moderate,Transactivation assays demonstrating altered transactivation (<20% of wt and/or reduced to levels similar to well established pathogenic variants such as R201Q or R166Q) OR ≥ 2 secondary assays demonstrating altered function.,"Gene-specific,Strength"
-RUNX1 (HGNC:10471),PS3,Supporting,Transactivation assays demonstrating enhanced transactivation (>115% of wt).,"Gene-specific,Strength"
-RUNX1 (HGNC:10471),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-RUNX1 (HGNC:10471),PS4,Strong,≥ 4 probands meeting at least one of the RUNX1-phenotypic criteria.,Disease-specific
-RUNX1 (HGNC:10471),PS4,Moderate,2-3 probands meeting at least one of the RUNX1-phenotypic criteria.,"Disease-specific,Strength"
-RUNX1 (HGNC:10471),PS4,Supporting,1 proband meeting at least one of the RUNX1-phenotypic criteria.,"Disease-specific,Strength"
-RUNX1 (HGNC:10471),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-RUNX1 (HGNC:10471),PM1,Moderate,"Variant affecting one of the following amino acid residues within he RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204.",Gene-Specific
-RUNX1 (HGNC:10471),PM1,Supporting,Variant affecting one of the other amino acid residues 89-204 within the RHD.,"Gene-specific,Strength"
-RUNX1 (HGNC:10471),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-RUNX1 (HGNC:10471),PM2,Supporting,Variant must be completely absent from all population databases.,Strength
-RUNX1 (HGNC:10471),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-RUNX1 (HGNC:10471),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-RUNX1 (HGNC:10471),PM4,Moderate,"In-frame deletion/insertion impacting at least one of the following amino acid residues within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204.",Gene-specific
-RUNX1 (HGNC:10471),PM4,Supporting,In-frame deletion/insertion impacting at least one of the other amino acid residues 89-204 within the RHD.,"Gene-specific,Strength"
-RUNX1 (HGNC:10471),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RUNX1 (HGNC:10471),PM5,Strong,Missense change at an AA residue where ≥ 2 different missense changes which have been determined to be pathogenic before. Not applicable in combination with PM1.,Strength
-RUNX1 (HGNC:10471),PM5,Moderate,Missense change at an amino acid residue where a different missense change which has been determined to be pathogenic before.,None
-RUNX1 (HGNC:10471),PM5,Supporting,Missense change at an amino acid residue where a different missense change which has been determined to be likely pathogenic before. PM5_supporting is also applied to nonsense/frameshift variants that are downstream of c.98 (in transcript NM_001754.4).,Strength
-RUNX1 (HGNC:10471),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-RUNX1 (HGNC:10471),PM6,Moderate,"Phenotypic specificity category: “Phenotype consistent with gene but not highly specific and high genetic heterogeneity” For each proven de novo case give 0.5 points, for each assumed de novo case give 0.25 point.
-Moderate = 1.0 points total.","Disease-specific,Strength"
-RUNX1 (HGNC:10471),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-RUNX1 (HGNC:10471),PP1,Strong,≥ 7 meioses observed within one or across multiple families.,"Disease-specific,Strength"
-RUNX1 (HGNC:10471),PP1,Moderate,Co-segregation with disease in multiple affected family members. 5 or 6 meioses observed within one or across multiple families.,"Disease-specific,Strength"
-RUNX1 (HGNC:10471),PP1,Supporting,3 or 4 meioses observed within one or across multiple families.,Disease-specific
-RUNX1 (HGNC:10471),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-RUNX1 (HGNC:10471),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-RUNX1 (HGNC:10471),PP3,Supporting,"For missense variants: REVEL score ≥ 0.88.
-For missense, synonymous and intronic (intron 4-8) variants: SpliceAI ≥ 0.38, including the creation of cryptic novel splice sites.","Gene-specific,Disease-specific"
-RUNX1 (HGNC:10471),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-RUNX1 (HGNC:10471),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RUNX1 (HGNC:10471),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-RUNX1 (HGNC:10471),BA1,Stand Alone,"Minor allele frequency between 0.0015 (0.15%) in any general continental population dataset with ≥ 2,000 alleles tested and variant present in ≥ 5 alleles.",Disease-specific
-RUNX1 (HGNC:10471),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-RUNX1 (HGNC:10471),BS1,Strong,"Minor allele frequency between 0.00015 (0.015%) and 0.0015 (0.15%) in any general continental population dataset with ≥ 2,000 alleles tested and variant present in ≥ 5 alleles.",Disease-specific
-RUNX1 (HGNC:10471),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",NA
-RUNX1 (HGNC:10471),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-RUNX1 (HGNC:10471),BS3,Strong,Transactivation assays demonstrating normal transactivation (80- 115% of wt) AND data from a secondary assay demonstrating normal function.,Gene-specific
-RUNX1 (HGNC:10471),BS3,Supporting,Transactivation assays demonstrating normal transactivation (80- 115% of wt).,"Gene-specific,Strength"
-RUNX1 (HGNC:10471),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-RUNX1 (HGNC:10471),BS4,Strong,Applied when seen in ≥ 2 informative meioses.,General recommendation
-RUNX1 (HGNC:10471),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-RUNX1 (HGNC:10471),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-RUNX1 (HGNC:10471),BP2,Supporting,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,None
-RUNX1 (HGNC:10471),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-RUNX1 (HGNC:10471),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-RUNX1 (HGNC:10471),BP4,Supporting,"For missense variants: REVEL score <0.50 AND SpliceAI ≤ 0.20.
-For synonymous and Intronic variants: SpliceAI ≤ 0.20.","Gene-specific,Disease-specific"
-RUNX1 (HGNC:10471),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-RUNX1 (HGNC:10471),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RUNX1 (HGNC:10471),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-RUNX1 (HGNC:10471),BP7,Supporting,BP7 is applicable for synonymous and intronic which SpliceAI ≤ 0.20 AND evolutionary conservation prediction algorithms predict the site as not conserved phyloP100 way (GRCh38/hg38) ≤2.0).,"Gene-specific,Disease-specific"
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPAHExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPAHExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
deleted file mode 100644
index 2496483ce0832fd52fc7f974cc5f60d019af7fff..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPAHExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
+++ /dev/null
@@ -1,136 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-PAH (HGNC:8582),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-PAH (HGNC:8582),PVS1,Very Strong,Null variant in a gene where loss of function is a known mechanism of disease.,None
-PAH (HGNC:8582),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-PAH (HGNC:8582),PS1,Strong,Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.,None
-PAH (HGNC:8582),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-PAH (HGNC:8582),PS2,Strong,De novo (paternity confirmed) in a patient with the disease and no family history.,None
-PAH (HGNC:8582),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-PAH (HGNC:8582),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect
-
-
-
-
-PAH enzyme activity assay demonstrating enzyme activity <50%
-
-
-RT-PCR evidence of missplicing for non-canonical intronic variants",Disease-specific
-PAH (HGNC:8582),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",NA
-PAH (HGNC:8582),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-PAH (HGNC:8582),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-PAH (HGNC:8582),PM2,Moderate,"Absent/rare from controls in an ethnically-matched cohort population sample.
-
-
-
-
-Threshold: <0.0002 (0.02%).",Disease-specific
-PAH (HGNC:8582),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-PAH (HGNC:8582),PM3,Very Strong,"For recessive disorders, detected in trans with a pathogenic variant.
-
-
-
-
-4 compound heterozygotes with 3 P/LP variants OR
-
-
-2 compound heterozygotes with 2 P/LP variants AND 4 homozygotes OR
-
-
-3 compound heterozygotes with 2 P/LP variants AND 2 homozygotes",Strength
-PAH (HGNC:8582),PM3,Strong,"For recessive disorders, detected in trans with a pathogenic variant.
-
-
-
-
-Compound heterozygous with 2 P/LP variants OR
-
-
-Compound heterozygous with 1 P/LP variant AND 2 homozygotes",Strength
-PAH (HGNC:8582),PM3,Moderate,"For recessive disorders, detected in trans with a pathogenic variant.",None
-PAH (HGNC:8582),PM3,Supporting,"Detected in trans with another variant:
-
-
-
-
-2 compound heterozygotes (with VUS in trans)
-
-
-2 homozygotes (allele drop out excluded)",Strength
-PAH (HGNC:8582),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-PAH (HGNC:8582),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,None
-PAH (HGNC:8582),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-PAH (HGNC:8582),PM5,Moderate,Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.,None
-PAH (HGNC:8582),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-PAH (HGNC:8582),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-PAH (HGNC:8582),PP1,Strong,"Co-segregation with disease in multiple affected family members:
-
-
-
-
-3 affected segregations + 0 unaffected segregations OR
-
-
-2 affected segregations + 3 unaffected segregations",Strength
-PAH (HGNC:8582),PP1,Moderate,"Co-segregation with disease in multiple affected family members
-
-
-
-
-2 affected segregations + 0 unaffected segregations",Strength
-PAH (HGNC:8582),PP1,Supporting,"Co-segregation with disease in multiple affected family members
-
-
-
-
-1 affected family member + 3 unaffected segregations",
-PAH (HGNC:8582),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-PAH (HGNC:8582),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-PAH (HGNC:8582),PP3,Supporting,Multiple lines of computational evidence support a deleterious effect on the gene or gene product,
-PAH (HGNC:8582),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-PAH (HGNC:8582),PP4,Moderate,Plasma Phe >120 µmol/L and exclusion of a defect of BH4 cofactor metabolism.,"Strength,Disease-specific"
-PAH (HGNC:8582),PP4,Supporting,Phenotype specific for disease with single genetic etiology.,
-PAH (HGNC:8582),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-PAH (HGNC:8582),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-PAH (HGNC:8582),BA1,Stand Alone,Allele frequency above 0.015 (1.5%),Disease-specific
-PAH (HGNC:8582),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-PAH (HGNC:8582),BS1,Strong,"Allele frequency greater than expected for disease (>0.002, 0.2%)",Disease-specific
-PAH (HGNC:8582),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-PAH (HGNC:8582),BS2,Strong,Observed in the homozygous state in a healthy adult,None
-PAH (HGNC:8582),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-PAH (HGNC:8582),BS3,Supporting,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function
-
-
-
-
-Enzyme activity >85%","Strength,Disease-specific"
-PAH (HGNC:8582),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-PAH (HGNC:8582),BS4,Strong,Lack of segregation in affected members of a family.,
-PAH (HGNC:8582),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-PAH (HGNC:8582),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-PAH (HGNC:8582),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-PAH (HGNC:8582),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-PAH (HGNC:8582),BP4,Supporting,Multiple lines of computational evidence suggest no impact on gene or gene product,None
-PAH (HGNC:8582),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-PAH (HGNC:8582),BP5,Supporting,Variant found in a case with an alternate molecular basis for disease,None
-PAH (HGNC:8582),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-PAH (HGNC:8582),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-PAH (HGNC:8582),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,None
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
deleted file mode 100644
index 785544a5c9cc25ecfc47f51cc541f30adafc1d83..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
+++ /dev/null
@@ -1,91 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-PTEN (HGNC:9588),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-PTEN (HGNC:9588),PVS1,Very Strong,"Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multi-exon deletion) predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.6).",Disease-specific
-PTEN (HGNC:9588),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-PTEN (HGNC:9588),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change OR different variant at same nucleotide position as a pathogenic splicing variant, where in silico models predict impact equal to or greater than the known pathogenic variant.",Disease-specific
-PTEN (HGNC:9588),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-PTEN (HGNC:9588),PS2,Very Strong,Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history.,Strength
-PTEN (HGNC:9588),PS2,Strong,De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history.,None
-PTEN (HGNC:9588),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-PTEN (HGNC:9588),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-
-
-
-
-Phosphatase activity <50% of wild-type
-
-
-RNA, mini-gene, or other assay shows impact on splicing",Disease-specific
-PTEN (HGNC:9588),PS3,Supporting,Abnormal in vitro cellular assay or transgenic model with phenotype different from wild type that does not meet PS3.,"Strength,Disease-specific"
-PTEN (HGNC:9588),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-PTEN (HGNC:9588),PS4,Very Strong,Probands with specificity score ≥16 (see text).,Strength
-PTEN (HGNC:9588),PS4,Strong,Probands with specificity score 4-15.5 (see text) OR The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.,Strength
-PTEN (HGNC:9588),PS4,Moderate,Probands with specificity score of 2-3.5 (see text).,Strength
-PTEN (HGNC:9588),PS4,Supporting,Phenotype specific for disease with single genetic etiology. Proband(s) with specificity score of 1-1.5 (see text).,Disease-specific
-PTEN (HGNC:9588),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-PTEN (HGNC:9588),PM1,Moderate,"Located in a mutational hot spot and/or critical and well-established functional domain. Defined to include residues in catalytic motifs: 90-94, 123-130, 166-168 (NP_ 000305.3)",Disease-specific
-PTEN (HGNC:9588),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-PTEN (HGNC:9588),PM2,Moderate,"Present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population. If multiple alleles are present within any subpopulation, allele frequency in that subpopulation must be <0.00002 (0.002%).",Disease-specific
-PTEN (HGNC:9588),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-PTEN (HGNC:9588),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-PTEN (HGNC:9588),PM4,Moderate,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Applies to in-frame insertions or deletions impacting at least one residue in a catalytic motif (see PM1), protein truncation with disruption starting 3’ of c.1121 (NM_000314.6), and variants causing protein extension.",Disease-specific
-PTEN (HGNC:9588),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-PTEN (HGNC:9588),PM5,Moderate,"Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic has been seen before. In addition, variant being interrogated must have BLOSUM62 score equal to or less than the known variant.",Disease-specific
-PTEN (HGNC:9588),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-PTEN (HGNC:9588),PM6,Very Strong,Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history.,Strength
-PTEN (HGNC:9588),PM6,Strong,Two probands with presumed de novo occurrence (maternity/ paternity not confirmed) with the disease and no family history,Strength
-PTEN (HGNC:9588),PM6,Moderate,"Assumed de novo, but without confirmation of paternity and maternity, in proband with the disease and no family history",None
-PTEN (HGNC:9588),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-PTEN (HGNC:9588),PP1,Strong,"Co-segregation with disease in multiple affected family members, with ≥7 meioses observed across at least two families.",Strength
-PTEN (HGNC:9588),PP1,Moderate,"Co-segregation with disease in multiple affected family members, with 5 or 6 meioses observed.",Strength
-PTEN (HGNC:9588),PP1,Supporting,"Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed.",Disease-specific
-PTEN (HGNC:9588),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,
-PTEN (HGNC:9588),PP2,Supporting,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,None
-PTEN (HGNC:9588),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-PTEN (HGNC:9588),PP3,Supporting,Multiple lines of computational evidence support a deleterious effect on the gene or gene product. To be applied only to synonymous or intronic variants where at least 2 out of 3 in silico models predict a splicing impact.,Disease-specific
-PTEN (HGNC:9588),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-PTEN (HGNC:9588),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-PTEN (HGNC:9588),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-PTEN (HGNC:9588),BA1,Stand Alone,"Allele frequency ≥0.01 (1%) in a studied population with ≥2,000 alleles tested and variant present in ≥5 alleles.",Disease-specific
-PTEN (HGNC:9588),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-PTEN (HGNC:9588),BS1,Strong,"Allele frequency from 0.001 (0.1%) up to 0.01 (1%) in a studied population with ≥2,000 alleles tested and variant present in ≥5 alleles.",Disease-specific
-PTEN (HGNC:9588),BS1,Supporting,"Allele frequency from 0.000043 (0.0043%) up to 0.001 (0.1%) in a studied population with ≥2,000 alleles tested and variant present in ≥5 alleles.","Strength,Disease-specific"
-PTEN (HGNC:9588),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-PTEN (HGNC:9588),BS2,Strong,"Observed in the homozygous state in a healthy or PHTS-unaffected individual. One observation if homozygous status confirmed, two if not confirmed. To be applied at supporting evidence level if BS1 is also applied.",Disease-specific
-PTEN (HGNC:9588),BS2,Supporting,"Two homozygous observations with no clinical data provided, or meets criteria for BS2 but BS1 is also applied.","Strength,Disease-specific"
-PTEN (HGNC:9588),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-PTEN (HGNC:9588),BS3,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function. To be applied for missense variants with both lipid phosphatase activity AND results from a second assay appropriate to the protein domain demonstrating no statistically significant difference from wild type. For intronic or synonymous variants, RNA, mini-gene or other splicing assay demonstrates no splicing impact.",Disease-specific
-PTEN (HGNC:9588),BS3,Supporting,In vitro or in vivo functional study or studies showing no damaging effect on protein function but BS3 not met.,"Strength,Disease-specific"
-PTEN (HGNC:9588),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-PTEN (HGNC:9588),BS4,Strong,Lack of segregation in affected members of two or more families.,Disease-specific
-PTEN (HGNC:9588),BS4,Supporting,Lack of segregation in affected members of one family.,"Strength,Disease-specific"
-PTEN (HGNC:9588),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-PTEN (HGNC:9588),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-PTEN (HGNC:9588),BP2,Supporting,Observed in trans with a pathogenic or likely pathogenic PTEN variant OR at least three observations in cis and/or phase unknown with different pathogenic/likely pathogenic PTEN variants.,Disease-specific
-PTEN (HGNC:9588),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-PTEN (HGNC:9588),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-PTEN (HGNC:9588),BP4,Supporting,Multiple lines of computational evidence suggest no impact on gene or gene product. To be applied only to synonymous or intronic variants where at least 2 out of 3 in silico models predict no splicing impact.,Disease-specific
-PTEN (HGNC:9588),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-PTEN (HGNC:9588),BP5,Supporting,Variant found in a case with an alternate molecular basis for disease. Other gene/disorder must be considered highly penetrant AND patient’s personal/family history must demonstrate no overlap between other gene and PTEN.,Disease-specific
-PTEN (HGNC:9588),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-PTEN (HGNC:9588),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-PTEN (HGNC:9588),BP7,Supporting,A synonymous (silent) or intronic variant at or beyond +7/-21 for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,Disease-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion1.0.0_version=1.0.0.csv
deleted file mode 100644
index d1721bba2b0a53574d94913f656e162c6948df89..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,95 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-PTEN (HGNC:9588),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-PTEN (HGNC:9588),PVS1,Very Strong,"Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multi-exon deletion) predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.6).",Disease-specific
-PTEN (HGNC:9588),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-PTEN (HGNC:9588),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change OR different variant at same nucleotide position as a pathogenic splicing variant, where in silico models predict impact equal to or greater than the known pathogenic variant.",Disease-specific
-PTEN (HGNC:9588),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-PTEN (HGNC:9588),PS2,Very Strong,Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history.,Strength
-PTEN (HGNC:9588),PS2,Strong,De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history.,None
-PTEN (HGNC:9588),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-PTEN (HGNC:9588),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-
-
-
-
-Phosphatase activity <50% of wild-type
-
-
-RNA, mini-gene, or other assay shows impact on splicing",Disease-specific
-PTEN (HGNC:9588),PS3,Supporting,Abnormal in vitro cellular assay or transgenic model with phenotype different from wild type that does not meet PS3.,"Disease-specific,Strength"
-PTEN (HGNC:9588),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-PTEN (HGNC:9588),PS4,Very Strong,Probands with specificity score ≥16 (see text).,Strength
-PTEN (HGNC:9588),PS4,Strong,Probands with specificity score 4-15.5 (see text) OR The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.,Strength
-PTEN (HGNC:9588),PS4,Moderate,Probands with specificity score of 2-3.5 (see text).,Strength
-PTEN (HGNC:9588),PS4,Supporting,Phenotype specific for disease with single genetic etiology. Proband(s) with specificity score of 1-1.5 (see text).,Disease-specific
-PTEN (HGNC:9588),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-PTEN (HGNC:9588),PM1,Moderate,"Located in a mutational hot spot and/or critical and well-established functional domain. Defined to include residues in catalytic motifs: 90-94, 123-130, 166-168 (NP_ 000305.3)",Disease-specific
-PTEN (HGNC:9588),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-PTEN (HGNC:9588),PM2,Moderate,"Present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population. If multiple alleles are present within any subpopulation, allele frequency in that subpopulation must be <0.00002 (0.002%).",Disease-specific
-PTEN (HGNC:9588),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-PTEN (HGNC:9588),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-PTEN (HGNC:9588),PM4,Moderate,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Applies to in-frame insertions or deletions impacting at least one residue in a catalytic motif (see PM1), protein truncation with disruption starting 3’ of c.1121 (NM_000314.6), and variants causing protein extension.",Disease-specific
-PTEN (HGNC:9588),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-PTEN (HGNC:9588),PM5,Moderate,"Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic has been seen before. In addition, variant being interrogated must have BLOSUM62 score equal to or less than the known variant.",Disease-specific
-PTEN (HGNC:9588),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-PTEN (HGNC:9588),PM6,Very Strong,Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history.,Strength
-PTEN (HGNC:9588),PM6,Strong,Two probands with presumed de novo occurrence (maternity/ paternity not confirmed) with the disease and no family history.,Strength
-PTEN (HGNC:9588),PM6,Moderate,"Assumed 
-de novo,
- but without confirmation of paternity and maternity, in proband with the disease and no family history.",None
-PTEN (HGNC:9588),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-PTEN (HGNC:9588),PP1,Strong,"Co-segregation with disease in multiple affected family members, with ≥7 meioses observed across at least two families.",Strength
-PTEN (HGNC:9588),PP1,Moderate,"Co-segregation with disease in multiple affected family members, with 5 or 6 meioses observed.",Strength
-PTEN (HGNC:9588),PP1,Supporting,"Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed.",Disease-specific
-PTEN (HGNC:9588),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,
-PTEN (HGNC:9588),PP2,Supporting,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,None
-PTEN (HGNC:9588),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-PTEN (HGNC:9588),PP3,Supporting,Multiple lines of computational evidence support a deleterious effect on the gene or gene product. To be applied only to synonymous or intronic variants where at least 2 out of 3 in silico models predict a splicing impact.,Disease-specific
-PTEN (HGNC:9588),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-PTEN (HGNC:9588),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-PTEN (HGNC:9588),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-PTEN (HGNC:9588),BA1,Stand Alone,"Allele frequency ≥0.01 (1%) in a studied population with ≥2,000 alleles tested and variant present in ≥5 alleles.",Disease-specific
-PTEN (HGNC:9588),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-PTEN (HGNC:9588),BS1,Strong,"Allele frequency from 0.001 (0.1%) up to 0.01 (1%) in a studied population with ≥2,000 alleles tested and variant present in ≥5 alleles.",Disease-specific
-PTEN (HGNC:9588),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-PTEN (HGNC:9588),BS2,Strong,"Observed in the homozygous state in a healthy or PHTS-unaffected individual. One observation if homozygous status confirmed, two if not confirmed. To be applied at supporting evidence level if BS1 is also applied.",Disease-specific
-PTEN (HGNC:9588),BS2,Supporting,"Two homozygous observations with no clinical data provided, or meets criteria for BS2 but BS1 is also applied.","Disease-specific,Strength"
-PTEN (HGNC:9588),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-PTEN (HGNC:9588),BS3,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function. To be applied for missense variants with both lipid phosphatase activity AND results from a second assay appropriate to the protein domain demonstrating no statistically significant difference from wild type. For intronic or synonymous variants, RNA, mini-gene or other splicing assay demonstrates no splicing impact.",Disease-specific
-PTEN (HGNC:9588),BS3,Supporting,"In vitro or
- 
-in vivo
- functional study or studies showing no damaging effect on protein function but BS3 not met.","Disease-specific,Strength"
-PTEN (HGNC:9588),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-PTEN (HGNC:9588),BS4,Strong,Lack of segregation in affected members of two or more families.,Disease-specific
-PTEN (HGNC:9588),BS4,Supporting,Lack of segregation in affected members of one family.,"Disease-specific,Strength"
-PTEN (HGNC:9588),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-PTEN (HGNC:9588),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-PTEN (HGNC:9588),BP2,Supporting,Observed in trans with a pathogenic or likely pathogenic PTEN variant OR at least three observations in cis and/or phase unknown with different pathogenic/likely pathogenic PTEN variants.,Disease-specific
-PTEN (HGNC:9588),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-PTEN (HGNC:9588),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-PTEN (HGNC:9588),BP4,Supporting,Multiple lines of computational evidence suggest no impact on gene or gene product. To be applied only to synonymous or intronic variants where at least 2 out of 3 in silico models predict no splicing impact.,Disease-specific
-PTEN (HGNC:9588),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-PTEN (HGNC:9588),BP5,Supporting,Variant found in a case with an alternate molecular basis for disease. Other gene/disorder must be considered highly penetrant AND patient’s personal/family history must demonstrate no overlap between other gene and PTEN.,Disease-specific
-PTEN (HGNC:9588),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-PTEN (HGNC:9588),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-PTEN (HGNC:9588),BP7,Supporting,A synonymous (silent) or intronic variant at or beyond +7/-21 for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,Disease-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.0.0_version=3.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.0.0_version=3.0.0.csv
deleted file mode 100644
index d313bc6e8c480aa9379aaab4f0d134615fa4f031..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.0.0_version=3.0.0.csv
+++ /dev/null
@@ -1,148 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-PTEN (HGNC:9588),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-PTEN (HGNC:9588),PVS1,Very Strong,Use PTEN PVS1 decision tree.,Disease-specific
-PTEN (HGNC:9588),PVS1,Strong,Use PTEN PVS1 decision tree.,Disease-specific
-PTEN (HGNC:9588),PVS1,Moderate,Use PTEN PVS1 decision tree.,Disease-specific
-PTEN (HGNC:9588),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-PTEN (HGNC:9588),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change OR different variant at same nucleotide position as a pathogenic splicing variant, where in silico models predict impact equal to or greater than the known pathogenic variant.",Disease-specific
-PTEN (HGNC:9588),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-PTEN (HGNC:9588),PS2,Very Strong,Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history.,Strength
-PTEN (HGNC:9588),PS2,Strong,De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history.,None
-PTEN (HGNC:9588),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-PTEN (HGNC:9588),PS3,Strong,"Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of a damaging effect on the gene or gene product.
-
-
-
-
-RNA, mini-gene, or other assay shows impact on splicing",Disease-specific
-PTEN (HGNC:9588),PS3,Moderate,"Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of a damaging effect on the gene or gene product.
-
-
-
-
-Phosphatase activity ≤ -1.11 per Mighell et al. 2018, PMID: 29706350.",Disease-specific
-PTEN (HGNC:9588),PS3,Supporting,"Phosphatase activity <50% of wild-type or abnormal 
-in vitro
- cellular assay or transgenic model with phenotype different from wild type that does not meet PS3_moderate.","Disease-specific,Strength"
-PTEN (HGNC:9588),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-PTEN (HGNC:9588),PS4,Very Strong,Probands with specificity score ≥16 (see text).,Strength
-PTEN (HGNC:9588),PS4,Strong,Probands with specificity score 4-15.5 (see text) OR The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.,Strength
-PTEN (HGNC:9588),PS4,Moderate,Probands with specificity score of 2-3.5 (see text).,Strength
-PTEN (HGNC:9588),PS4,Supporting,Phenotype specific for disease with single genetic etiology. Proband(s) with specificity score of 1-1.5 (see text).,Disease-specific
-PTEN (HGNC:9588),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-PTEN (HGNC:9588),PM1,Moderate,"Located in a mutational hot spot and/or critical and well-established functional domain. Defined to include residues in catalytic motifs: 90-94, 123-130, 166-168 (NP_ 000305.3)",Disease-specific
-PTEN (HGNC:9588),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-PTEN (HGNC:9588),PM2,Supporting,"Absent in population
-
-
-
-
-Databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population.  If multiple alleles are present within any subpopulation, allele frequency in that subpopulation must be <0.00002 (0.002%).",Disease-specific
-PTEN (HGNC:9588),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-PTEN (HGNC:9588),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-PTEN (HGNC:9588),PM4,Moderate,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Applies to in-frame insertions or deletions impacting at least one residue in a catalytic motif (see PM1), and variants causing protein extension.",Disease-specific
-PTEN (HGNC:9588),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-PTEN (HGNC:9588),PM5,Moderate,"Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic has been seen before. In addition, variant being interrogated must have BLOSUM62 score equal to or less than the known variant.",Disease-specific
-PTEN (HGNC:9588),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-PTEN (HGNC:9588),PM6,Very Strong,Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history.,Strength
-PTEN (HGNC:9588),PM6,Strong,"Two probands with presumed 
-de novo
- occurrence (maternity/ paternity not confirmed) with the disease and no family history.
-
-
-
-
-May also be used for a proband with presumed de novo occurrence for an individual with a highly specific phenotype (meets criteria to count towards PS4)",Strength
-PTEN (HGNC:9588),PM6,Moderate,"Assumed 
-de novo,
- but without confirmation of paternity and maternity, in proband with the disease and no family history.",None
-PTEN (HGNC:9588),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-PTEN (HGNC:9588),PP1,Strong,"Co-segregation with disease in multiple affected family members, with ≥7 meioses observed across at least two families.",Strength
-PTEN (HGNC:9588),PP1,Moderate,"Co-segregation with disease in multiple affected family members, with 5 or 6 meioses observed.",Strength
-PTEN (HGNC:9588),PP1,Supporting,"Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed.",Disease-specific
-PTEN (HGNC:9588),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,
-PTEN (HGNC:9588),PP2,Supporting,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,None
-PTEN (HGNC:9588),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-PTEN (HGNC:9588),PP3,Supporting,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product.
-
-
-
-
-Splicing variants: Concordance of SpliceAl and VarSeak
-
-
-Missense variants: REVEL score > 0.7",Disease-specific
-PTEN (HGNC:9588),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-PTEN (HGNC:9588),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-PTEN (HGNC:9588),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-PTEN (HGNC:9588),BA1,Stand Alone,gnomAD Filtering allele frequency >0.00056 (0.056%),Disease-specific
-PTEN (HGNC:9588),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-PTEN (HGNC:9588),BS1,Strong,gnomAD Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%),Disease-specific
-PTEN (HGNC:9588),BS1,Supporting,Allele frequency from 0.0000043 (0.00043%) up to 0.000043 (0.0043%).,"Disease-specific,Strength"
-PTEN (HGNC:9588),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-PTEN (HGNC:9588),BS2,Strong,"Observed in the homozygous state in a healthy or PHTS-unaffected individual. One observation if homozygous status confirmed, two if not confirmed. To be applied at supporting evidence level if BS1 is also applied.",Disease-specific
-PTEN (HGNC:9588),BS2,Supporting,"Two homozygous observations with no clinical data provided, or meets criteria for BS2 but BS1 is also applied.","Disease-specific,Strength"
-PTEN (HGNC:9588),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-PTEN (HGNC:9588),BS3,Strong,"Well-established 
-in vitro
- or 
-in vivo
- functional studies shows no damaging effect on protein function. To be applied to intronic or synonymous variants, RNA, mini-gene or other splicing assay demonstrating no splicing impact.",Disease-specific
-PTEN (HGNC:9588),BS3,Supporting,"In vitro
- or 
-in vivo
- functional study or studies showing no damaging effect on protein function.
-
-
-
-
-Phosphatase activity >0 per Mighell et al. 2018, PMID: 29706350.","Disease-specific,Strength"
-PTEN (HGNC:9588),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-PTEN (HGNC:9588),BS4,Strong,Lack of segregation in affected members of two or more families.,Disease-specific
-PTEN (HGNC:9588),BS4,Supporting,Lack of segregation in affected members of one family.,"Disease-specific,Strength"
-PTEN (HGNC:9588),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-PTEN (HGNC:9588),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-PTEN (HGNC:9588),BP2,Supporting,Observed in trans with a pathogenic or likely pathogenic PTEN variant OR at least three observations in cis and/or phase unknown with different pathogenic/likely pathogenic PTEN variants.,Disease-specific
-PTEN (HGNC:9588),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-PTEN (HGNC:9588),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-PTEN (HGNC:9588),BP4,Supporting,"Multiple lines of computational evidence suggest no impact on gene or gene product. 
-
-
-
-
-Splicing variants: Concordance of SpliceAl and VarSeak
-
-
-Missense variants: REVEL scores < 0.5",Disease-specific
-PTEN (HGNC:9588),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-PTEN (HGNC:9588),BP5,Supporting,Variant found in a case with an alternate molecular basis for disease. Other gene/disorder must be considered highly penetrant AND patient’s personal/family history must demonstrate no overlap between other gene and PTEN.,Disease-specific
-PTEN (HGNC:9588),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-PTEN (HGNC:9588),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-PTEN (HGNC:9588),BP7,Supporting,A synonymous (silent) or intronic variant at or beyond +7/-21 for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice.,Disease-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
deleted file mode 100644
index d313bc6e8c480aa9379aaab4f0d134615fa4f031..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
+++ /dev/null
@@ -1,148 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-PTEN (HGNC:9588),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-PTEN (HGNC:9588),PVS1,Very Strong,Use PTEN PVS1 decision tree.,Disease-specific
-PTEN (HGNC:9588),PVS1,Strong,Use PTEN PVS1 decision tree.,Disease-specific
-PTEN (HGNC:9588),PVS1,Moderate,Use PTEN PVS1 decision tree.,Disease-specific
-PTEN (HGNC:9588),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-PTEN (HGNC:9588),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change OR different variant at same nucleotide position as a pathogenic splicing variant, where in silico models predict impact equal to or greater than the known pathogenic variant.",Disease-specific
-PTEN (HGNC:9588),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-PTEN (HGNC:9588),PS2,Very Strong,Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history.,Strength
-PTEN (HGNC:9588),PS2,Strong,De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history.,None
-PTEN (HGNC:9588),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-PTEN (HGNC:9588),PS3,Strong,"Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of a damaging effect on the gene or gene product.
-
-
-
-
-RNA, mini-gene, or other assay shows impact on splicing",Disease-specific
-PTEN (HGNC:9588),PS3,Moderate,"Well-established 
-in vitro
- or 
-in vivo
- functional studies supportive of a damaging effect on the gene or gene product.
-
-
-
-
-Phosphatase activity ≤ -1.11 per Mighell et al. 2018, PMID: 29706350.",Disease-specific
-PTEN (HGNC:9588),PS3,Supporting,"Phosphatase activity <50% of wild-type or abnormal 
-in vitro
- cellular assay or transgenic model with phenotype different from wild type that does not meet PS3_moderate.","Disease-specific,Strength"
-PTEN (HGNC:9588),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-PTEN (HGNC:9588),PS4,Very Strong,Probands with specificity score ≥16 (see text).,Strength
-PTEN (HGNC:9588),PS4,Strong,Probands with specificity score 4-15.5 (see text) OR The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.,Strength
-PTEN (HGNC:9588),PS4,Moderate,Probands with specificity score of 2-3.5 (see text).,Strength
-PTEN (HGNC:9588),PS4,Supporting,Phenotype specific for disease with single genetic etiology. Proband(s) with specificity score of 1-1.5 (see text).,Disease-specific
-PTEN (HGNC:9588),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-PTEN (HGNC:9588),PM1,Moderate,"Located in a mutational hot spot and/or critical and well-established functional domain. Defined to include residues in catalytic motifs: 90-94, 123-130, 166-168 (NP_ 000305.3)",Disease-specific
-PTEN (HGNC:9588),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-PTEN (HGNC:9588),PM2,Supporting,"Absent in population
-
-
-
-
-Databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population.  If multiple alleles are present within any subpopulation, allele frequency in that subpopulation must be <0.00002 (0.002%).",Disease-specific
-PTEN (HGNC:9588),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-PTEN (HGNC:9588),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-PTEN (HGNC:9588),PM4,Moderate,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Applies to in-frame insertions or deletions impacting at least one residue in a catalytic motif (see PM1), and variants causing protein extension.",Disease-specific
-PTEN (HGNC:9588),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-PTEN (HGNC:9588),PM5,Moderate,"Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic has been seen before. In addition, variant being interrogated must have BLOSUM62 score equal to or less than the known variant.",Disease-specific
-PTEN (HGNC:9588),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-PTEN (HGNC:9588),PM6,Very Strong,Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history.,Strength
-PTEN (HGNC:9588),PM6,Strong,"Two probands with presumed 
-de novo
- occurrence (maternity/ paternity not confirmed) with the disease and no family history.
-
-
-
-
-May also be used for a proband with presumed de novo occurrence for an individual with a highly specific phenotype (meets criteria to count towards PS4)",Strength
-PTEN (HGNC:9588),PM6,Moderate,"Assumed 
-de novo,
- but without confirmation of paternity and maternity, in proband with the disease and no family history.",None
-PTEN (HGNC:9588),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-PTEN (HGNC:9588),PP1,Strong,"Co-segregation with disease in multiple affected family members, with ≥7 meioses observed across at least two families.",Strength
-PTEN (HGNC:9588),PP1,Moderate,"Co-segregation with disease in multiple affected family members, with 5 or 6 meioses observed.",Strength
-PTEN (HGNC:9588),PP1,Supporting,"Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed.",Disease-specific
-PTEN (HGNC:9588),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,
-PTEN (HGNC:9588),PP2,Supporting,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,None
-PTEN (HGNC:9588),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-PTEN (HGNC:9588),PP3,Supporting,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product.
-
-
-
-
-Splicing variants: Concordance of SpliceAl and VarSeak
-
-
-Missense variants: REVEL score > 0.7",Disease-specific
-PTEN (HGNC:9588),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-PTEN (HGNC:9588),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-PTEN (HGNC:9588),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-PTEN (HGNC:9588),BA1,Stand Alone,gnomAD Filtering allele frequency >0.00056 (0.056%),Disease-specific
-PTEN (HGNC:9588),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-PTEN (HGNC:9588),BS1,Strong,gnomAD Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%),Disease-specific
-PTEN (HGNC:9588),BS1,Supporting,Allele frequency from 0.0000043 (0.00043%) up to 0.000043 (0.0043%).,"Disease-specific,Strength"
-PTEN (HGNC:9588),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-PTEN (HGNC:9588),BS2,Strong,"Observed in the homozygous state in a healthy or PHTS-unaffected individual. One observation if homozygous status confirmed, two if not confirmed. To be applied at supporting evidence level if BS1 is also applied.",Disease-specific
-PTEN (HGNC:9588),BS2,Supporting,"Two homozygous observations with no clinical data provided, or meets criteria for BS2 but BS1 is also applied.","Disease-specific,Strength"
-PTEN (HGNC:9588),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-PTEN (HGNC:9588),BS3,Strong,"Well-established 
-in vitro
- or 
-in vivo
- functional studies shows no damaging effect on protein function. To be applied to intronic or synonymous variants, RNA, mini-gene or other splicing assay demonstrating no splicing impact.",Disease-specific
-PTEN (HGNC:9588),BS3,Supporting,"In vitro
- or 
-in vivo
- functional study or studies showing no damaging effect on protein function.
-
-
-
-
-Phosphatase activity >0 per Mighell et al. 2018, PMID: 29706350.","Disease-specific,Strength"
-PTEN (HGNC:9588),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-PTEN (HGNC:9588),BS4,Strong,Lack of segregation in affected members of two or more families.,Disease-specific
-PTEN (HGNC:9588),BS4,Supporting,Lack of segregation in affected members of one family.,"Disease-specific,Strength"
-PTEN (HGNC:9588),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-PTEN (HGNC:9588),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-PTEN (HGNC:9588),BP2,Supporting,Observed in trans with a pathogenic or likely pathogenic PTEN variant OR at least three observations in cis and/or phase unknown with different pathogenic/likely pathogenic PTEN variants.,Disease-specific
-PTEN (HGNC:9588),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-PTEN (HGNC:9588),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-PTEN (HGNC:9588),BP4,Supporting,"Multiple lines of computational evidence suggest no impact on gene or gene product. 
-
-
-
-
-Splicing variants: Concordance of SpliceAl and VarSeak
-
-
-Missense variants: REVEL scores < 0.5",Disease-specific
-PTEN (HGNC:9588),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-PTEN (HGNC:9588),BP5,Supporting,Variant found in a case with an alternate molecular basis for disease. Other gene/disorder must be considered highly penetrant AND patient’s personal/family history must demonstrate no overlap between other gene and PTEN.,Disease-specific
-PTEN (HGNC:9588),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-PTEN (HGNC:9588),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-PTEN (HGNC:9588),BP7,Supporting,A synonymous (silent) or intronic variant at or beyond +7/-21 for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice.,Disease-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
deleted file mode 100644
index 722cd8130ad89b2655f95ae675ebc0f4d8ab079b..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
+++ /dev/null
@@ -1,191 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-PAH (HGNC:8582),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-PAH (HGNC:8582),PVS1,Very Strong,"Applicable as described in Tayoun et al. 2018.
-
-
-
-
-Any nonsense or frameshift variant occurring upstream of c.1285
-
-
-Any canonical splice site predicted to disrupt reading frame and undergo nonsense mediated decay
-
-
-
-
-PVS1 (RNA): splicing assay data - assays demonstrating a variant leads to aberrant splicing profile that can be categorized against a PVS1 decision tree
-
-
-
-
-Use the PVS1 decision tree to determine code strength
-
-
-Applicable as described in Walker et al. (PMID: 36865205)",Disease-specific
-PAH (HGNC:8582),PVS1,Strong,"Use PVS1_strong with:
-
-
-
-
-Any nonsense or frameshift variant occurring downstream of c.1285
-
-
-Any canonical splice site predicted to preserve reading frame (skipping of exons 1, 9, 10) or affect the last exon (exon 13)
-
-
-Initiator codon variant",Disease-specific
-PAH (HGNC:8582),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-PAH (HGNC:8582),PS1,Strong,"Same predicted splicing impact as a previously classified (likely) pathogenic variant
-
-
-Applicable as described in Walker et al. (PMID: 36865205)",Disease-specific
-PAH (HGNC:8582),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-PAH (HGNC:8582),PS2,Strong,"Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. Only applicable when proband has a known pathogenic variant in trans with the de novo variant.",Disease-specific
-PAH (HGNC:8582),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-PAH (HGNC:8582),PS3,Moderate,"Functional studies with sufficient analyses to calculate OddsPath reaching strong have not been identified. Therefore, the strength of this criteria is modified to PS3_moderate or PS3_supporting for future or existing studies.
-
-
-In vitro enzyme activity <50% compared to wild type controls.
-
-
-
-
-Expression systems placing the mutant (and wild-type) cDNAs into plasmid vectors and introducing these into human or other mammalian host cells, which is the closest available approximation to the in vivo situation (e.g., COS cells) (Trunzo et al. Gene. 2016. 594:138-143. PMID: 27620137).
-
-
-With ≥11 benign/pathogenic variant controls used in assay
-
-
-NOTE: no papers that meet PS3_Moderate criteria have been identified by the PAH VCEP at time of this specification update. However, there may be future studies that meet the above criteria where a moderate level of evidence can be applied.",Disease-specific
-PAH (HGNC:8582),PS3,Supporting,"In vitro enzyme activity ≤50% compared to wild type controls
-
-
-
-
-with ≤10 benign/pathogenic variant controls used in assay",Strength
-PAH (HGNC:8582),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",NA
-PAH (HGNC:8582),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-PAH (HGNC:8582),PM1,Moderate,"Active site residues in PAH include: Tyr138, Arg158, Val245, Tyr268, Thr278, Pro279, Glu289, Ala300, Asp315, Phe331, Ala345, Gly346, Ser349, Tyr377
-
-
-Substrate binding residues in PAH are: 46-48, 63-69
-
-
-Cofactor binding residues in PAH are: His285, His290, Glu330, 246-266, 280-283, 322-326, 377-379
-
-
-Do not apply if PP3_Strong applies",Gene-specific
-PAH (HGNC:8582),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-PAH (HGNC:8582),PM2,Supporting,"Threshold <0.0002 (0.02%)
-
-
-
-
-The 0.0002 cutoff is based on disease frequency of 1:12,000 and the most common PAH pathogenic variant, R408W, the ExAC frequency is 0.0006594 (ExAC MAF: 0.001109 74/66718 European Non-Finnish) and gnomAD overall: 0.0009056 (gnomAD MAF: 0.001728 219/126,700 European Non-Finnish).",Strength
-PAH (HGNC:8582),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-PAH (HGNC:8582),PM3,Very Strong,Applicable as described in SVI recommendations for in trans criterion,Strength
-PAH (HGNC:8582),PM3,Strong,Applicable as described in SVI recommendations for in trans criterion,Strength
-PAH (HGNC:8582),PM3,Moderate,Applicable as described in SVI recommendations for in trans criterion,Strength
-PAH (HGNC:8582),PM3,Supporting,Applicable as described in SVI recommendations for in trans criterion,Strength
-PAH (HGNC:8582),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-PAH (HGNC:8582),PM4,Moderate,Applicable as described,No change
-PAH (HGNC:8582),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-PAH (HGNC:8582),PM5,Moderate,Applicable as described.,No change
-PAH (HGNC:8582),PM5,Supporting,Applicable when the different missense change is likely pathogenic.,Strength
-PAH (HGNC:8582),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-PAH (HGNC:8582),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-PAH (HGNC:8582),PP1,Strong,"3 affected segregations + 0 unaffected segregations OR
-
-
-2 affected segregations + 3 unaffected segregations",Strength
-PAH (HGNC:8582),PP1,Moderate,2 affected segregations + 0 unaffected segregations,Strength
-PAH (HGNC:8582),PP1,Supporting,1 affected family member + 3 unaffected segregations,Strength
-PAH (HGNC:8582),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-PAH (HGNC:8582),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-PAH (HGNC:8582),PP3,Strong,"Applicable as described in Pejaver et al (PMID: 36413997): REVEL score ≥0.932 for missense variants
-
-
-PP3 + PM1 should not exceed Strong",Strength
-PAH (HGNC:8582),PP3,Moderate,Applicable as described in Pejaver et al (PMID: 36413997): REVEL score 0.773 - 0.932 for missense variants,Strength
-PAH (HGNC:8582),PP3,Supporting,"Applicable as described in Pejaver et al. (PMID: 36413997):
-
-
-
-
-REVEL score of 0.644 - 0.733 for missense variants
-
-
-In frame deletion or insertion predicted deleterious by 2 out of 3 tools (PROVEAN, MutationTaster, MutPred-InDel)
-
-
-Predicted impact on splicing by SpliceAI (score >0.5)",Strength
-PAH (HGNC:8582),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-PAH (HGNC:8582),PP4,Moderate,"Plasma phenylalanine concentration persistently above 120 µmol/L (2mg/dL), and either normal urine pterins and normal DHPR activity, or sequencing of genes in the BH4 cofactor metabolism pathway to exclude a defect of BH4 cofactor metabolism.","Disease-specific,Strength"
-PAH (HGNC:8582),PP4,Supporting,"A plasma phenylalanine concentration persistently above 120umol/L (2mg/dL) without analysis of urine pterins, DHPR activity, or sequencing to exclude defects of BH4 cofactor metabolism.",Strength
-PAH (HGNC:8582),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-PAH (HGNC:8582),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-PAH (HGNC:8582),BA1,Stand Alone,"An allele frequency ≥0.015 (1.5%), which is calculated with genetic heterogeneity of 90% to account for defects of BH4 metabolism, and penetrance of 80% to account for individuals who come to attention after becoming clinically symptomatic.",Disease-specific
-PAH (HGNC:8582),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-PAH (HGNC:8582),BS1,Strong,Allele frequency ≥0.002 (0.2%),Disease-specific
-PAH (HGNC:8582),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-PAH (HGNC:8582),BS2,Strong,Only to be used when variant is observed in the homozygous state in a healthy adult.,None
-PAH (HGNC:8582),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-PAH (HGNC:8582),BS3,Supporting,"In vitro enzyme activity >85% compared to wild type
-
-
-
-
-Expression systems: placing the mutant (and wildtype) cDNA into plasmid vectors and introducing these into host cells. Transiently transfected human or other mammalian host cells are the closest available approximation to the in vivo situation (e.g., COS cells) (Trunzo, et al. Gene. 2016. 594:138-143).","Disease-specific,Strength"
-PAH (HGNC:8582),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-PAH (HGNC:8582),BS4,Strong,Applicable as described,None
-PAH (HGNC:8582),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-PAH (HGNC:8582),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-PAH (HGNC:8582),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-PAH (HGNC:8582),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-PAH (HGNC:8582),BP4,Strong,Applicable as described in Pejaver et al.,No change
-PAH (HGNC:8582),BP4,Moderate,Applicable as described in Pejaver et al.,No change
-PAH (HGNC:8582),BP4,Supporting,"Applicable as described in Pejaver et al.
-
-
-
-
-REVEL score of 0.183 - 0.290 for missense variants
-
-
-In frame deletion or insertion predicted benign by PROVEAN, MutationTaster, and MutPred-InDel
-
-
-No predicted impact on splicing by SpliceAI (score <0.1)","Gene-specific,None"
-PAH (HGNC:8582),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-PAH (HGNC:8582),BP5,Supporting,Applicable as described,No change
-PAH (HGNC:8582),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-PAH (HGNC:8582),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-PAH (HGNC:8582),BP7,Strong,Applicable as described by Walker et al. (PMID: 36865205).,Strength
-PAH (HGNC:8582),BP7,Supporting,"Per SVI recommendations (PMID: 36865205), use BP7 only if BP4 is met; for variants with experimental evidence supporting that they do not alter splicing, use BP7_strong (RNA)
-
-
-
-
-intronic variants must be outside +7/-21 nt
-
-
-exonic variants must be outside first and last 3 bases of exon","Gene-specific,None"
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2.0_version=2.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2.0_version=2.0.0.csv
deleted file mode 100644
index cb752fb0941b063bf918b42c16552dcbe1ad36d4..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2.0_version=2.0.0.csv
+++ /dev/null
@@ -1,140 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-ITGA2B (HGNC:6138),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7)
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact
- • Use caution in the presence of multiple transcripts",
-ITGA2B (HGNC:6138),PVS1,Very Strong,Use decision tree as per SVI WG with specified “regions critical to protein function”.,
-ITGA2B (HGNC:6138),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level",
-ITGA2B (HGNC:6138),PS1,Strong,Use with no specification.,
-ITGA2B (HGNC:6138),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity",
-ITGA2B (HGNC:6138),PS2,Strong,"Use proposed SVI point recommendations.
-
-
-
-
-Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant",
-ITGA2B (HGNC:6138),PS2,Moderate,"Use proposed SVI point recommendations.
-
-
-
-
-Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant",
-ITGA2B (HGNC:6138),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established",
-ITGA2B (HGNC:6138),PS3,Strong,"In a transgenic animal model, must demonstrate minimal to no function.
-OR
-
-
-In a model organism or heterologous cell line, EITHER (A) when expression is normal or reduced, disruption of protein function must be demonstrated OR (B) Absent surface protein expression (<5%).",
-ITGA2B (HGNC:6138),PS3,Moderate,"In a model organism or heterologous cell line, significantly reduced surface protein expression (5-25%).",
-ITGA2B (HGNC:6138),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-ITGA2B (HGNC:6138),PS4,Strong,Rule does not apply due to rarity of disorder and lack of appropriate studies.,
-ITGA2B (HGNC:6138),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation,
-ITGA2B (HGNC:6138),PM1,Moderate,Rule does not apply due to genes being highly polymorphic.,
-ITGA2B (HGNC:6138),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium
-Caveat: Population data for indels may be poorly called by next generation sequencing",
-ITGA2B (HGNC:6138),PM2,Moderate,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium",
-ITGA2B (HGNC:6138),PM2,Supporting,"Prevalence <1/10,000 (<0.0001) alleles in gnomAD.",
-ITGA2B (HGNC:6138),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase",
-ITGA2B (HGNC:6138),PM3,Very Strong,Use proposed SVI point recommendations. Both variants must be classified using ITGA2B/ITGB3 Rule Specifications.,
-ITGA2B (HGNC:6138),PM3,Strong,Use proposed SVI point recommendations. Both variants must be classified using ITGA2B/ITGB3 Rule Specifications.,
-ITGA2B (HGNC:6138),PM3,Moderate,Use proposed SVI point recommendations. Both variants must be classified using ITGA2B/ITGB3 Rule Specifications.,
-ITGA2B (HGNC:6138),PM3,Supporting,Use proposed SVI point recommendations. Both variants must be classified using ITGA2B/ITGB3 Rule Specifications.,
-ITGA2B (HGNC:6138),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-ITGA2B (HGNC:6138),PM4,Moderate,Use with no specification.,
-ITGA2B (HGNC:6138),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
-Example: Arg156His is pathogenic; now you observe Arg156Cys
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level",
-ITGA2B (HGNC:6138),PM5,Moderate,Use with no specification.,
-ITGA2B (HGNC:6138),PM5,Supporting,Use at adjusted strength.,
-ITGA2B (HGNC:6138),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity",
-ITGA2B (HGNC:6138),PM6,Very Strong,"Use proposed SVI point recommendations.
-
-
-
-
-Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant",
-ITGA2B (HGNC:6138),PM6,Strong,"Use proposed SVI point recommendations.
-
-
-
-
-Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant",
-ITGA2B (HGNC:6138),PM6,Moderate,"Use proposed SVI point recommendations.
-
-
-
-
-Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant",
-ITGA2B (HGNC:6138),PM6,Supporting,"Use proposed SVI point recommendations.
-
-
-
-
-Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant",
-ITGA2B (HGNC:6138),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease
-Note: May be used as stronger evidence with increasing segregation data",
-ITGA2B (HGNC:6138),PP1,Strong,"Segregations in proband plus >2 affected relatives.
-
-
-
-
-Affected relatives must have both variants identified in proband.",
-ITGA2B (HGNC:6138),PP1,Moderate,"Segregation in proband plus 2 affected relatives.
-
-
-
-
-Affected relatives must have both variants identified in proband.",
-ITGA2B (HGNC:6138),PP1,Supporting,"Segregation in proband plus 1 affected relative.
-
-
-
-
-Affected relatives must have both variants identified in proband.",
-ITGA2B (HGNC:6138),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease,NA
-ITGA2B (HGNC:6138),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-ITGA2B (HGNC:6138),PP3,Supporting,REVEL score of ≥ 0.7 OR >2 independent in silico missense predictors predict a damaging impact.,
-ITGA2B (HGNC:6138),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology,
-ITGA2B (HGNC:6138),PP4,Strong,Proband with clinical diagnosis of GT based on the presence of mucocutaneous bleeding and appropriate lab abnormalities. Full sequencing of both genes is required at this strength,
-ITGA2B (HGNC:6138),PP4,Moderate,Proband with clinical diagnosis of GT based on the presence of mucocutaneous bleeding and appropriate lab abnormalities.,
-ITGA2B (HGNC:6138),PP4,Supporting,Patients phenotype or family history is highly specific for a disease with a single genetic etiology,
-ITGA2B (HGNC:6138),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-ITGA2B (HGNC:6138),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium",
-ITGA2B (HGNC:6138),BA1,Stand Alone,Frequency cutoff of 0.24% (>0.0024 at 99.99% CI w/subpopulation w/min of 5 alleles).,
-ITGA2B (HGNC:6138),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-ITGA2B (HGNC:6138),BS1,Strong,Frequency cutoff of 0.158% (>0.00158 at 99.99% CI w/subpopulation w/min of 5 alleles),
-ITGA2B (HGNC:6138),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age",
-ITGA2B (HGNC:6138),BS2,Strong,1 homozygote who is unaffected proven with at least aggregometry.,
-ITGA2B (HGNC:6138),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-ITGA2B (HGNC:6138),BS3,Strong,"Must demonstrate normal aggregometry in a transgenic mouse model.
- OR
-
-
-In a heterologous cell line, must demonstrate BOTH normal expression and normal protein function",
-ITGA2B (HGNC:6138),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation",
-ITGA2B (HGNC:6138),BS4,Strong,Variant not detected in an affected family member.,
-ITGA2B (HGNC:6138),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease,
-ITGA2B (HGNC:6138),BP1,Supporting,Rule does not apply as truncating variants do not predominate and missense variants are a known cause of disease.,
-ITGA2B (HGNC:6138),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-ITGA2B (HGNC:6138),BP2,Supporting,Use as written for recessive variants (i.e. - variant must be observed in cis with a pathogenic variant),
-ITGA2B (HGNC:6138),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-ITGA2B (HGNC:6138),BP3,Supporting,Use with no specification,
-ITGA2B (HGNC:6138),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-ITGA2B (HGNC:6138),BP4,Supporting,REVEL score of < 0.25,
-ITGA2B (HGNC:6138),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-ITGA2B (HGNC:6138),BP5,Supporting,Do not use this rule as an individual can be a carrier of an unrelated pathogenic variant for a recessive disorder.,
-ITGA2B (HGNC:6138),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-ITGA2B (HGNC:6138),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-ITGA2B (HGNC:6138),BP7,Supporting,Use with no specification.,
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2.1_version=2.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2.1_version=2.1.0.csv
deleted file mode 100644
index dee13473b19e1c53865e1a533b41e6139c6d9ad6..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2.1_version=2.1.0.csv
+++ /dev/null
@@ -1,151 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-ITGA2B (HGNC:6138),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-ITGA2B (HGNC:6138),PVS1,Very Strong,Use decision tree as per SVI WG with specified “regions critical to protein function”.,
-ITGA2B (HGNC:6138),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-ITGA2B (HGNC:6138),PS1,Strong,Use with no specification.,
-ITGA2B (HGNC:6138),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-ITGA2B (HGNC:6138),PS2,Strong,"Use proposed SVI point recommendations.
-
-
-
-
-Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant",
-ITGA2B (HGNC:6138),PS2,Moderate,"Use proposed SVI point recommendations.
-
-
-
-
-Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant",
-ITGA2B (HGNC:6138),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-ITGA2B (HGNC:6138),PS3,Strong,"In a transgenic animal model, must demonstrate minimal to no function.
-OR
-
-
-In a model organism or heterologous cell line, EITHER (A) when expression is normal or reduced, disruption of protein function must be demonstrated OR (B) Absent surface protein expression (<5%).",
-ITGA2B (HGNC:6138),PS3,Moderate,"In a model organism or heterologous cell line, significantly reduced surface protein expression (5
-
-
-
-
-25%).",
-ITGA2B (HGNC:6138),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-ITGA2B (HGNC:6138),PS4,Strong,Rule does not apply due to rarity of disorder and lack of appropriate studies.,
-ITGA2B (HGNC:6138),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-ITGA2B (HGNC:6138),PM1,Moderate,Rule does not apply due to genes being highly polymorphic.,
-ITGA2B (HGNC:6138),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-ITGA2B (HGNC:6138),PM2,Moderate,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium",
-ITGA2B (HGNC:6138),PM2,Supporting,"Prevalence <1/10,000 (<0.0001) alleles in gnomAD.",
-ITGA2B (HGNC:6138),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-ITGA2B (HGNC:6138),PM3,Very Strong,Use proposed SVI point recommendations. Both variants must be classified using ITGA2B/ITGB3 Rule Specifications.,
-ITGA2B (HGNC:6138),PM3,Strong,Use proposed SVI point recommendations. Both variants must be classified using ITGA2B/ITGB3 Rule Specifications.,
-ITGA2B (HGNC:6138),PM3,Moderate,Use proposed SVI point recommendations. Both variants must be classified using ITGA2B/ITGB3 Rule Specifications.,
-ITGA2B (HGNC:6138),PM3,Supporting,Use proposed SVI point recommendations. Both variants must be classified using ITGA2B/ITGB3 Rule Specifications.,
-ITGA2B (HGNC:6138),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-ITGA2B (HGNC:6138),PM4,Moderate,Use with no specification.,
-ITGA2B (HGNC:6138),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-ITGA2B (HGNC:6138),PM5,Moderate,Use with no specification.,
-ITGA2B (HGNC:6138),PM5,Supporting,Use at adjusted strength.,
-ITGA2B (HGNC:6138),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-ITGA2B (HGNC:6138),PM6,Very Strong,"Use proposed SVI point recommendations.
-
-
-
-
-Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant",
-ITGA2B (HGNC:6138),PM6,Strong,"Use proposed SVI point recommendations.
-
-
-
-
-Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant",
-ITGA2B (HGNC:6138),PM6,Moderate,"Use proposed SVI point recommendations.
-
-
-
-
-Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant",
-ITGA2B (HGNC:6138),PM6,Supporting,"Use proposed SVI point recommendations.
-
-
-
-
-Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant",
-ITGA2B (HGNC:6138),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-ITGA2B (HGNC:6138),PP1,Strong,"Segregations in proband plus >2 affected relatives.
-
-
-
-
-Affected relatives must have both variants identified in proband.",
-ITGA2B (HGNC:6138),PP1,Moderate,"Segregation in proband plus 2 affected relatives.
-
-
-
-
-Affected relatives must have both variants identified in proband.",
-ITGA2B (HGNC:6138),PP1,Supporting,"Segregation in proband plus 1 affected relative.
-
-
-
-
-Affected relatives must have both variants identified in proband.",
-ITGA2B (HGNC:6138),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-ITGA2B (HGNC:6138),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-ITGA2B (HGNC:6138),PP3,Supporting,"REVEL score of ≥ 0.7
-  OR
-
-
-
-
-2 independent in silico missense predictors predict a damaging impact",
-ITGA2B (HGNC:6138),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-ITGA2B (HGNC:6138),PP4,Strong,Proband with clinical diagnosis of GT based on the presence of mucocutaneous bleeding and appropriate lab abnormalities. Full sequencing of both genes is required at this strength,
-ITGA2B (HGNC:6138),PP4,Moderate,Proband with clinical diagnosis of GT based on the presence of mucocutaneous bleeding and appropriate lab abnormalities.,
-ITGA2B (HGNC:6138),PP4,Supporting,Patients phenotype or family history is highly specific for a disease with a single genetic etiology,
-ITGA2B (HGNC:6138),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-ITGA2B (HGNC:6138),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-ITGA2B (HGNC:6138),BA1,Stand Alone,Frequency cutoff of 0.24% (>0.0024 at 99.99% CI w/subpopulation w/min of 5 alleles).,
-ITGA2B (HGNC:6138),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-ITGA2B (HGNC:6138),BS1,Strong,Frequency cutoff of 0.158% (>0.00158 at 99.99% CI w/subpopulation w/min of 5 alleles),
-ITGA2B (HGNC:6138),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-ITGA2B (HGNC:6138),BS2,Strong,1 homozygote who is unaffected proven with at least aggregometry.,
-ITGA2B (HGNC:6138),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-ITGA2B (HGNC:6138),BS3,Strong,"Must demonstrate normal aggregometry in a transgenic mouse model.
- OR
-
-
-In a heterologous cell line, must demonstrate BOTH normal expression and normal protein function",
-ITGA2B (HGNC:6138),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-ITGA2B (HGNC:6138),BS4,Strong,Variant not detected in an affected family member.,
-ITGA2B (HGNC:6138),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-ITGA2B (HGNC:6138),BP1,Supporting,Rule does not apply as truncating variants do not predominate and missense variants are a known cause of disease.,
-ITGA2B (HGNC:6138),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-ITGA2B (HGNC:6138),BP2,Supporting,Use as written for recessive variants (i.e. - variant must be observed in cis with a pathogenic variant),
-ITGA2B (HGNC:6138),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-ITGA2B (HGNC:6138),BP3,Supporting,Use with no specification,
-ITGA2B (HGNC:6138),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-ITGA2B (HGNC:6138),BP4,Supporting,REVEL score of < 0.25,
-ITGA2B (HGNC:6138),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-ITGA2B (HGNC:6138),BP5,Supporting,Do not use this rule as an individual can be a carrier of an unrelated pathogenic variant for a recessive disorder.,
-ITGA2B (HGNC:6138),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-ITGA2B (HGNC:6138),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-ITGA2B (HGNC:6138),BP7,Supporting,Use with no specification.,
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGP1BAVersion1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGP1BAVersion1.0.0_version=1.0.0.csv
deleted file mode 100644
index 6bf6ecab6cfd2a07448d0ac0c2d88478ec895180..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGP1BAVersion1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,115 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-GP1BA (HGNC:4439),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-GP1BA (HGNC:4439),PVS1,Very Strong,"Use 
-GP1BA
- modified decision tree as per SVI WG.",Gene-specific
-GP1BA (HGNC:4439),PVS1,Strong,"Use 
-GP1BA
- modified decision tree as per SVI WG.",Gene-specific
-GP1BA (HGNC:4439),PVS1,Moderate,"Use 
-GP1BA
- modified decision tree as per SVI WG.",Gene-specific
-GP1BA (HGNC:4439),PVS1,Supporting,"Use 
-GP1BA
- modified decision tree as per SVI WG.",Gene-specific
-GP1BA (HGNC:4439),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-GP1BA (HGNC:4439),PS1,Strong,"Use as originally specified, but the comparison variant must reach a pathogenic classification using these rule specifications in order to apply code.",General recommendation
-GP1BA (HGNC:4439),PS1,Moderate,"Use as originally specified, but the comparison variant must reach a likely pathogenic classification using these rule specifications in order to apply code.",General recommendation
-GP1BA (HGNC:4439),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-GP1BA (HGNC:4439),PS2,Very Strong,Use proposed SVI point recommendations. See further instruction below. Total of 4 points.,Disease-specific
-GP1BA (HGNC:4439),PS2,Strong,Use proposed SVI point recommendations. See further instruction below. Total of 2 points.,Disease-specific
-GP1BA (HGNC:4439),PS2,Moderate,Use proposed SVI point recommendations. See further instruction below. Total of 1 point.,Disease-specific
-GP1BA (HGNC:4439),PS2,Supporting,Use proposed SVI point recommendations. See further instruction below. Total of 0.5 point.,Disease-specific
-GP1BA (HGNC:4439),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-GP1BA (HGNC:4439),PS3,Strong,"In a transgenic animal model, must demonstrate minimal to no function.",Disease-specific
-GP1BA (HGNC:4439),PS3,Supporting,"Functional assays measuring quantity of GP1ba expression on cell surface measured by flow cytometry analysis of GPIb and GPIX when there is absent or near absent expression, >75% reduction (see spreadsheet for more detail).",Disease-specific
-GP1BA (HGNC:4439),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-GP1BA (HGNC:4439),PS4,Moderate,See instructions below for scoring heterozygous individuals only. Moderate strength applicable for score of 2+ points.,Disease-specific
-GP1BA (HGNC:4439),PS4,Supporting,See instructions below for scoring heterozygous individuals only. Supporting strength applicable for scores ranging from 1-1.75,Disease-specific
-GP1BA (HGNC:4439),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-GP1BA (HGNC:4439),PM1,Moderate,"Disulfide bonds in GPIb are well-established as critical to function, both for interaction with GPIX (PMID: 12036872) and receptor binding to von Willebrand factor (PMID: 18647229). PM1 can be applied when the following cysteine residues (at which there are no known benign variants) are altered: 20, 33, 225, 227, 264, 280, 526, 527.",Gene-specific
-GP1BA (HGNC:4439),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-GP1BA (HGNC:4439),PM2,Supporting,gnomAD MAF of less than or equal to 0.0001114.,"Disease-specific,Gene-specific"
-GP1BA (HGNC:4439),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-GP1BA (HGNC:4439),PM3,Very Strong,Use proposed SVI point recommendations. Both variants must be classified using these rule specifications.,Disease-specific
-GP1BA (HGNC:4439),PM3,Strong,Use proposed SVI point recommendations. Both variants must be classified using these rule specifications.,Disease-specific
-GP1BA (HGNC:4439),PM3,Moderate,Use proposed SVI point recommendations. Both variants must be classified using these rule specifications.,Disease-specific
-GP1BA (HGNC:4439),PM3,Supporting,Use proposed SVI point recommendations. Both variants must be classified using these rule specifications.,Disease-specific
-GP1BA (HGNC:4439),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-GP1BA (HGNC:4439),PM4,Moderate,Use with no specification.,No change
-GP1BA (HGNC:4439),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-GP1BA (HGNC:4439),PM5,Moderate,"Use as originally specified, but the comparison variant must reach a pathogenic classification using the these rule specifications in order to apply code.",General recommendation
-GP1BA (HGNC:4439),PM5,Supporting,"Use as originally specified, but the comparison variant must reach a likely pathogenic classification using the these rule specifications in order to apply code.",General recommendation
-GP1BA (HGNC:4439),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-GP1BA (HGNC:4439),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-GP1BA (HGNC:4439),PP1,Strong,See instructions below for scoring system. Total segregation score 3+ points.,Disease-specific
-GP1BA (HGNC:4439),PP1,Moderate,See instructions below for scoring system. Total segregation score 2-2.75 points.,Disease-specific
-GP1BA (HGNC:4439),PP1,Supporting,See instructions below for scoring system. Total segregation score 1-1.75 points.,Disease-specific
-GP1BA (HGNC:4439),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-GP1BA (HGNC:4439),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-GP1BA (HGNC:4439),PP3,Moderate,"REVEL score of ≥0.773 based on recommendations of Pejaver et al., 2022 (PMID: 36413997).",Gene-specific
-GP1BA (HGNC:4439),PP3,Supporting,"REVEL score of ≥0.644 (to <0.773), based on recommendations of Pejaver et al., 2022 (PMID: 36413997).
-
-
-OR suggested splicing effect using SpliceAI greater than or equal to 0.5.",Gene-specific
-GP1BA (HGNC:4439),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-GP1BA (HGNC:4439),PP4,Moderate,"Must meet both criteria:
-
-
-1)Proband with platelet aggregation study absent for ristocetin and present for all other agonists OR flow cytometry or Western blot less than 10% expression of GPIba.
-
-
-2)Proband must have full sequencing of all three BSS genes (
-GP1BA, GP1BB
- and 
-GP9
-) and deletion/duplication analysis.",Disease-specific
-GP1BA (HGNC:4439),PP4,Supporting,"Proband with platelet aggregation study absent for ristocetin and present for all other agonists, OR 
-
-
-Flow cytometry or Western blot less than 10% expression of GPIba.",Disease-specific
-GP1BA (HGNC:4439),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-GP1BA (HGNC:4439),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-GP1BA (HGNC:4439),BA1,Stand Alone,gnomAD MAF of greater than or equal to 0.001 (or 0.1%).,Gene-specific
-GP1BA (HGNC:4439),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-GP1BA (HGNC:4439),BS1,Strong,gnomAD MAF greater than or equal to 0.0005 but less than 0.001.,Gene-specific
-GP1BA (HGNC:4439),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-GP1BA (HGNC:4439),BS2,Strong,Use this rule with 1 or more homozygotes who are unaffected (proven with aggregometry OR flow cytometry AND normal platelet count AND normal platelet size).,Disease-specific
-GP1BA (HGNC:4439),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-GP1BA (HGNC:4439),BS3,Strong,Must demonstrate normal aggregometry in a transgenic mouse model,Disease-specific
-GP1BA (HGNC:4439),BS3,Supporting,"In a heterologous cell line, must demonstrate BOTH normal expression and normal protein function as compared to wildtype.",Disease-specific
-GP1BA (HGNC:4439),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-GP1BA (HGNC:4439),BS4,Strong,Variant not tracking in an affected family member.,Disease-specific
-GP1BA (HGNC:4439),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-GP1BA (HGNC:4439),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-GP1BA (HGNC:4439),BP2,Supporting,Use as written for recessive variants (i.e. - variant must be observed in cis with a pathogenic variant).,Disease-specific
-GP1BA (HGNC:4439),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-GP1BA (HGNC:4439),BP3,Supporting,Use with no specification,None
-GP1BA (HGNC:4439),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-GP1BA (HGNC:4439),BP4,Supporting,"For a missense variant apply when REVEL score is < 0.290, based on recommendations of Pejaver et al., 2022 (PMID: 36413997) AND SpliceAI score is zero.
-
-
-OR for a synonymous or intronic variant apply when SpliceAI score is zero.",Gene-specific
-GP1BA (HGNC:4439),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-GP1BA (HGNC:4439),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-GP1BA (HGNC:4439),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-GP1BA (HGNC:4439),BP7,Supporting,Use SpliceAI to rule out possible splicing defect (score = 0.2 or less) and reference PhyloP (score = 1.5 or less) to assess conservation.,Gene-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGP1BBVersion1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGP1BBVersion1.0.0_version=1.0.0.csv
deleted file mode 100644
index aebcecf89f1b4b595bdb8c70e45e098f39f59706..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGP1BBVersion1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,126 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-GP1BB (HGNC:4440),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-GP1BB (HGNC:4440),PVS1,Very Strong,"Use 
-GP1BB
- modified decision tree as per SVI WG.",Gene-specific
-GP1BB (HGNC:4440),PVS1,Strong,"Use 
-GP1BB
- modified decision tree as per SVI WG.",Gene-specific
-GP1BB (HGNC:4440),PVS1,Moderate,"Use 
-GP1BB
- modified decision tree as per SVI WG.",Gene-specific
-GP1BB (HGNC:4440),PVS1,Supporting,"Use 
-GP1BB
- modified decision tree as per SVI WG.",Gene-specific
-GP1BB (HGNC:4440),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-GP1BB (HGNC:4440),PS1,Strong,"Use as originally specified, but the comparison variant must reach a pathogenic classification using the these rule specifications in order to apply code.",General recommendation
-GP1BB (HGNC:4440),PS1,Moderate,"Use as originally specified, but the comparison variant must reach a likely pathogenic classification using the these rule specifications in order to apply code.",General recommendation
-GP1BB (HGNC:4440),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-GP1BB (HGNC:4440),PS2,Very Strong,Use proposed SVI point recommendations. See further instruction below. Total of 4 points.,Disease-specific
-GP1BB (HGNC:4440),PS2,Strong,Use proposed SVI point recommendations. See further instruction below. Total of 2 points.,Disease-specific
-GP1BB (HGNC:4440),PS2,Moderate,Use proposed SVI point recommendations. See further instruction below. Total of 1 point.,Disease-specific
-GP1BB (HGNC:4440),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-GP1BB (HGNC:4440),PS3,Strong,"In a transgenic animal model, must demonstrate minimal to no function.",Disease-specific
-GP1BB (HGNC:4440),PS3,Supporting,Functional assays measuring quantity of GP1ba and/or GPIX expression on cell surface measured by flow cytometry (see spreadsheet for more detail).,Disease-specific
-GP1BB (HGNC:4440),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-GP1BB (HGNC:4440),PS4,Moderate,See instructions below for scoring heterozygous individuals only. Moderate strength applicable for score of 2+ points.,Disease-specific
-GP1BB (HGNC:4440),PS4,Supporting,See instructions below for scoring heterozygous individuals only. Supporting strength applicable for scores ranging from 1-1.75,Disease-specific
-GP1BB (HGNC:4440),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-GP1BB (HGNC:4440),PM1,Moderate,"Disulfide bonds in GPIb are well-established as critical to function, both for interaction with GPIX (PMID: 12036872) and receptor binding to von Willebrand factor (PMID: 18647229). PM1 can be applied when the following cysteine residues (at which there are no known benign variants) are altered: 93, 95, 118, 141, and 147.",Gene-specific
-GP1BB (HGNC:4440),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-GP1BB (HGNC:4440),PM2,Supporting,gnomAD MAF of less than or equal to 0.00006517.,"Disease-specific,Gene-specific"
-GP1BB (HGNC:4440),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-GP1BB (HGNC:4440),PM3,Very Strong,"Use proposed SVI point recommendations. Both variants must be classified using these rule specifications, with the exception that a 22q11.2 deletion in trans (
-https://www.ncbi.nlm.nih.gov/books/NBK1523/
-) may be automatically scored 1pt with confirmation that deletion includes the 
-GP1BB
- gene.",General recommendation
-GP1BB (HGNC:4440),PM3,Strong,"Use proposed SVI point recommendations. Both variants must be classified using these rule specifications, with the exception that a 22q11.2 deletion in trans (
-https://www.ncbi.nlm.nih.gov/books/NBK1523/
-) may be automatically scored 1pt with confirmation that deletion includes the 
-GP1BB
- gene.",General recommendation
-GP1BB (HGNC:4440),PM3,Moderate,"Use proposed SVI point recommendations. Both variants must be classified using these rule specifications, with the exception that a 22q11.2 deletion in trans (
-https://www.ncbi.nlm.nih.gov/books/NBK1523/
-) may be automatically scored 1pt with confirmation that deletion includes the 
-GP1BB
- gene.",General recommendation
-GP1BB (HGNC:4440),PM3,Supporting,Use proposed SVI point recommendations. Both variants must be classified using these rule specifications.,General recommendation
-GP1BB (HGNC:4440),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-GP1BB (HGNC:4440),PM4,Moderate,Use with no specification.,No change
-GP1BB (HGNC:4440),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-GP1BB (HGNC:4440),PM5,Moderate,"Use as originally specified, but the comparison variant must reach a pathogenic classification using these rule specifications in order to apply code.",General recommendation
-GP1BB (HGNC:4440),PM5,Supporting,"Use as originally specified, but the comparison variant must reach a likely pathogenic classification using these rule specifications in order to apply code.",General recommendation
-GP1BB (HGNC:4440),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-GP1BB (HGNC:4440),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-GP1BB (HGNC:4440),PP1,Strong,See instructions below for scoring system. Total segregation score 3+ points.,Disease-specific
-GP1BB (HGNC:4440),PP1,Moderate,See instructions below for scoring system. Total segregation score 2-2.75 points.,Disease-specific
-GP1BB (HGNC:4440),PP1,Supporting,See instructions below for scoring system. Total segregation score 1-1.75 points.,Disease-specific
-GP1BB (HGNC:4440),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-GP1BB (HGNC:4440),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-GP1BB (HGNC:4440),PP3,Moderate,"REVEL score of ≥0.773 based on recommendations of Pejaver et al., 2022 (PMID: 36413997).",Gene-specific
-GP1BB (HGNC:4440),PP3,Supporting,"REVEL score of ≥0.644 (to <0.773), based on recommendations of Pejaver et al., 2022 (PMID: 36413997).
-
-
-OR suggested splicing effect using SpliceAI greater than or equal to 0.5.",Gene-specific
-GP1BB (HGNC:4440),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-GP1BB (HGNC:4440),PP4,Moderate,"Must meet both criteria:
-
-
-1)Proband with platelet aggregation study absent for ristocetin and present for all other agonists OR flow cytometry or Western blot less than 10% expression of GPIba 
-
-
-2)Proband must have full sequencing of all three BSS genes (
-GP1BA, GP1BB
- and 
-GP9
-) and deletion/duplication analysis.",Disease-specific
-GP1BB (HGNC:4440),PP4,Supporting,"Proband with platelet aggregation study absent for ristocetin and present for all other agonists, OR 
-
-
-Flow cytometry or Western blot less than 10% expression of GPIba.",Disease-specific
-GP1BB (HGNC:4440),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-GP1BB (HGNC:4440),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-GP1BB (HGNC:4440),BA1,Stand Alone,gnomAD MAF greater than or equal to 0.001 (or 0.1%) in gnomAD.,Gene-specific
-GP1BB (HGNC:4440),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-GP1BB (HGNC:4440),BS1,Strong,gnomAD MAF greater than or equal to 0.0005 but less than 0.001.,Gene-specific
-GP1BB (HGNC:4440),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-GP1BB (HGNC:4440),BS2,Strong,Use this rule with 1 or more homozygotes who are unaffected (proven with aggregometry OR flow cytometry AND normal platelet count AND normal platelet size).,Disease-specific
-GP1BB (HGNC:4440),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-GP1BB (HGNC:4440),BS3,Strong,Must demonstrate normal aggregometry in a transgenic mouse model,Disease-specific
-GP1BB (HGNC:4440),BS3,Supporting,"In a heterologous cell line, must demonstrate BOTH normal expression and normal protein function as compared to wildtype.",Disease-specific
-GP1BB (HGNC:4440),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-GP1BB (HGNC:4440),BS4,Strong,Variant not tracking in an affected family member.,Disease-specific
-GP1BB (HGNC:4440),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-GP1BB (HGNC:4440),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-GP1BB (HGNC:4440),BP2,Supporting,Use as written for recessive variants (i.e. - variant must be observed in cis with a pathogenic variant),Disease-specific
-GP1BB (HGNC:4440),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-GP1BB (HGNC:4440),BP3,Supporting,Use with no specification,None
-GP1BB (HGNC:4440),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-GP1BB (HGNC:4440),BP4,Supporting,"For a missense variant apply when REVEL score is < 0.290, based on recommendations of Pejaver et al., 2022 (PMID: 36413997) AND SpliceAI score is zero.
-
-
-OR for a synonymous or intronic variant apply when SpliceAI score is zero.",Gene-specific
-GP1BB (HGNC:4440),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-GP1BB (HGNC:4440),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-GP1BB (HGNC:4440),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-GP1BB (HGNC:4440),BP7,Supporting,Use SpliceAI to rule out possible splicing defect (score = 0.2 or less) and reference PhyloP (score = 1.5 or less) to assess conservation.,Gene-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGP9Version1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGP9Version1.0.0_version=1.0.0.csv
deleted file mode 100644
index bbcc5c5b52fc32a13e2f41c893bef72a35c28c5e..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGP9Version1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,116 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-GP9 (HGNC:4444),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-GP9 (HGNC:4444),PVS1,Very Strong,"Use 
-GP9
- modified decision tree as per SVI WG.",Gene-specific
-GP9 (HGNC:4444),PVS1,Strong,"Use 
-GP9
- modified decision tree as per SVI WG.",Gene-specific
-GP9 (HGNC:4444),PVS1,Moderate,"Use 
-GP9
- modified decision tree as per SVI WG.",Gene-specific
-GP9 (HGNC:4444),PVS1,Supporting,"Use 
-GP9
- modified decision tree as per SVI WG.",Gene-specific
-GP9 (HGNC:4444),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-GP9 (HGNC:4444),PS1,Strong,"Use as originally specified, but the comparison variant must reach a pathogenic classification using the these rule specifications in order to apply code.",General recommendation
-GP9 (HGNC:4444),PS1,Moderate,"Use as originally specified, but the comparison variant must reach a likely pathogenic classification using the these rule specifications in order to apply code.",General recommendation
-GP9 (HGNC:4444),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-GP9 (HGNC:4444),PS2,Very Strong,Use proposed SVI point recommendations. See further instruction below. Total of 4 points.,Disease-specific
-GP9 (HGNC:4444),PS2,Strong,Use proposed SVI point recommendations. See further instruction below. Total of 2 points.,Disease-specific
-GP9 (HGNC:4444),PS2,Moderate,Use proposed SVI point recommendations. See further instruction below. Total of 1 point.,Disease-specific
-GP9 (HGNC:4444),PS2,Supporting,Use proposed SVI point recommendations. See further instruction below. Total of 0.5 point.,Disease-specific
-GP9 (HGNC:4444),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-GP9 (HGNC:4444),PS3,Strong,"In a transgenic animal model, must demonstrate minimal to no function.",Disease-specific
-GP9 (HGNC:4444),PS3,Supporting,"Functional assays measuring quantity of GP9 expression on cell surface measured by flow cytometry analysis of GPIb and GPIX when there is absent or near absent expression, >75% reduction (see spreadsheet for more detail).",Disease-specific
-GP9 (HGNC:4444),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-GP9 (HGNC:4444),PS4,Moderate,See instructions below for scoring heterozygous individuals only. Moderate strength applicable for score of 2+ points.,Disease-specific
-GP9 (HGNC:4444),PS4,Supporting,See instructions below for scoring heterozygous individuals only. Supporting strength applicable for scores ranging from 1-1.75,Disease-specific
-GP9 (HGNC:4444),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-GP9 (HGNC:4444),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-GP9 (HGNC:4444),PM2,Supporting,gnomAD MAF of less than or equal to 0.0000329.,"Disease-specific,Gene-specific"
-GP9 (HGNC:4444),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-GP9 (HGNC:4444),PM3,Very Strong,Use proposed SVI point recommendations (see below). Both variants must be classified using these rule specifications.,Disease-specific
-GP9 (HGNC:4444),PM3,Strong,Use proposed SVI point recommendations (see below). Both variants must be classified using these rule specifications.,Disease-specific
-GP9 (HGNC:4444),PM3,Moderate,Use proposed SVI point recommendations (see below). Both variants must be classified using these rule specifications.,Disease-specific
-GP9 (HGNC:4444),PM3,Supporting,Use proposed SVI point recommendations (see below). Both variants must be classified using these rule specifications.,Disease-specific
-GP9 (HGNC:4444),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-GP9 (HGNC:4444),PM4,Moderate,Use with no specification.,No change
-GP9 (HGNC:4444),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-GP9 (HGNC:4444),PM5,Moderate,"Use as originally specified, but the comparison variant must reach a pathogenic classification using these rule specifications in order to apply code.",General recommendation
-GP9 (HGNC:4444),PM5,Supporting,"Use as originally specified, but the comparison variant must reach a likely pathogenic classification using these rule specifications in order to apply code.",General recommendation
-GP9 (HGNC:4444),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-GP9 (HGNC:4444),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-GP9 (HGNC:4444),PP1,Strong,See instructions below for scoring system. Total segregation score 3+ points.,Disease-specific
-GP9 (HGNC:4444),PP1,Moderate,See instructions below for scoring system. Total segregation score 2-2.75 points.,Disease-specific
-GP9 (HGNC:4444),PP1,Supporting,See instructions below for scoring system. Total segregation score 1-1.75 points.,Disease-specific
-GP9 (HGNC:4444),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-GP9 (HGNC:4444),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-GP9 (HGNC:4444),PP3,Moderate,"REVEL score of ≥0.773 based on recommendations of Pejaver et al., 2022 (PMID: 36413997).",Gene-specific
-GP9 (HGNC:4444),PP3,Supporting,"REVEL score of ≥0.644 (to <0.773), based on recommendations of Pejaver et al., 2022 (PMID: 36413997),
-
-
-OR suggested splicing affect using SpliceAI greater than or equal to 0.5.",Gene-specific
-GP9 (HGNC:4444),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-GP9 (HGNC:4444),PP4,Moderate,"Must meet both criteria: 
-
-
-
-
-Proband with platelet aggregation study absent for ristocetin and present for all other agonists OR flow cytometry or Western blot less than 10% expression of GPIba 
-
-
-Proband must have full sequencing of all three BSS genes (
-GP1BA, GP1BB
- and 
-GP9
-) and deletion/duplication analysis.",Disease-specific
-GP9 (HGNC:4444),PP4,Supporting,"Proband with platelet aggregation study absent for ristocetin and present for all other agonists, OR 
-
-
-Flow cytometry or Western blot less than 10% expression of GPIba.",Disease-specific
-GP9 (HGNC:4444),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-GP9 (HGNC:4444),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-GP9 (HGNC:4444),BA1,Stand Alone,gnomAD MAF of greater than or equal to 0.001 (or 0.1%).,Gene-specific
-GP9 (HGNC:4444),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-GP9 (HGNC:4444),BS1,Strong,gnomAD MAF of greater than or equal to 0.0007 but less than 0.001.,Gene-specific
-GP9 (HGNC:4444),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-GP9 (HGNC:4444),BS2,Strong,Use this rule with 1 or more homozygotes who are unaffected (proven with aggregometry OR flow cytometry AND normal platelet count AND normal platelet size).,Disease-specific
-GP9 (HGNC:4444),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-GP9 (HGNC:4444),BS3,Strong,Must demonstrate normal aggregometry in a transgenic mouse model,Disease-specific
-GP9 (HGNC:4444),BS3,Supporting,"In a heterologous cell line, must demonstrate BOTH normal expression and normal protein function as compared to wildtype.",Disease-specific
-GP9 (HGNC:4444),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-GP9 (HGNC:4444),BS4,Strong,Variant not tracking in an affected family member.,Disease-specific
-GP9 (HGNC:4444),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-GP9 (HGNC:4444),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-GP9 (HGNC:4444),BP2,Supporting,Use as written for recessive variants (i.e. - variant must be observed in cis with a pathogenic variant),Disease-specific
-GP9 (HGNC:4444),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-GP9 (HGNC:4444),BP3,Supporting,Use with no specification,None
-GP9 (HGNC:4444),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-GP9 (HGNC:4444),BP4,Supporting,"For a missense variant apply when REVEL score is < 0.290, based on recommendations of Pejaver et al., 2022 (PMID: 36413997) AND SpliceAI score is zero.
-
-
-OR for a synonymous or intronic variant apply when SpliceAI score is zero.",Gene-specific
-GP9 (HGNC:4444),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-GP9 (HGNC:4444),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-GP9 (HGNC:4444),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-GP9 (HGNC:4444),BP7,Supporting,Use SpliceAI to rule out possible splicing defect (score = 0.2 or less) and reference PhyloP (score = 1.5 or less) to assess conservation.,Gene-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforITGA2BVersion1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforITGA2BVersion1.0.0_version=1.0.0.csv
deleted file mode 100644
index 07fa221b7886b7fe05b12fd05565eb053ea7ef96..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforITGA2BVersion1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,216 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-ITGA2B (HGNC:6138),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-ITGA2B (HGNC:6138),PVS1,Very Strong,Use decision tree as per SVI WG with specified “regions critical to protein function”.,
-ITGA2B (HGNC:6138),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-ITGA2B (HGNC:6138),PS1,Strong,"Use with no specification.
-
-
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-ITGA2B (HGNC:6138),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-ITGA2B (HGNC:6138),PS2,Very Strong,"Use proposed SVI point recommendations. 
-
-
-
-
-Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant.",
-ITGA2B (HGNC:6138),PS2,Strong,"Use proposed SVI point recommendations.
-
-
-
-
-Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant
-
-
-
-
-
-
-Use only when proband has an additional pathogenic or likely pathogenic variant with the de novo variant. Additionally, the P/LP variant must have been classified as such by the Platelet VCEP.
-
-
-Use ClinGen SVI’s proposed point recommendation table to determine the appropriate evidence code weight (see below). To be scored at the highest level with “Phenotype highly specific for gene” the proband must meet the PP4 criteria.",
-ITGA2B (HGNC:6138),PS2,Moderate,"Use proposed SVI point recommendations.
-
-
-
-
-Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant",
-ITGA2B (HGNC:6138),PS2,Supporting,"Use proposed SVI point recommendations.
-
-
-
-
-Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant",
-ITGA2B (HGNC:6138),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-ITGA2B (HGNC:6138),PS3,Strong,"In a transgenic animal model, must demonstrate minimal to no function (flow cytometry JON/A, aggregation, or alternate assay analyzing integrin function) OR
-
-
-In a model organism or heterologous cell line, EITHER (A) when expression is normal or reduced (>5% expression compared to WT), disruption of protein function must be demonstrated by significantly reduced binding to fibrinogen or ligand mimetic antibodies (e.g. PAC-1) OR (B) Absent surface protein expression (<5% expression compared to WT) shown by at least 1 of 2 of the following assays: flow cytometry or Western blotting.",
-ITGA2B (HGNC:6138),PS3,Moderate,"In a model organism or heterologous cell line, significantly reduced surface protein expression (5-25% expression compared to WT) on at least 1 of 2 of the following assays: flow cytometry or Western blotting.",
-ITGA2B (HGNC:6138),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",NA
-ITGA2B (HGNC:6138),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-ITGA2B (HGNC:6138),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-ITGA2B (HGNC:6138),PM2,Supporting,"Prevalence <1/10,000 (<0.0001) alleles in gnomAD.
-
-
-
-
-This evidence code is available when a variant is present in fewer than 1 in 10,000 alleles in the ExAC or gnomAD population cohorts.
-
-
-This cutoff was recommended based on work from Buitrago, et al showing that none of the established GT pathogenic variants were identified in ~32,000 alleles studies; suggesting that pathogenic variants have allele frequencies less than 0.01% in studied populations (PMID: 25827233)",
-ITGA2B (HGNC:6138),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-ITGA2B (HGNC:6138),PM3,Very Strong,Use proposed SVI point recommendations. Both variants must be classified using ITGA2B/ITGB3 Rule Specifications.,
-ITGA2B (HGNC:6138),PM3,Strong,Use proposed SVI point recommendations. Both variants must be classified using ITGA2B/ITGB3 Rule Specifications.,
-ITGA2B (HGNC:6138),PM3,Moderate,Use proposed SVI point recommendations. Both variants must be classified using ITGA2B/ITGB3 Rule Specifications.,
-ITGA2B (HGNC:6138),PM3,Supporting,Use proposed SVI point recommendations. Both variants must be classified using ITGA2B/ITGB3 Rule Specifications.,
-ITGA2B (HGNC:6138),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-ITGA2B (HGNC:6138),PM4,Moderate,This rule can be applied as originally intended by the ACMG/AMP guidelines.,
-ITGA2B (HGNC:6138),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-ITGA2B (HGNC:6138),PM5,Moderate,The strength of this rule may be adjusted based on the classification of the previously observed variant,
-ITGA2B (HGNC:6138),PM5,Supporting,Use at adjusted strength. Novel missense change at an amino acid residue where a different missense change determined to be likely pathogenic has been seen before.,
-ITGA2B (HGNC:6138),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-ITGA2B (HGNC:6138),PM6,Very Strong,"Use proposed SVI point recommendations. 
-
-
-
-
-Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant.",
-ITGA2B (HGNC:6138),PM6,Strong,"Use proposed SVI point recommendations.
-
-
-
-
-Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant",
-ITGA2B (HGNC:6138),PM6,Moderate,"Use proposed SVI point recommendations.
-
-
-
-
-Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant
-
-
-
-
-Use only when proband has a pathogenic or likely pathogenic variant in trans with the de novo variant.
-
-
-Use ClinGen SVI’s proposed point recommendation table to determine the appropriate evidence code weight (see PS2). To be scored at the highest level with “Phenotype highly specific for gene” the patient must meet the PP4 criteria.",
-ITGA2B (HGNC:6138),PM6,Supporting,"Use proposed SVI point recommendations.
-
-
-
-
-Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant",
-ITGA2B (HGNC:6138),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-ITGA2B (HGNC:6138),PP1,Strong,"Segregations in proband plus >2 affected relatives.
-
-
-
-
-Affected relatives must have both variants identified in proband.",
-ITGA2B (HGNC:6138),PP1,Moderate,"Segregation in proband plus 2 affected relatives.
-
-
-
-
-Affected relatives must have both variants identified in proband.",
-ITGA2B (HGNC:6138),PP1,Supporting,"Segregation in proband plus 1 affected relative.
-
-
-
-
-Affected relatives must have both variants identified in proband.",
-ITGA2B (HGNC:6138),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-ITGA2B (HGNC:6138),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-ITGA2B (HGNC:6138),PP3,Supporting,"REVEL score of > 0.7 OR >2 independent in silico missense predictors predict a damaging impact.
-
-
-For missense variants:
-
-
-
-
-REVEL score of > 0.7 is required for use of this rule code.
-Buitrago et al. (PNAS 2015) reported that three commonly used computational algorithms (Polyphen, SIFT, and CADD) to predict Pathogenicity had a 69–98% sensitivity in detecting GT pathogenic variants. (PMID: 25827233).
-
-
-
-
-For splicing variants:
-
-
-
-
->2 independent in silico missense predictors predict a damaging impact
-We have used Human Splicing Finder and Maximum Entropy Scan with the following parameters: (1) the threshold for a position to be considered a splice site is >65 for HSF and >3 for MaxEntScan, (2) a broken splice site is defined as a position that has shifted below the threshold with a difference in score of <-10% for HSF or <-30% for MaxEntScan, and (3) a new splice site is defined as a position that has shifted above the threshold where the difference in score is >10% for HSF or >30% for MaxEntScan.",
-ITGA2B (HGNC:6138),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-ITGA2B (HGNC:6138),PP4,Strong,Proband with clinical diagnosis of GT based on the presence of mucocutaneous bleeding and appropriate lab abnormalities. Full sequencing of both genes is required at this strength,
-ITGA2B (HGNC:6138),PP4,Moderate,Proband with clinical diagnosis of GT based on the presence of mucocutaneous bleeding and appropriate lab abnormalities. Full sequencing of both genes is required at this strength.,
-ITGA2B (HGNC:6138),PP4,Supporting,Proband with clinical diagnosis of GT based on the presence of mucocutaneous bleeding and appropriate lab abnormalities.,
-ITGA2B (HGNC:6138),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-ITGA2B (HGNC:6138),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-ITGA2B (HGNC:6138),BA1,Stand Alone,Frequency cutoff of 0.24% (>0.0024 at 99.99% CI w/subpopulation w/min of 5 alleles).,
-ITGA2B (HGNC:6138),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-ITGA2B (HGNC:6138),BS1,Strong,"Frequency cutoff of 0.158% (>0.00158 at 99.99% CI w/subpopulation w/min of 5 alleles).
-
-
-
-
-Use a minor allele frequency cutoff of >0.00158 but <0.0024 (99.99% CI, sub-population must have a minimum of 5 alleles present in the sub-population) based on the Whiffen-Ware calculator.
-
-
-To set the strong MAF cutoff, we use the rationale discussed above and accounted for the two known genes associated with GT; whereas the above calculation assumed only one causative gene.",
-ITGA2B (HGNC:6138),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-ITGA2B (HGNC:6138),BS2,Strong,">1 homozygote who is unaffected proven with at least aggregometry.
-
-
-
-
-This evidence code is available when the variant is identified in >1 homozygotes who are unaffected (proven with at least aggregometry).
-
-
-It is important to note that in order to use this rule one must have phenotypic information about an individual who is homozygous for a particular variant. This means one could not use population data (i.e. gnomAD or ExAC) as evidence. This code would more likely be used in the setting of gene panel testing, where an individual with a different phenotype was found to be homozygous for a variant in one of those two genes.",
-ITGA2B (HGNC:6138),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-ITGA2B (HGNC:6138),BS3,Strong,"Must demonstrate normal aggregometry in a transgenic mouse model. OR
-
-
-In a heterologous cell line, must demonstrate BOTH normal expression and normal protein function.",
-ITGA2B (HGNC:6138),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-ITGA2B (HGNC:6138),BS4,Strong,Variant not detected in an affected family member.,
-ITGA2B (HGNC:6138),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-ITGA2B (HGNC:6138),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-ITGA2B (HGNC:6138),BP2,Supporting,Use as written for recessive variants (i.e. - variant must be observed in cis with a pathogenic variant),
-ITGA2B (HGNC:6138),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-ITGA2B (HGNC:6138),BP3,Supporting,"This rule can be applied as originally intended by the ACMG/AMP guidelines in the ITG3B gene, which has three repetitive microsatellite regions. There are no known repetitive regions in the ITGA2B gene.",
-ITGA2B (HGNC:6138),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-ITGA2B (HGNC:6138),BP4,Supporting,"REVEL score of < 0.25.
-
-
-Use this code for missense variants with a REVEL score of < 0.25.
-● This recommendation was based on evaluating the REVEL scores of variants assessed as benign by this VCEP using our rule specifications with the exception of this rule code. All benign and likely benign variants fell under this threshold.
-● We are not recommending the use of other missense in silico model predictors at this time due to a previous concern about their validity for these genes as demonstrated by Buitrago et al. (PNAS 2015). They found that the three computational algorithms they used were less reliable predicting non-pathogenicity of previously known benign variants. (PMID: 25827233)",
-ITGA2B (HGNC:6138),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-ITGA2B (HGNC:6138),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-ITGA2B (HGNC:6138),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-ITGA2B (HGNC:6138),BP7,Supporting,Use with no specification. This rule can be applied as originally intended by the ACMG/AMP guidelines.,
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPulmonaryHypertensionExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBMPR2Version1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPulmonaryHypertensionExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBMPR2Version1.0.0_version=1.0.0.csv
deleted file mode 100644
index 5c3423c0e86255596904bb637f47adb554607982..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPulmonaryHypertensionExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBMPR2Version1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,124 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-BMPR2 (HGNC:1078),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-BMPR2 (HGNC:1078),PVS1,Very Strong,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Caveats:
-
-
-
-
-Use caution interpreting LOF variants at the extreme 3’ end of a gene.
-
-
-Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
-
-
-
-
-**Use the PVS1 decision tree guide.",Gene-specific
-BMPR2 (HGNC:1078),PVS1,Strong,Use the PVS1 decision tree guide.,"Gene-specific,Strength"
-BMPR2 (HGNC:1078),PVS1,Moderate,Use the PVS1 decision tree guide.,"Gene-specific,Strength"
-BMPR2 (HGNC:1078),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-BMPR2 (HGNC:1078),PS1,Strong,"Same amino acid change as a previously established 
-pathogenic
- variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",None
-BMPR2 (HGNC:1078),PS1,Moderate,"Same amino acid change as a previously established 
-likely pathogenic
- variant regardless of nucleotide change.",Strength
-BMPR2 (HGNC:1078),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-BMPR2 (HGNC:1078),PS2,Strong,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",No change
-BMPR2 (HGNC:1078),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-BMPR2 (HGNC:1078),PS3,Strong,"Use the BMPR2 functional assay document for guidance on allowable assays. Known variant validation controls (i.e. established pathogenic and benign variants) are required. One exception is if the same functional assay has been performed for the same variant by two independent groups and demonstrated to have the same functional effect by both groups. Also applicable for non-canonical splice site variants when RNA splice site assay data is available demonstrating abnormal splicing; positive and negative controls are required, preferably from patients and matched unaffected individuals. Note that splicing assay results may be tissue-sensitive.","General recommendation,Gene-specific"
-BMPR2 (HGNC:1078),PS3,Supporting,"Use the BMPR2 functional assay document for guidance on allowable assays. If no known variant validation controls (i.e. established pathogenic and benign variants) were used, then score at the supporting strength.",General recommendation
-BMPR2 (HGNC:1078),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-BMPR2 (HGNC:1078),PS4,Strong,"Prior observation of the variant in >4 unrelated patients with the same phenotype, and its absence in controls.",Disease-specific
-BMPR2 (HGNC:1078),PS4,Moderate,"Prior observation of the variant in >3 unrelated patients with the same phenotype, and its absence in controls.","Disease-specific,Strength"
-BMPR2 (HGNC:1078),PS4,Supporting,"Prior observation of the variant in >1 unrelated patients with the same phenotype, and its absence in controls.","Disease-specific,Strength"
-BMPR2 (HGNC:1078),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-BMPR2 (HGNC:1078),PM1,Strong,"Variant changes a 
-critical
- amino acid. Extracellular domain: p.Cys34, Cys60, Cys66, Cys84, Cys94, Cys99, Cys116, Cys117, Cys118, Cys123. Kinase domain: p.Gly210, Gly212, Lys230, Glu/Asn245, Asp333, Asn338, Asp351, Gly353 Glu386, Asp405, Gly410, Arg491. KD heterodimerization: p.Asp485, Gln486, Asp487, Ala488, Arg489, Ala490, Arg491, Leu492.
-
-
-Note that p.Gln42Arg, Gly47Gln, Gln82His, Thr102Ala, Ser107Pro, Gly182Asp, Met186Val, Glu503Asp, Arg899X, and Arg899Pro have been demonstrated 
-non-critical/not necessary
- for kinase activity based on a luciferase assay (apply BS3).","Gene-specific,Strength"
-BMPR2 (HGNC:1078),PM1,Moderate,"Variant changes an amino acid in the extracellular domain (aa 33-131) or kinase domain (aa 203-504) but without functional evidence indicating critical or non-critical.
-
-
-Note that p.Cys34, Cys60, Cys66, Cys84, Cys94, Cys99, Cys116, Cys117, Cys118, Cys123, Gly210, Gly212, Lys230, Glu/Asn245, Asp333, Asn338, Asp351, Gly353 Glu386, Asp405, Gly410, Asp485, Gln486, Asp487, Ala488, Arg489, Ala490, Arg491, Arg491, and Leu492 have been demonstrated 
-critical
- (apply PM1_strong).
-
-
-Note that p.Gln42Arg, Gly47Gln, Gln82His, Thr102Ala, Ser107Pro, Gly182Asp, Met186Val, Glu503Asp, Arg899X, and Arg899Pro have been demonstrated 
-non-critical/not necessary
- for kinase activity based on a luciferase assay (apply BS3).",Gene-specific
-BMPR2 (HGNC:1078),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-BMPR2 (HGNC:1078),PM2,Supporting,"Present at <0.01% among gnomAD controls, using the subpopulation with the highest frequency and at least 1,000 allele counts. Caveat: Population data for indels may be poorly called by next generation sequencing.",Disease-specific
-BMPR2 (HGNC:1078),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-BMPR2 (HGNC:1078),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-BMPR2 (HGNC:1078),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,No change
-BMPR2 (HGNC:1078),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-BMPR2 (HGNC:1078),PM5,Moderate,"Novel missense change at an amino acid residue where a different missense change determined to be 
-pathogenic
- has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.  Also applicable for variants affecting the same splice site as a confirmed splice variant with similar or worse splicing in silico predictions",General recommendation
-BMPR2 (HGNC:1078),PM5,Supporting,"Novel missense change at an amino acid residue where a different missense change determined to be 
-likely pathogenic
- has been seen before.",Strength
-BMPR2 (HGNC:1078),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-BMPR2 (HGNC:1078),PM6,Moderate,"Assumed de novo, but without confirmation of paternity and maternity.",No change
-BMPR2 (HGNC:1078),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-BMPR2 (HGNC:1078),PP1,Strong,Co-segregation with disease in ≥7 affected family members.,Strength
-BMPR2 (HGNC:1078),PP1,Moderate,Co-segregation with disease in ≥5 affected family members.,Strength
-BMPR2 (HGNC:1078),PP1,Supporting,Co-segregation with disease in ≥3 affected family members.,Strength
-BMPR2 (HGNC:1078),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-BMPR2 (HGNC:1078),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-BMPR2 (HGNC:1078),PP3,Supporting,"REVEL ≥0.75 for missense variants or Splice AI ≥0.2 for non-canonical splice variants. No up/downgrading. If no REVEL score or SpliceAI prediction is available, then CADD ≥20 can be used. Note: can be applied additively with PS3 if applicable.",General recommendation
-BMPR2 (HGNC:1078),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-BMPR2 (HGNC:1078),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-BMPR2 (HGNC:1078),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-BMPR2 (HGNC:1078),BA1,Stand Alone,"Allele frequency is above 1% in gnomAD, including any sub-population with at least 1,000 allele counts.",Disease-specific
-BMPR2 (HGNC:1078),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-BMPR2 (HGNC:1078),BS1,Strong,"Allele frequency >=0.1% among gnomAD controls, using the subpopulation with the highest frequency and at least 1,000 allele counts.",Disease-specific
-BMPR2 (HGNC:1078),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-BMPR2 (HGNC:1078),BS2,Strong,Observed in ≥3 homozygotes in gnomAD controls or reported in the literature (healthy adult individuals).,"Disease-specific,Gene-specific"
-BMPR2 (HGNC:1078),BS2,Supporting,Observed in ≥2 homozygotes in gnomAD controls or reported in the literature (healthy adult individuals).,"Disease-specific,Gene-specific"
-BMPR2 (HGNC:1078),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-BMPR2 (HGNC:1078),BS3,Strong,"Use the BMPR2 functional assay document for acceptable assays and guidance. Note that p.Gln42Arg, Gly47Gln, Gln82His, Thr102Ala, Ser107Pro, Gly182Asp, Met186Val, Glu503Asp, Arg899X, and Arg899Pro have been demonstrated non-critical/not necessary for kinase activity based on a luciferase assay (apply BS3).
-
-
-Note that p.Cys34, Cys60, Cys66, Cys84, Cys94, Cys99, Cys116, Cys117, Cys118, Cys123, Gly210, Gly212, Lys230, Glu/Asn245, Asp333, Asn338, Asp351, Gly353 Glu386, Asp405, Gly410, Asp485, Gln486, Asp487, Ala488, Arg489, Ala490, Arg491, Arg491, and Leu492 have been demonstrated 
-critical
- (apply PM1_strong).",Gene-specific
-BMPR2 (HGNC:1078),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-BMPR2 (HGNC:1078),BS4,Strong,Lack of variant segregation in affected members of a family.,No change
-BMPR2 (HGNC:1078),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-BMPR2 (HGNC:1078),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-BMPR2 (HGNC:1078),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-BMPR2 (HGNC:1078),BP3,Supporting,In frame-deletions/insertions in a repetitive region without a known function.,No change
-BMPR2 (HGNC:1078),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-BMPR2 (HGNC:1078),BP4,Supporting,"REVEL ≤0.25 for missense variants or Splice AI ≤0.1 for non-canonical splice variants. No up/downgrading. If no REVEL or. Splice AI available, then CADD ≤ 10 can be used.",General recommendation
-BMPR2 (HGNC:1078),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-BMPR2 (HGNC:1078),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-BMPR2 (HGNC:1078),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-BMPR2 (HGNC:1078),BP7,Strong,"If BP7 is met and negative RNA splicing assay data is available, then apply BP7_strong. Acceptable splicing assays should have positive and negative controls, preferably from patients and matched unaffected individuals. Note that splicing assay results may be tissue-sensitive.",Strength
-BMPR2 (HGNC:1078),BP7,Supporting,"A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. Applicable after assignment of BP4 for no adverse splicing predictions, and inclusive of exonic and intronic variants. Not applicable for synonymous variants located at the first base or the last three bases of an exon.",No change
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPulmonaryHypertensionExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBMPR2Version1.1.0_version=1.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPulmonaryHypertensionExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBMPR2Version1.1.0_version=1.1.0.csv
deleted file mode 100644
index 5c3423c0e86255596904bb637f47adb554607982..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenPulmonaryHypertensionExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBMPR2Version1.1.0_version=1.1.0.csv
+++ /dev/null
@@ -1,124 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-BMPR2 (HGNC:1078),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-BMPR2 (HGNC:1078),PVS1,Very Strong,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Caveats:
-
-
-
-
-Use caution interpreting LOF variants at the extreme 3’ end of a gene.
-
-
-Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
-
-
-
-
-**Use the PVS1 decision tree guide.",Gene-specific
-BMPR2 (HGNC:1078),PVS1,Strong,Use the PVS1 decision tree guide.,"Gene-specific,Strength"
-BMPR2 (HGNC:1078),PVS1,Moderate,Use the PVS1 decision tree guide.,"Gene-specific,Strength"
-BMPR2 (HGNC:1078),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-BMPR2 (HGNC:1078),PS1,Strong,"Same amino acid change as a previously established 
-pathogenic
- variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",None
-BMPR2 (HGNC:1078),PS1,Moderate,"Same amino acid change as a previously established 
-likely pathogenic
- variant regardless of nucleotide change.",Strength
-BMPR2 (HGNC:1078),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-BMPR2 (HGNC:1078),PS2,Strong,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",No change
-BMPR2 (HGNC:1078),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-BMPR2 (HGNC:1078),PS3,Strong,"Use the BMPR2 functional assay document for guidance on allowable assays. Known variant validation controls (i.e. established pathogenic and benign variants) are required. One exception is if the same functional assay has been performed for the same variant by two independent groups and demonstrated to have the same functional effect by both groups. Also applicable for non-canonical splice site variants when RNA splice site assay data is available demonstrating abnormal splicing; positive and negative controls are required, preferably from patients and matched unaffected individuals. Note that splicing assay results may be tissue-sensitive.","General recommendation,Gene-specific"
-BMPR2 (HGNC:1078),PS3,Supporting,"Use the BMPR2 functional assay document for guidance on allowable assays. If no known variant validation controls (i.e. established pathogenic and benign variants) were used, then score at the supporting strength.",General recommendation
-BMPR2 (HGNC:1078),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-BMPR2 (HGNC:1078),PS4,Strong,"Prior observation of the variant in >4 unrelated patients with the same phenotype, and its absence in controls.",Disease-specific
-BMPR2 (HGNC:1078),PS4,Moderate,"Prior observation of the variant in >3 unrelated patients with the same phenotype, and its absence in controls.","Disease-specific,Strength"
-BMPR2 (HGNC:1078),PS4,Supporting,"Prior observation of the variant in >1 unrelated patients with the same phenotype, and its absence in controls.","Disease-specific,Strength"
-BMPR2 (HGNC:1078),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-BMPR2 (HGNC:1078),PM1,Strong,"Variant changes a 
-critical
- amino acid. Extracellular domain: p.Cys34, Cys60, Cys66, Cys84, Cys94, Cys99, Cys116, Cys117, Cys118, Cys123. Kinase domain: p.Gly210, Gly212, Lys230, Glu/Asn245, Asp333, Asn338, Asp351, Gly353 Glu386, Asp405, Gly410, Arg491. KD heterodimerization: p.Asp485, Gln486, Asp487, Ala488, Arg489, Ala490, Arg491, Leu492.
-
-
-Note that p.Gln42Arg, Gly47Gln, Gln82His, Thr102Ala, Ser107Pro, Gly182Asp, Met186Val, Glu503Asp, Arg899X, and Arg899Pro have been demonstrated 
-non-critical/not necessary
- for kinase activity based on a luciferase assay (apply BS3).","Gene-specific,Strength"
-BMPR2 (HGNC:1078),PM1,Moderate,"Variant changes an amino acid in the extracellular domain (aa 33-131) or kinase domain (aa 203-504) but without functional evidence indicating critical or non-critical.
-
-
-Note that p.Cys34, Cys60, Cys66, Cys84, Cys94, Cys99, Cys116, Cys117, Cys118, Cys123, Gly210, Gly212, Lys230, Glu/Asn245, Asp333, Asn338, Asp351, Gly353 Glu386, Asp405, Gly410, Asp485, Gln486, Asp487, Ala488, Arg489, Ala490, Arg491, Arg491, and Leu492 have been demonstrated 
-critical
- (apply PM1_strong).
-
-
-Note that p.Gln42Arg, Gly47Gln, Gln82His, Thr102Ala, Ser107Pro, Gly182Asp, Met186Val, Glu503Asp, Arg899X, and Arg899Pro have been demonstrated 
-non-critical/not necessary
- for kinase activity based on a luciferase assay (apply BS3).",Gene-specific
-BMPR2 (HGNC:1078),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-BMPR2 (HGNC:1078),PM2,Supporting,"Present at <0.01% among gnomAD controls, using the subpopulation with the highest frequency and at least 1,000 allele counts. Caveat: Population data for indels may be poorly called by next generation sequencing.",Disease-specific
-BMPR2 (HGNC:1078),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-BMPR2 (HGNC:1078),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-BMPR2 (HGNC:1078),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,No change
-BMPR2 (HGNC:1078),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-BMPR2 (HGNC:1078),PM5,Moderate,"Novel missense change at an amino acid residue where a different missense change determined to be 
-pathogenic
- has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.  Also applicable for variants affecting the same splice site as a confirmed splice variant with similar or worse splicing in silico predictions",General recommendation
-BMPR2 (HGNC:1078),PM5,Supporting,"Novel missense change at an amino acid residue where a different missense change determined to be 
-likely pathogenic
- has been seen before.",Strength
-BMPR2 (HGNC:1078),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-BMPR2 (HGNC:1078),PM6,Moderate,"Assumed de novo, but without confirmation of paternity and maternity.",No change
-BMPR2 (HGNC:1078),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-BMPR2 (HGNC:1078),PP1,Strong,Co-segregation with disease in ≥7 affected family members.,Strength
-BMPR2 (HGNC:1078),PP1,Moderate,Co-segregation with disease in ≥5 affected family members.,Strength
-BMPR2 (HGNC:1078),PP1,Supporting,Co-segregation with disease in ≥3 affected family members.,Strength
-BMPR2 (HGNC:1078),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-BMPR2 (HGNC:1078),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-BMPR2 (HGNC:1078),PP3,Supporting,"REVEL ≥0.75 for missense variants or Splice AI ≥0.2 for non-canonical splice variants. No up/downgrading. If no REVEL score or SpliceAI prediction is available, then CADD ≥20 can be used. Note: can be applied additively with PS3 if applicable.",General recommendation
-BMPR2 (HGNC:1078),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-BMPR2 (HGNC:1078),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-BMPR2 (HGNC:1078),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-BMPR2 (HGNC:1078),BA1,Stand Alone,"Allele frequency is above 1% in gnomAD, including any sub-population with at least 1,000 allele counts.",Disease-specific
-BMPR2 (HGNC:1078),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-BMPR2 (HGNC:1078),BS1,Strong,"Allele frequency >=0.1% among gnomAD controls, using the subpopulation with the highest frequency and at least 1,000 allele counts.",Disease-specific
-BMPR2 (HGNC:1078),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-BMPR2 (HGNC:1078),BS2,Strong,Observed in ≥3 homozygotes in gnomAD controls or reported in the literature (healthy adult individuals).,"Disease-specific,Gene-specific"
-BMPR2 (HGNC:1078),BS2,Supporting,Observed in ≥2 homozygotes in gnomAD controls or reported in the literature (healthy adult individuals).,"Disease-specific,Gene-specific"
-BMPR2 (HGNC:1078),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-BMPR2 (HGNC:1078),BS3,Strong,"Use the BMPR2 functional assay document for acceptable assays and guidance. Note that p.Gln42Arg, Gly47Gln, Gln82His, Thr102Ala, Ser107Pro, Gly182Asp, Met186Val, Glu503Asp, Arg899X, and Arg899Pro have been demonstrated non-critical/not necessary for kinase activity based on a luciferase assay (apply BS3).
-
-
-Note that p.Cys34, Cys60, Cys66, Cys84, Cys94, Cys99, Cys116, Cys117, Cys118, Cys123, Gly210, Gly212, Lys230, Glu/Asn245, Asp333, Asn338, Asp351, Gly353 Glu386, Asp405, Gly410, Asp485, Gln486, Asp487, Ala488, Arg489, Ala490, Arg491, Arg491, and Leu492 have been demonstrated 
-critical
- (apply PM1_strong).",Gene-specific
-BMPR2 (HGNC:1078),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-BMPR2 (HGNC:1078),BS4,Strong,Lack of variant segregation in affected members of a family.,No change
-BMPR2 (HGNC:1078),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-BMPR2 (HGNC:1078),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-BMPR2 (HGNC:1078),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-BMPR2 (HGNC:1078),BP3,Supporting,In frame-deletions/insertions in a repetitive region without a known function.,No change
-BMPR2 (HGNC:1078),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-BMPR2 (HGNC:1078),BP4,Supporting,"REVEL ≤0.25 for missense variants or Splice AI ≤0.1 for non-canonical splice variants. No up/downgrading. If no REVEL or. Splice AI available, then CADD ≤ 10 can be used.",General recommendation
-BMPR2 (HGNC:1078),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-BMPR2 (HGNC:1078),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-BMPR2 (HGNC:1078),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-BMPR2 (HGNC:1078),BP7,Strong,"If BP7 is met and negative RNA splicing assay data is available, then apply BP7_strong. Acceptable splicing assays should have positive and negative controls, preferably from patients and matched unaffected individuals. Note that splicing assay results may be tissue-sensitive.",Strength
-BMPR2 (HGNC:1078),BP7,Supporting,"A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. Applicable after assignment of BP4 for no adverse splicing predictions, and inclusive of exonic and intronic variants. Not applicable for synonymous variants located at the first base or the last three bases of an exon.",No change
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
deleted file mode 100644
index 56f7b408f602d2f047175449a6332265dae33e4b..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
+++ /dev/null
@@ -1,95 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-SHOC2 (HGNC:15454),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-SHOC2 (HGNC:15454),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SHOC2 (HGNC:15454),PS1,Strong,"Previously established variant must be established as pathogenic per these criteria for germline RASopathy variants. This evidence rule can also be applied for the any observed analogous residue positions/regions throughout the gene in highly analogous groupings below:
-Group 1: HRAS, NRAS, KRAS
- Group 2: MAP2K1, MAP2K2
-Group 3: SOS1, SOS2",Analogous Gene
-SHOC2 (HGNC:15454),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-SHOC2 (HGNC:15454),PS2,Very Strong,≥2 independent occurrences of PS2 OR ≥2 independent occurrences of PM6 and one occurrence of PS2. Evidence from literature must be fully evaluated to support independent events.,Strength
-SHOC2 (HGNC:15454),PS2,Strong,De novo (paternity confirmed) in a patient with the disease and no family history.,None
-SHOC2 (HGNC:15454),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-SHOC2 (HGNC:15454),PS3,Strong,Approved functional studies are available for each individual gene in the supplemental material. Additional functional studies can be submitted to the expert panel for approval.,Disease-specific
-SHOC2 (HGNC:15454),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-SHOC2 (HGNC:15454),PS4,Strong,≥5 independent occurrences.,General
-SHOC2 (HGNC:15454),PS4,Moderate,≥3 independent occurrences.,Strength
-SHOC2 (HGNC:15454),PS4,Supporting,≥1 independent occurrences.,Strength
-SHOC2 (HGNC:15454),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-SHOC2 (HGNC:15454),PM1,Moderate,"See supplemental material for approved functional domains and residues. This evidence rule can also be applied for the same analogous residue positions/regions in highly analogous groupings below:
-Group 1: HRAS, NRAS, KRAS
-Group 2: MAP2K1, MAP2K2
-Group 3: SOS1, SOS2",Analogous Gene
-SHOC2 (HGNC:15454),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-SHOC2 (HGNC:15454),PM2,Moderate,The variant must be completely absent from all population databases.,General
-SHOC2 (HGNC:15454),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-SHOC2 (HGNC:15454),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-SHOC2 (HGNC:15454),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,None
-SHOC2 (HGNC:15454),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SHOC2 (HGNC:15454),PM5,Strong,"Previously established variant must be established as pathogenic per these criteria. Amino acid changes of variants should be concordant with pathogenicity based on how conservative or non-conservative (within the context of amino acid chain groupings) the residue change is relative to the known pathogenic residue changes. This evidence rule can also be used for pathogenic missense variants seen in the same analogous residue position in highly analogous groupings below:
-Group 1: HRAS, NRAS, KRAS
-Group 2: MAP2K1, MAP2K2 Group 3: SOS1, SOS2
-This rule should not be used as independent criteria for calculating pathogenicity in conjunction with PM1 if the amino acid residue being interrogated is explicitly designated as a “mutational hot-spot”. For example, Gly12 in HRAS is listed as a hot-spot for PM1 usage. In these situations, only PM1 should be used when combining criteria for final variant classification in order to avoid premature designation of a likely pathogenic classification in the absence of other evidence for pathogenicity.
-≥2 different pathogenic missense changes seen before at same residue of missense change.",Strength
-SHOC2 (HGNC:15454),PM5,Moderate,"Previously established variant must be established as pathogenic per these criteria. Amino acid changes of variants should be concordant with pathogenicity based on how conservative or non-conservative (within the context of amino acid chain groupings) the residue change is relative to the known pathogenic residue changes. This evidence rule can also be used for pathogenic missense variants seen in the same analogous residue position in highly analogous groupings below:
-Group 1: HRAS, NRAS, KRAS
-Group 2: MAP2K1, MAP2K2 Group 3: SOS1, SOS2
-This rule should not be used as independent criteria for calculating pathogenicity in conjunction with PM1 if the amino acid residue being interrogated is explicitly designated as a “mutational hot-spot”. For example, Gly12 in HRAS is listed as a hot-spot for PM1 usage. In these situations, only PM1 should be used when combining criteria for final variant classification in order to avoid premature designation of a likely pathogenic classification in the absence of other evidence for pathogenicity.",Analogous Gene
-SHOC2 (HGNC:15454),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-SHOC2 (HGNC:15454),PM6,Strong,≥2 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.,Strength
-SHOC2 (HGNC:15454),PM6,Moderate,Confirmed de novo without confirmation of paternity and maternity.,None
-SHOC2 (HGNC:15454),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-SHOC2 (HGNC:15454),PP1,Strong,"Usage of PP1 requires at least three informative meioses. Segregation in more than one family is recommended.
-≥7 informative meioses.",Strength
-SHOC2 (HGNC:15454),PP1,Moderate,"Usage of PP1 requires at least three informative meioses. Segregation in more than one family is recommended.
-≥5 informative meioses.",Strength
-SHOC2 (HGNC:15454),PP1,Supporting,Usage of PP1 requires at least three informative meioses. Segregation in more than one family is recommended.,General
-SHOC2 (HGNC:15454),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,
-SHOC2 (HGNC:15454),PP2,Supporting,PP2 is applicable to all RASopathy genes described and curated herein.,Disease-specific
-SHOC2 (HGNC:15454),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-SHOC2 (HGNC:15454),PP3,Supporting,Multiple lines of computational evidence support a deleterious effect on the gene or gene product.,None
-SHOC2 (HGNC:15454),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-SHOC2 (HGNC:15454),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SHOC2 (HGNC:15454),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-SHOC2 (HGNC:15454),BA1,Stand Alone,An allele frequency ≥0.05% was approved. See supplemental material for additional frequency information.,Disease-specific
-SHOC2 (HGNC:15454),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-SHOC2 (HGNC:15454),BS1,Strong,An allele frequency ≥0.025% was approved. See supplemental material for additional frequency information.,Disease-specific
-SHOC2 (HGNC:15454),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-SHOC2 (HGNC:15454),BS2,Strong,"Due to variable expressivity and severity, extensive clinical workup for RASopathy spectrum features is warranted, thus general population data should not be used for this criterion. Clinical laboratories are encouraged to accumulate more than 3 instances of well phenotyped family members before applying this strong criterion.",General
-SHOC2 (HGNC:15454),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-SHOC2 (HGNC:15454),BS3,Strong,Approved functional studies are available for each individual gene in the supplemental material. Additional functional studies can be submitted to the expert panel for approval.,Disease-specific
-SHOC2 (HGNC:15454),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-SHOC2 (HGNC:15454),BS4,Strong,Requires only one informative meiosis and does not require an additional piece of supporting evidence to classify variant as likely benign.,General
-SHOC2 (HGNC:15454),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-SHOC2 (HGNC:15454),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-SHOC2 (HGNC:15454),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-SHOC2 (HGNC:15454),BP2,Supporting,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.,None
-SHOC2 (HGNC:15454),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-SHOC2 (HGNC:15454),BP3,Supporting,In frame-deletions/insertions in a repetitive region without a known function.,None
-SHOC2 (HGNC:15454),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SHOC2 (HGNC:15454),BP4,Supporting,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SHOC2 (HGNC:15454),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-SHOC2 (HGNC:15454),BP5,Supporting,Variant found in a case with an alternate molecular basis for disease.,Variant found in a case with an alternate molecular basis for disease
-SHOC2 (HGNC:15454),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SHOC2 (HGNC:15454),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-SHOC2 (HGNC:15454),BP7,Supporting,"A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
-This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.",General
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRAFVersion2.0.0_version=2.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRAFVersion2.0.0_version=2.0.0.csv
deleted file mode 100644
index 30d33e05165ffe73520b615bf86f09cbd0acdcf3..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRAFVersion2.0.0_version=2.0.0.csv
+++ /dev/null
@@ -1,88 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-BRAF (HGNC:1097),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-BRAF (HGNC:1097),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-BRAF (HGNC:1097),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-BRAF
- and 
-RAF1
-.",Analogous Gene
-BRAF (HGNC:1097),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-BRAF (HGNC:1097),PS2,Very Strong,4 Points.,Strength
-BRAF (HGNC:1097),PS2,Strong,2 Points.,None
-BRAF (HGNC:1097),PS2,Moderate,1 Point.,Strength
-BRAF (HGNC:1097),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-BRAF (HGNC:1097),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-BRAF (HGNC:1097),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-BRAF (HGNC:1097),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-BRAF (HGNC:1097),PS4,Strong,≥5 points.,Disease-specific
-BRAF (HGNC:1097),PS4,Moderate,≥3 points.,Strength
-BRAF (HGNC:1097),PS4,Supporting,≥1 points.,Strength
-BRAF (HGNC:1097),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-BRAF (HGNC:1097),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (exon 6, exon 11, P-loop [AA 459-474], CR3 activation segment [AA 594-627]). Not applicable to specific amino acid residues (see BP5).",Gene-specific
-BRAF (HGNC:1097),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-BRAF (HGNC:1097),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-BRAF (HGNC:1097),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-BRAF (HGNC:1097),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-BRAF (HGNC:1097),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-BRAF (HGNC:1097),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-BRAF (HGNC:1097),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-BRAF (HGNC:1097),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,"Analogous Gene,Disease-specific"
-BRAF (HGNC:1097),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-BRAF (HGNC:1097),PM6,Strong,2 Points.,Strength
-BRAF (HGNC:1097),PM6,Moderate,1 Point.,None
-BRAF (HGNC:1097),PM6,Supporting,0.5 Points.,Strength
-BRAF (HGNC:1097),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-BRAF (HGNC:1097),PP1,Strong,≥7 informative meioses.,Strength
-BRAF (HGNC:1097),PP1,Moderate,≥5 informative meioses.,Strength
-BRAF (HGNC:1097),PP1,Supporting,≥3 informative meioses.,Disease-specific
-BRAF (HGNC:1097),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,
-BRAF (HGNC:1097),PP2,Supporting,Missense z score is >3.09 in gnomAD.,Disease-specific
-BRAF (HGNC:1097),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-BRAF (HGNC:1097),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-BRAF (HGNC:1097),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-BRAF (HGNC:1097),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-BRAF (HGNC:1097),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-BRAF (HGNC:1097),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-BRAF (HGNC:1097),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-BRAF (HGNC:1097),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-BRAF (HGNC:1097),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-BRAF (HGNC:1097),BS2,Strong,-4 Points.,Strength
-BRAF (HGNC:1097),BS2,Supporting,-1 Point.,Strength
-BRAF (HGNC:1097),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-BRAF (HGNC:1097),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-BRAF (HGNC:1097),BS4,Strong,Requires only one informative meiosis.,General recommendation
-BRAF (HGNC:1097),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-BRAF (HGNC:1097),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-BRAF (HGNC:1097),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-BRAF (HGNC:1097),BP2,Strong,≥ (-4) Points.,Strength
-BRAF (HGNC:1097),BP2,Moderate,≥ (-2) Points.,Strength
-BRAF (HGNC:1097),BP2,Supporting,≥ (-1) Point.,None
-BRAF (HGNC:1097),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-BRAF (HGNC:1097),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-BRAF (HGNC:1097),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-BRAF (HGNC:1097),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-BRAF (HGNC:1097),BP5,Strong,≥ (-4) Points.,Strength
-BRAF (HGNC:1097),BP5,Moderate,≥ (-2) Points.,Strength
-BRAF (HGNC:1097),BP5,Supporting,≥ (-1) Point.,None
-BRAF (HGNC:1097),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-BRAF (HGNC:1097),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-BRAF (HGNC:1097),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRAFVersion2.1.0_version=2.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRAFVersion2.1.0_version=2.1.0.csv
deleted file mode 100644
index 219ed3c8c7102024585148855dcbc876c0b41478..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRAFVersion2.1.0_version=2.1.0.csv
+++ /dev/null
@@ -1,88 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-BRAF (HGNC:1097),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-BRAF (HGNC:1097),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-BRAF (HGNC:1097),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-BRAF
- and 
-RAF1
-.",Analogous Gene
-BRAF (HGNC:1097),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-BRAF (HGNC:1097),PS2,Very Strong,4 Points.,Strength
-BRAF (HGNC:1097),PS2,Strong,2 Points.,None
-BRAF (HGNC:1097),PS2,Moderate,1 Point.,Strength
-BRAF (HGNC:1097),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-BRAF (HGNC:1097),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-BRAF (HGNC:1097),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-BRAF (HGNC:1097),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-BRAF (HGNC:1097),PS4,Strong,≥5 points.,Disease-specific
-BRAF (HGNC:1097),PS4,Moderate,≥3 points.,Strength
-BRAF (HGNC:1097),PS4,Supporting,≥1 points.,Strength
-BRAF (HGNC:1097),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-BRAF (HGNC:1097),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (exon 6, exon 11, P-loop [AA 459-474], CR3 activation segment [AA 594-627]). Not applicable to specific amino acid residues (see PM5).",Gene-specific
-BRAF (HGNC:1097),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-BRAF (HGNC:1097),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-BRAF (HGNC:1097),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-BRAF (HGNC:1097),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-BRAF (HGNC:1097),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-BRAF (HGNC:1097),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-BRAF (HGNC:1097),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-BRAF (HGNC:1097),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,"Analogous Gene,Disease-specific"
-BRAF (HGNC:1097),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-BRAF (HGNC:1097),PM6,Strong,2 Points.,Strength
-BRAF (HGNC:1097),PM6,Moderate,1 Point.,None
-BRAF (HGNC:1097),PM6,Supporting,0.5 Points.,Strength
-BRAF (HGNC:1097),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-BRAF (HGNC:1097),PP1,Strong,≥7 informative meioses.,Strength
-BRAF (HGNC:1097),PP1,Moderate,≥5 informative meioses.,Strength
-BRAF (HGNC:1097),PP1,Supporting,≥3 informative meioses.,Disease-specific
-BRAF (HGNC:1097),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,
-BRAF (HGNC:1097),PP2,Supporting,Missense z score is >3.09 in gnomAD.,Disease-specific
-BRAF (HGNC:1097),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-BRAF (HGNC:1097),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-BRAF (HGNC:1097),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-BRAF (HGNC:1097),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-BRAF (HGNC:1097),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-BRAF (HGNC:1097),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-BRAF (HGNC:1097),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-BRAF (HGNC:1097),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-BRAF (HGNC:1097),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-BRAF (HGNC:1097),BS2,Strong,-4 Points.,Strength
-BRAF (HGNC:1097),BS2,Supporting,-1 Point.,Strength
-BRAF (HGNC:1097),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-BRAF (HGNC:1097),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-BRAF (HGNC:1097),BS4,Strong,Requires only one informative meiosis.,General recommendation
-BRAF (HGNC:1097),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-BRAF (HGNC:1097),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-BRAF (HGNC:1097),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-BRAF (HGNC:1097),BP2,Strong,≥ (-4) Points.,Strength
-BRAF (HGNC:1097),BP2,Moderate,≥ (-2) Points.,Strength
-BRAF (HGNC:1097),BP2,Supporting,≥ (-1) Point.,None
-BRAF (HGNC:1097),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-BRAF (HGNC:1097),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-BRAF (HGNC:1097),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-BRAF (HGNC:1097),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-BRAF (HGNC:1097),BP5,Strong,≥ (-4) Points.,Strength
-BRAF (HGNC:1097),BP5,Moderate,≥ (-2) Points.,Strength
-BRAF (HGNC:1097),BP5,Supporting,≥ (-1) Point.,None
-BRAF (HGNC:1097),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-BRAF (HGNC:1097),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-BRAF (HGNC:1097),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRAFVersion2.2.0_version=2.2.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRAFVersion2.2.0_version=2.2.0.csv
deleted file mode 100644
index 219ed3c8c7102024585148855dcbc876c0b41478..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRAFVersion2.2.0_version=2.2.0.csv
+++ /dev/null
@@ -1,88 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-BRAF (HGNC:1097),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-BRAF (HGNC:1097),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-BRAF (HGNC:1097),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-BRAF
- and 
-RAF1
-.",Analogous Gene
-BRAF (HGNC:1097),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-BRAF (HGNC:1097),PS2,Very Strong,4 Points.,Strength
-BRAF (HGNC:1097),PS2,Strong,2 Points.,None
-BRAF (HGNC:1097),PS2,Moderate,1 Point.,Strength
-BRAF (HGNC:1097),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-BRAF (HGNC:1097),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-BRAF (HGNC:1097),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-BRAF (HGNC:1097),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-BRAF (HGNC:1097),PS4,Strong,≥5 points.,Disease-specific
-BRAF (HGNC:1097),PS4,Moderate,≥3 points.,Strength
-BRAF (HGNC:1097),PS4,Supporting,≥1 points.,Strength
-BRAF (HGNC:1097),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-BRAF (HGNC:1097),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (exon 6, exon 11, P-loop [AA 459-474], CR3 activation segment [AA 594-627]). Not applicable to specific amino acid residues (see PM5).",Gene-specific
-BRAF (HGNC:1097),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-BRAF (HGNC:1097),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-BRAF (HGNC:1097),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-BRAF (HGNC:1097),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-BRAF (HGNC:1097),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-BRAF (HGNC:1097),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-BRAF (HGNC:1097),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-BRAF (HGNC:1097),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,"Analogous Gene,Disease-specific"
-BRAF (HGNC:1097),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-BRAF (HGNC:1097),PM6,Strong,2 Points.,Strength
-BRAF (HGNC:1097),PM6,Moderate,1 Point.,None
-BRAF (HGNC:1097),PM6,Supporting,0.5 Points.,Strength
-BRAF (HGNC:1097),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-BRAF (HGNC:1097),PP1,Strong,≥7 informative meioses.,Strength
-BRAF (HGNC:1097),PP1,Moderate,≥5 informative meioses.,Strength
-BRAF (HGNC:1097),PP1,Supporting,≥3 informative meioses.,Disease-specific
-BRAF (HGNC:1097),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,
-BRAF (HGNC:1097),PP2,Supporting,Missense z score is >3.09 in gnomAD.,Disease-specific
-BRAF (HGNC:1097),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-BRAF (HGNC:1097),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-BRAF (HGNC:1097),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-BRAF (HGNC:1097),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-BRAF (HGNC:1097),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-BRAF (HGNC:1097),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-BRAF (HGNC:1097),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-BRAF (HGNC:1097),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-BRAF (HGNC:1097),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-BRAF (HGNC:1097),BS2,Strong,-4 Points.,Strength
-BRAF (HGNC:1097),BS2,Supporting,-1 Point.,Strength
-BRAF (HGNC:1097),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-BRAF (HGNC:1097),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-BRAF (HGNC:1097),BS4,Strong,Requires only one informative meiosis.,General recommendation
-BRAF (HGNC:1097),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-BRAF (HGNC:1097),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-BRAF (HGNC:1097),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-BRAF (HGNC:1097),BP2,Strong,≥ (-4) Points.,Strength
-BRAF (HGNC:1097),BP2,Moderate,≥ (-2) Points.,Strength
-BRAF (HGNC:1097),BP2,Supporting,≥ (-1) Point.,None
-BRAF (HGNC:1097),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-BRAF (HGNC:1097),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-BRAF (HGNC:1097),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-BRAF (HGNC:1097),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-BRAF (HGNC:1097),BP5,Strong,≥ (-4) Points.,Strength
-BRAF (HGNC:1097),BP5,Moderate,≥ (-2) Points.,Strength
-BRAF (HGNC:1097),BP5,Supporting,≥ (-1) Point.,None
-BRAF (HGNC:1097),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-BRAF (HGNC:1097),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-BRAF (HGNC:1097),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRAFVersion2.3.0_version=2.3.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRAFVersion2.3.0_version=2.3.0.csv
deleted file mode 100644
index 62509f4503a14d253183d8640650cd2dfd0642d6..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRAFVersion2.3.0_version=2.3.0.csv
+++ /dev/null
@@ -1,88 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-BRAF (HGNC:1097),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-BRAF (HGNC:1097),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-BRAF (HGNC:1097),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-BRAF
- and 
-RAF1
-.",Analogous Gene
-BRAF (HGNC:1097),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-BRAF (HGNC:1097),PS2,Very Strong,4 Points.,Strength
-BRAF (HGNC:1097),PS2,Strong,2 Points.,None
-BRAF (HGNC:1097),PS2,Moderate,1 Point.,Strength
-BRAF (HGNC:1097),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-BRAF (HGNC:1097),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-BRAF (HGNC:1097),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-BRAF (HGNC:1097),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-BRAF (HGNC:1097),PS4,Strong,≥5 points.,Disease-specific
-BRAF (HGNC:1097),PS4,Moderate,≥3 points.,Strength
-BRAF (HGNC:1097),PS4,Supporting,≥1 points.,Strength
-BRAF (HGNC:1097),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-BRAF (HGNC:1097),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (exon 6, exon 11, P-loop [AA 459-474], CR3 activation segment [AA 594-627]). Not applicable to specific amino acid residues (see PM5).",Gene-specific
-BRAF (HGNC:1097),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-BRAF (HGNC:1097),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-BRAF (HGNC:1097),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-BRAF (HGNC:1097),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-BRAF (HGNC:1097),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-BRAF (HGNC:1097),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-BRAF (HGNC:1097),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-BRAF (HGNC:1097),PM5,Moderate,1 [likely] pathogenic residue change at the same codon.,"Analogous Gene,Disease-specific"
-BRAF (HGNC:1097),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-BRAF (HGNC:1097),PM6,Strong,2 Points.,Strength
-BRAF (HGNC:1097),PM6,Moderate,1 Point.,None
-BRAF (HGNC:1097),PM6,Supporting,0.5 Points.,Strength
-BRAF (HGNC:1097),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-BRAF (HGNC:1097),PP1,Strong,≥7 informative meioses.,Strength
-BRAF (HGNC:1097),PP1,Moderate,≥5 informative meioses.,Strength
-BRAF (HGNC:1097),PP1,Supporting,≥3 informative meioses.,Disease-specific
-BRAF (HGNC:1097),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,
-BRAF (HGNC:1097),PP2,Supporting,Missense z score is >3.09 in gnomAD.,Disease-specific
-BRAF (HGNC:1097),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-BRAF (HGNC:1097),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-BRAF (HGNC:1097),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-BRAF (HGNC:1097),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-BRAF (HGNC:1097),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-BRAF (HGNC:1097),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-BRAF (HGNC:1097),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-BRAF (HGNC:1097),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-BRAF (HGNC:1097),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-BRAF (HGNC:1097),BS2,Strong,-4 Points.,Strength
-BRAF (HGNC:1097),BS2,Supporting,-1 Point.,Strength
-BRAF (HGNC:1097),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-BRAF (HGNC:1097),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-BRAF (HGNC:1097),BS4,Strong,Requires only one informative meiosis.,General recommendation
-BRAF (HGNC:1097),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-BRAF (HGNC:1097),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-BRAF (HGNC:1097),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-BRAF (HGNC:1097),BP2,Strong,≥ (-4) Points.,Strength
-BRAF (HGNC:1097),BP2,Moderate,≥ (-2) Points.,Strength
-BRAF (HGNC:1097),BP2,Supporting,≥ (-1) Point.,None
-BRAF (HGNC:1097),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-BRAF (HGNC:1097),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-BRAF (HGNC:1097),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-BRAF (HGNC:1097),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-BRAF (HGNC:1097),BP5,Strong,≥ (-4) Points.,Strength
-BRAF (HGNC:1097),BP5,Moderate,≥ (-2) Points.,Strength
-BRAF (HGNC:1097),BP5,Supporting,≥ (-1) Point.,None
-BRAF (HGNC:1097),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-BRAF (HGNC:1097),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-BRAF (HGNC:1097),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHRASVersion2.0.0_version=2.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHRASVersion2.0.0_version=2.0.0.csv
deleted file mode 100644
index 4e57a9e6860b0f7616a6703dd58ba3234b2120b2..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHRASVersion2.0.0_version=2.0.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-HRAS (HGNC:5173),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-HRAS (HGNC:5173),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-HRAS (HGNC:5173),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-HRAS, KRAS, MRAS, NRAS, RIT1,
- and 
-RRAS2.",Analogous Gene
-HRAS (HGNC:5173),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-HRAS (HGNC:5173),PS2,Very Strong,4 Points.,Strength
-HRAS (HGNC:5173),PS2,Strong,2 Points.,None
-HRAS (HGNC:5173),PS2,Moderate,1 Point.,Strength
-HRAS (HGNC:5173),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-HRAS (HGNC:5173),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-HRAS (HGNC:5173),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-HRAS (HGNC:5173),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-HRAS (HGNC:5173),PS4,Strong,≥5 points.,Disease-specific
-HRAS (HGNC:5173),PS4,Moderate,≥3 points.,Strength
-HRAS (HGNC:5173),PS4,Supporting,≥1 points.,Strength
-HRAS (HGNC:5173),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-HRAS (HGNC:5173),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (P-loop [AA 10-17], SW1 [AA 25-40], SW2 [AA 57-64], SAK [AA 145-156]). Not applicable to specific amino acid residues (see BP5).",Gene-specific
-HRAS (HGNC:5173),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-HRAS (HGNC:5173),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-HRAS (HGNC:5173),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-HRAS (HGNC:5173),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-HRAS (HGNC:5173),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-HRAS (HGNC:5173),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-HRAS (HGNC:5173),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-HRAS (HGNC:5173),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,"Analogous Gene,Disease-specific"
-HRAS (HGNC:5173),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-HRAS (HGNC:5173),PM6,Strong,2 Points.,Strength
-HRAS (HGNC:5173),PM6,Moderate,1 Point.,None
-HRAS (HGNC:5173),PM6,Supporting,0.5 Points.,Strength
-HRAS (HGNC:5173),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-HRAS (HGNC:5173),PP1,Strong,≥7 informative meioses.,Strength
-HRAS (HGNC:5173),PP1,Moderate,≥5 informative meioses.,Strength
-HRAS (HGNC:5173),PP1,Supporting,≥3 informative meioses.,Disease-specific
-HRAS (HGNC:5173),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-HRAS (HGNC:5173),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-HRAS (HGNC:5173),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-HRAS (HGNC:5173),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-HRAS (HGNC:5173),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-HRAS (HGNC:5173),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-HRAS (HGNC:5173),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-HRAS (HGNC:5173),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-HRAS (HGNC:5173),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-HRAS (HGNC:5173),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-HRAS (HGNC:5173),BS2,Strong,-4 Points.,Strength
-HRAS (HGNC:5173),BS2,Supporting,-1 Point.,Strength
-HRAS (HGNC:5173),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-HRAS (HGNC:5173),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-HRAS (HGNC:5173),BS4,Strong,Requires only one informative meiosis.,General recommendation
-HRAS (HGNC:5173),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-HRAS (HGNC:5173),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-HRAS (HGNC:5173),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-HRAS (HGNC:5173),BP2,Strong,≥ (-4) Points.,Strength
-HRAS (HGNC:5173),BP2,Moderate,≥ (-2) Points.,Strength
-HRAS (HGNC:5173),BP2,Supporting,≥ (-1) Point.,None
-HRAS (HGNC:5173),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-HRAS (HGNC:5173),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-HRAS (HGNC:5173),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-HRAS (HGNC:5173),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-HRAS (HGNC:5173),BP5,Strong,≥ (-4) Points.,Strength
-HRAS (HGNC:5173),BP5,Moderate,≥ (-2) Points.,Strength
-HRAS (HGNC:5173),BP5,Supporting,≥ (-1) Point.,None
-HRAS (HGNC:5173),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-HRAS (HGNC:5173),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-HRAS (HGNC:5173),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHRASVersion2.1.0_version=2.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHRASVersion2.1.0_version=2.1.0.csv
deleted file mode 100644
index 8268cfa5c13b58b9437ffdce1004103c528995b3..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHRASVersion2.1.0_version=2.1.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-HRAS (HGNC:5173),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-HRAS (HGNC:5173),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-HRAS (HGNC:5173),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-HRAS, KRAS, MRAS, NRAS, RIT1,
- and 
-RRAS2.",Analogous Gene
-HRAS (HGNC:5173),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-HRAS (HGNC:5173),PS2,Very Strong,4 Points.,Strength
-HRAS (HGNC:5173),PS2,Strong,2 Points.,None
-HRAS (HGNC:5173),PS2,Moderate,1 Point.,Strength
-HRAS (HGNC:5173),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-HRAS (HGNC:5173),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-HRAS (HGNC:5173),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-HRAS (HGNC:5173),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-HRAS (HGNC:5173),PS4,Strong,≥5 points.,Disease-specific
-HRAS (HGNC:5173),PS4,Moderate,≥3 points.,Strength
-HRAS (HGNC:5173),PS4,Supporting,≥1 points.,Strength
-HRAS (HGNC:5173),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-HRAS (HGNC:5173),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (P-loop [AA 10-17], SW1 [AA 25-40], SW2 [AA 57-64], SAK [AA 145-156]). Not applicable to specific amino acid residues (see PM5).",Gene-specific
-HRAS (HGNC:5173),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-HRAS (HGNC:5173),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-HRAS (HGNC:5173),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-HRAS (HGNC:5173),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-HRAS (HGNC:5173),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-HRAS (HGNC:5173),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-HRAS (HGNC:5173),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-HRAS (HGNC:5173),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,"Analogous Gene,Disease-specific"
-HRAS (HGNC:5173),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-HRAS (HGNC:5173),PM6,Strong,2 Points.,Strength
-HRAS (HGNC:5173),PM6,Moderate,1 Point.,None
-HRAS (HGNC:5173),PM6,Supporting,0.5 Points.,Strength
-HRAS (HGNC:5173),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-HRAS (HGNC:5173),PP1,Strong,≥7 informative meioses.,Strength
-HRAS (HGNC:5173),PP1,Moderate,≥5 informative meioses.,Strength
-HRAS (HGNC:5173),PP1,Supporting,≥3 informative meioses.,Disease-specific
-HRAS (HGNC:5173),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-HRAS (HGNC:5173),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-HRAS (HGNC:5173),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-HRAS (HGNC:5173),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-HRAS (HGNC:5173),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-HRAS (HGNC:5173),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-HRAS (HGNC:5173),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-HRAS (HGNC:5173),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-HRAS (HGNC:5173),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-HRAS (HGNC:5173),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-HRAS (HGNC:5173),BS2,Strong,-4 Points.,Strength
-HRAS (HGNC:5173),BS2,Supporting,-1 Point.,Strength
-HRAS (HGNC:5173),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-HRAS (HGNC:5173),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-HRAS (HGNC:5173),BS4,Strong,Requires only one informative meiosis.,General recommendation
-HRAS (HGNC:5173),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-HRAS (HGNC:5173),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-HRAS (HGNC:5173),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-HRAS (HGNC:5173),BP2,Strong,≥ (-4) Points.,Strength
-HRAS (HGNC:5173),BP2,Moderate,≥ (-2) Points.,Strength
-HRAS (HGNC:5173),BP2,Supporting,≥ (-1) Point.,None
-HRAS (HGNC:5173),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-HRAS (HGNC:5173),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-HRAS (HGNC:5173),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-HRAS (HGNC:5173),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-HRAS (HGNC:5173),BP5,Strong,≥ (-4) Points.,Strength
-HRAS (HGNC:5173),BP5,Moderate,≥ (-2) Points.,Strength
-HRAS (HGNC:5173),BP5,Supporting,≥ (-1) Point.,None
-HRAS (HGNC:5173),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-HRAS (HGNC:5173),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-HRAS (HGNC:5173),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHRASVersion2.2.0_version=2.2.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHRASVersion2.2.0_version=2.2.0.csv
deleted file mode 100644
index 8268cfa5c13b58b9437ffdce1004103c528995b3..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHRASVersion2.2.0_version=2.2.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-HRAS (HGNC:5173),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-HRAS (HGNC:5173),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-HRAS (HGNC:5173),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-HRAS, KRAS, MRAS, NRAS, RIT1,
- and 
-RRAS2.",Analogous Gene
-HRAS (HGNC:5173),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-HRAS (HGNC:5173),PS2,Very Strong,4 Points.,Strength
-HRAS (HGNC:5173),PS2,Strong,2 Points.,None
-HRAS (HGNC:5173),PS2,Moderate,1 Point.,Strength
-HRAS (HGNC:5173),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-HRAS (HGNC:5173),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-HRAS (HGNC:5173),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-HRAS (HGNC:5173),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-HRAS (HGNC:5173),PS4,Strong,≥5 points.,Disease-specific
-HRAS (HGNC:5173),PS4,Moderate,≥3 points.,Strength
-HRAS (HGNC:5173),PS4,Supporting,≥1 points.,Strength
-HRAS (HGNC:5173),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-HRAS (HGNC:5173),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (P-loop [AA 10-17], SW1 [AA 25-40], SW2 [AA 57-64], SAK [AA 145-156]). Not applicable to specific amino acid residues (see PM5).",Gene-specific
-HRAS (HGNC:5173),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-HRAS (HGNC:5173),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-HRAS (HGNC:5173),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-HRAS (HGNC:5173),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-HRAS (HGNC:5173),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-HRAS (HGNC:5173),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-HRAS (HGNC:5173),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-HRAS (HGNC:5173),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,"Analogous Gene,Disease-specific"
-HRAS (HGNC:5173),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-HRAS (HGNC:5173),PM6,Strong,2 Points.,Strength
-HRAS (HGNC:5173),PM6,Moderate,1 Point.,None
-HRAS (HGNC:5173),PM6,Supporting,0.5 Points.,Strength
-HRAS (HGNC:5173),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-HRAS (HGNC:5173),PP1,Strong,≥7 informative meioses.,Strength
-HRAS (HGNC:5173),PP1,Moderate,≥5 informative meioses.,Strength
-HRAS (HGNC:5173),PP1,Supporting,≥3 informative meioses.,Disease-specific
-HRAS (HGNC:5173),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-HRAS (HGNC:5173),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-HRAS (HGNC:5173),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-HRAS (HGNC:5173),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-HRAS (HGNC:5173),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-HRAS (HGNC:5173),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-HRAS (HGNC:5173),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-HRAS (HGNC:5173),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-HRAS (HGNC:5173),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-HRAS (HGNC:5173),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-HRAS (HGNC:5173),BS2,Strong,-4 Points.,Strength
-HRAS (HGNC:5173),BS2,Supporting,-1 Point.,Strength
-HRAS (HGNC:5173),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-HRAS (HGNC:5173),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-HRAS (HGNC:5173),BS4,Strong,Requires only one informative meiosis.,General recommendation
-HRAS (HGNC:5173),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-HRAS (HGNC:5173),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-HRAS (HGNC:5173),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-HRAS (HGNC:5173),BP2,Strong,≥ (-4) Points.,Strength
-HRAS (HGNC:5173),BP2,Moderate,≥ (-2) Points.,Strength
-HRAS (HGNC:5173),BP2,Supporting,≥ (-1) Point.,None
-HRAS (HGNC:5173),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-HRAS (HGNC:5173),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-HRAS (HGNC:5173),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-HRAS (HGNC:5173),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-HRAS (HGNC:5173),BP5,Strong,≥ (-4) Points.,Strength
-HRAS (HGNC:5173),BP5,Moderate,≥ (-2) Points.,Strength
-HRAS (HGNC:5173),BP5,Supporting,≥ (-1) Point.,None
-HRAS (HGNC:5173),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-HRAS (HGNC:5173),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-HRAS (HGNC:5173),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHRASVersion2.3.0_version=2.3.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHRASVersion2.3.0_version=2.3.0.csv
deleted file mode 100644
index df0e35487bd61df18a4e232eac9976a262d7f21f..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHRASVersion2.3.0_version=2.3.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-HRAS (HGNC:5173),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-HRAS (HGNC:5173),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-HRAS (HGNC:5173),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-HRAS, KRAS, MRAS, NRAS, RIT1,
- and 
-RRAS2.",Analogous Gene
-HRAS (HGNC:5173),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-HRAS (HGNC:5173),PS2,Very Strong,4 Points.,Strength
-HRAS (HGNC:5173),PS2,Strong,2 Points.,None
-HRAS (HGNC:5173),PS2,Moderate,1 Point.,Strength
-HRAS (HGNC:5173),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-HRAS (HGNC:5173),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-HRAS (HGNC:5173),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-HRAS (HGNC:5173),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-HRAS (HGNC:5173),PS4,Strong,≥5 points.,Disease-specific
-HRAS (HGNC:5173),PS4,Moderate,≥3 points.,Strength
-HRAS (HGNC:5173),PS4,Supporting,≥1 points.,Strength
-HRAS (HGNC:5173),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-HRAS (HGNC:5173),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (P-loop [AA 10-17], SW1 [AA 25-40], SW2 [AA 57-64], SAK [AA 145-156]). Not applicable to specific amino acid residues (see PM5).",Gene-specific
-HRAS (HGNC:5173),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-HRAS (HGNC:5173),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-HRAS (HGNC:5173),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-HRAS (HGNC:5173),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-HRAS (HGNC:5173),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-HRAS (HGNC:5173),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-HRAS (HGNC:5173),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-HRAS (HGNC:5173),PM5,Moderate,1 [likely] pathogenic residue change at the same codon.,"Analogous Gene,Disease-specific"
-HRAS (HGNC:5173),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-HRAS (HGNC:5173),PM6,Strong,2 Points.,Strength
-HRAS (HGNC:5173),PM6,Moderate,1 Point.,None
-HRAS (HGNC:5173),PM6,Supporting,0.5 Points.,Strength
-HRAS (HGNC:5173),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-HRAS (HGNC:5173),PP1,Strong,≥7 informative meioses.,Strength
-HRAS (HGNC:5173),PP1,Moderate,≥5 informative meioses.,Strength
-HRAS (HGNC:5173),PP1,Supporting,≥3 informative meioses.,Disease-specific
-HRAS (HGNC:5173),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-HRAS (HGNC:5173),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-HRAS (HGNC:5173),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-HRAS (HGNC:5173),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-HRAS (HGNC:5173),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-HRAS (HGNC:5173),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-HRAS (HGNC:5173),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-HRAS (HGNC:5173),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-HRAS (HGNC:5173),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-HRAS (HGNC:5173),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-HRAS (HGNC:5173),BS2,Strong,-4 Points.,Strength
-HRAS (HGNC:5173),BS2,Supporting,-1 Point.,Strength
-HRAS (HGNC:5173),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-HRAS (HGNC:5173),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-HRAS (HGNC:5173),BS4,Strong,Requires only one informative meiosis.,General recommendation
-HRAS (HGNC:5173),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-HRAS (HGNC:5173),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-HRAS (HGNC:5173),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-HRAS (HGNC:5173),BP2,Strong,≥ (-4) Points.,Strength
-HRAS (HGNC:5173),BP2,Moderate,≥ (-2) Points.,Strength
-HRAS (HGNC:5173),BP2,Supporting,≥ (-1) Point.,None
-HRAS (HGNC:5173),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-HRAS (HGNC:5173),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-HRAS (HGNC:5173),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-HRAS (HGNC:5173),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-HRAS (HGNC:5173),BP5,Strong,≥ (-4) Points.,Strength
-HRAS (HGNC:5173),BP5,Moderate,≥ (-2) Points.,Strength
-HRAS (HGNC:5173),BP5,Supporting,≥ (-1) Point.,None
-HRAS (HGNC:5173),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-HRAS (HGNC:5173),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-HRAS (HGNC:5173),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforKRASVersion2.0.0_version=2.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforKRASVersion2.0.0_version=2.0.0.csv
deleted file mode 100644
index 59e14a309c003883e673295376389575eeff2a8c..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforKRASVersion2.0.0_version=2.0.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-KRAS (HGNC:6407),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-KRAS (HGNC:6407),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-KRAS (HGNC:6407),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-HRAS, KRAS, MRAS, NRAS, RIT1,
- and 
-RRAS2.",Analogous Gene
-KRAS (HGNC:6407),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-KRAS (HGNC:6407),PS2,Very Strong,4 Points.,Strength
-KRAS (HGNC:6407),PS2,Strong,2 Points.,None
-KRAS (HGNC:6407),PS2,Moderate,1 Point.,Strength
-KRAS (HGNC:6407),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-KRAS (HGNC:6407),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-KRAS (HGNC:6407),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-KRAS (HGNC:6407),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-KRAS (HGNC:6407),PS4,Strong,≥5 points.,Disease-specific
-KRAS (HGNC:6407),PS4,Moderate,≥3 points.,Strength
-KRAS (HGNC:6407),PS4,Supporting,≥1 points.,Strength
-KRAS (HGNC:6407),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-KRAS (HGNC:6407),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (P-loop [AA 10-17], SW1 [AA 25-40], SW2 [AA 57-64], SAK [AA 145-156]). Not applicable to specific amino acid residues (see BP5).",Gene-specific
-KRAS (HGNC:6407),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-KRAS (HGNC:6407),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-KRAS (HGNC:6407),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-KRAS (HGNC:6407),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-KRAS (HGNC:6407),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-KRAS (HGNC:6407),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-KRAS (HGNC:6407),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-KRAS (HGNC:6407),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,"Analogous Gene,Disease-specific"
-KRAS (HGNC:6407),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-KRAS (HGNC:6407),PM6,Strong,2 Points.,Strength
-KRAS (HGNC:6407),PM6,Moderate,1 Point.,None
-KRAS (HGNC:6407),PM6,Supporting,0.5 Points.,Strength
-KRAS (HGNC:6407),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-KRAS (HGNC:6407),PP1,Strong,≥7 informative meioses.,Strength
-KRAS (HGNC:6407),PP1,Moderate,≥5 informative meioses.,Strength
-KRAS (HGNC:6407),PP1,Supporting,≥3 informative meioses.,Disease-specific
-KRAS (HGNC:6407),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-KRAS (HGNC:6407),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-KRAS (HGNC:6407),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-KRAS (HGNC:6407),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-KRAS (HGNC:6407),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-KRAS (HGNC:6407),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-KRAS (HGNC:6407),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-KRAS (HGNC:6407),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-KRAS (HGNC:6407),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-KRAS (HGNC:6407),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-KRAS (HGNC:6407),BS2,Strong,-4 Points.,Strength
-KRAS (HGNC:6407),BS2,Supporting,-1 Point.,Strength
-KRAS (HGNC:6407),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-KRAS (HGNC:6407),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-KRAS (HGNC:6407),BS4,Strong,Requires only one informative meiosis.,General recommendation
-KRAS (HGNC:6407),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-KRAS (HGNC:6407),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-KRAS (HGNC:6407),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-KRAS (HGNC:6407),BP2,Strong,≥ (-4) Points.,Strength
-KRAS (HGNC:6407),BP2,Moderate,≥ (-2) Points.,Strength
-KRAS (HGNC:6407),BP2,Supporting,≥ (-1) Point.,None
-KRAS (HGNC:6407),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-KRAS (HGNC:6407),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-KRAS (HGNC:6407),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-KRAS (HGNC:6407),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-KRAS (HGNC:6407),BP5,Strong,≥ (-4) Points.,Strength
-KRAS (HGNC:6407),BP5,Moderate,≥ (-2) Points.,Strength
-KRAS (HGNC:6407),BP5,Supporting,≥ (-1) Point.,None
-KRAS (HGNC:6407),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-KRAS (HGNC:6407),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-KRAS (HGNC:6407),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforKRASVersion2.1.0_version=2.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforKRASVersion2.1.0_version=2.1.0.csv
deleted file mode 100644
index 6a6f22f978af7e93302766ec5dc4bc324bb76440..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforKRASVersion2.1.0_version=2.1.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-KRAS (HGNC:6407),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-KRAS (HGNC:6407),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-KRAS (HGNC:6407),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-HRAS, KRAS, MRAS, NRAS, RIT1,
- and 
-RRAS2.",Analogous Gene
-KRAS (HGNC:6407),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-KRAS (HGNC:6407),PS2,Very Strong,4 Points.,Strength
-KRAS (HGNC:6407),PS2,Strong,2 Points.,None
-KRAS (HGNC:6407),PS2,Moderate,1 Point.,Strength
-KRAS (HGNC:6407),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-KRAS (HGNC:6407),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-KRAS (HGNC:6407),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-KRAS (HGNC:6407),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-KRAS (HGNC:6407),PS4,Strong,≥5 points.,Disease-specific
-KRAS (HGNC:6407),PS4,Moderate,≥3 points.,Strength
-KRAS (HGNC:6407),PS4,Supporting,≥1 points.,Strength
-KRAS (HGNC:6407),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-KRAS (HGNC:6407),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (P-loop [AA 10-17], SW1 [AA 25-40], SW2 [AA 57-64], SAK [AA 145-156]). Not applicable to specific amino acid residues (see PM5).",Gene-specific
-KRAS (HGNC:6407),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-KRAS (HGNC:6407),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-KRAS (HGNC:6407),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-KRAS (HGNC:6407),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-KRAS (HGNC:6407),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-KRAS (HGNC:6407),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-KRAS (HGNC:6407),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-KRAS (HGNC:6407),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,"Analogous Gene,Disease-specific"
-KRAS (HGNC:6407),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-KRAS (HGNC:6407),PM6,Strong,2 Points.,Strength
-KRAS (HGNC:6407),PM6,Moderate,1 Point.,None
-KRAS (HGNC:6407),PM6,Supporting,0.5 Points.,Strength
-KRAS (HGNC:6407),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-KRAS (HGNC:6407),PP1,Strong,≥7 informative meioses.,Strength
-KRAS (HGNC:6407),PP1,Moderate,≥5 informative meioses.,Strength
-KRAS (HGNC:6407),PP1,Supporting,≥3 informative meioses.,Disease-specific
-KRAS (HGNC:6407),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-KRAS (HGNC:6407),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-KRAS (HGNC:6407),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-KRAS (HGNC:6407),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-KRAS (HGNC:6407),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-KRAS (HGNC:6407),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-KRAS (HGNC:6407),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-KRAS (HGNC:6407),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-KRAS (HGNC:6407),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-KRAS (HGNC:6407),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-KRAS (HGNC:6407),BS2,Strong,-4 Points.,Strength
-KRAS (HGNC:6407),BS2,Supporting,-1 Point.,Strength
-KRAS (HGNC:6407),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-KRAS (HGNC:6407),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-KRAS (HGNC:6407),BS4,Strong,Requires only one informative meiosis.,General recommendation
-KRAS (HGNC:6407),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-KRAS (HGNC:6407),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-KRAS (HGNC:6407),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-KRAS (HGNC:6407),BP2,Strong,≥ (-4) Points.,Strength
-KRAS (HGNC:6407),BP2,Moderate,≥ (-2) Points.,Strength
-KRAS (HGNC:6407),BP2,Supporting,≥ (-1) Point.,None
-KRAS (HGNC:6407),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-KRAS (HGNC:6407),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-KRAS (HGNC:6407),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-KRAS (HGNC:6407),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-KRAS (HGNC:6407),BP5,Strong,≥ (-4) Points.,Strength
-KRAS (HGNC:6407),BP5,Moderate,≥ (-2) Points.,Strength
-KRAS (HGNC:6407),BP5,Supporting,≥ (-1) Point.,None
-KRAS (HGNC:6407),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-KRAS (HGNC:6407),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-KRAS (HGNC:6407),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforKRASVersion2.2.0_version=2.2.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforKRASVersion2.2.0_version=2.2.0.csv
deleted file mode 100644
index 6a6f22f978af7e93302766ec5dc4bc324bb76440..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforKRASVersion2.2.0_version=2.2.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-KRAS (HGNC:6407),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-KRAS (HGNC:6407),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-KRAS (HGNC:6407),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-HRAS, KRAS, MRAS, NRAS, RIT1,
- and 
-RRAS2.",Analogous Gene
-KRAS (HGNC:6407),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-KRAS (HGNC:6407),PS2,Very Strong,4 Points.,Strength
-KRAS (HGNC:6407),PS2,Strong,2 Points.,None
-KRAS (HGNC:6407),PS2,Moderate,1 Point.,Strength
-KRAS (HGNC:6407),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-KRAS (HGNC:6407),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-KRAS (HGNC:6407),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-KRAS (HGNC:6407),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-KRAS (HGNC:6407),PS4,Strong,≥5 points.,Disease-specific
-KRAS (HGNC:6407),PS4,Moderate,≥3 points.,Strength
-KRAS (HGNC:6407),PS4,Supporting,≥1 points.,Strength
-KRAS (HGNC:6407),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-KRAS (HGNC:6407),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (P-loop [AA 10-17], SW1 [AA 25-40], SW2 [AA 57-64], SAK [AA 145-156]). Not applicable to specific amino acid residues (see PM5).",Gene-specific
-KRAS (HGNC:6407),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-KRAS (HGNC:6407),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-KRAS (HGNC:6407),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-KRAS (HGNC:6407),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-KRAS (HGNC:6407),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-KRAS (HGNC:6407),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-KRAS (HGNC:6407),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-KRAS (HGNC:6407),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,"Analogous Gene,Disease-specific"
-KRAS (HGNC:6407),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-KRAS (HGNC:6407),PM6,Strong,2 Points.,Strength
-KRAS (HGNC:6407),PM6,Moderate,1 Point.,None
-KRAS (HGNC:6407),PM6,Supporting,0.5 Points.,Strength
-KRAS (HGNC:6407),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-KRAS (HGNC:6407),PP1,Strong,≥7 informative meioses.,Strength
-KRAS (HGNC:6407),PP1,Moderate,≥5 informative meioses.,Strength
-KRAS (HGNC:6407),PP1,Supporting,≥3 informative meioses.,Disease-specific
-KRAS (HGNC:6407),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-KRAS (HGNC:6407),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-KRAS (HGNC:6407),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-KRAS (HGNC:6407),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-KRAS (HGNC:6407),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-KRAS (HGNC:6407),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-KRAS (HGNC:6407),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-KRAS (HGNC:6407),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-KRAS (HGNC:6407),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-KRAS (HGNC:6407),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-KRAS (HGNC:6407),BS2,Strong,-4 Points.,Strength
-KRAS (HGNC:6407),BS2,Supporting,-1 Point.,Strength
-KRAS (HGNC:6407),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-KRAS (HGNC:6407),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-KRAS (HGNC:6407),BS4,Strong,Requires only one informative meiosis.,General recommendation
-KRAS (HGNC:6407),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-KRAS (HGNC:6407),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-KRAS (HGNC:6407),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-KRAS (HGNC:6407),BP2,Strong,≥ (-4) Points.,Strength
-KRAS (HGNC:6407),BP2,Moderate,≥ (-2) Points.,Strength
-KRAS (HGNC:6407),BP2,Supporting,≥ (-1) Point.,None
-KRAS (HGNC:6407),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-KRAS (HGNC:6407),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-KRAS (HGNC:6407),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-KRAS (HGNC:6407),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-KRAS (HGNC:6407),BP5,Strong,≥ (-4) Points.,Strength
-KRAS (HGNC:6407),BP5,Moderate,≥ (-2) Points.,Strength
-KRAS (HGNC:6407),BP5,Supporting,≥ (-1) Point.,None
-KRAS (HGNC:6407),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-KRAS (HGNC:6407),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-KRAS (HGNC:6407),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforKRASVersion2.3.0_version=2.3.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforKRASVersion2.3.0_version=2.3.0.csv
deleted file mode 100644
index 95458cd25d78d3eec16d33026f8d5eeacb323397..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforKRASVersion2.3.0_version=2.3.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-KRAS (HGNC:6407),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-KRAS (HGNC:6407),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-KRAS (HGNC:6407),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-HRAS, KRAS, MRAS, NRAS, RIT1,
- and 
-RRAS2.",Analogous Gene
-KRAS (HGNC:6407),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-KRAS (HGNC:6407),PS2,Very Strong,4 Points.,Strength
-KRAS (HGNC:6407),PS2,Strong,2 Points.,None
-KRAS (HGNC:6407),PS2,Moderate,1 Point.,Strength
-KRAS (HGNC:6407),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-KRAS (HGNC:6407),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-KRAS (HGNC:6407),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-KRAS (HGNC:6407),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-KRAS (HGNC:6407),PS4,Strong,≥5 points.,Disease-specific
-KRAS (HGNC:6407),PS4,Moderate,≥3 points.,Strength
-KRAS (HGNC:6407),PS4,Supporting,≥1 points.,Strength
-KRAS (HGNC:6407),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-KRAS (HGNC:6407),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (P-loop [AA 10-17], SW1 [AA 25-40], SW2 [AA 57-64], SAK [AA 145-156]). Not applicable to specific amino acid residues (see PM5).",Gene-specific
-KRAS (HGNC:6407),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-KRAS (HGNC:6407),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-KRAS (HGNC:6407),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-KRAS (HGNC:6407),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-KRAS (HGNC:6407),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-KRAS (HGNC:6407),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-KRAS (HGNC:6407),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-KRAS (HGNC:6407),PM5,Moderate,1 [likely] pathogenic residue change at the same codon.,"Analogous Gene,Disease-specific"
-KRAS (HGNC:6407),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-KRAS (HGNC:6407),PM6,Strong,2 Points.,Strength
-KRAS (HGNC:6407),PM6,Moderate,1 Point.,None
-KRAS (HGNC:6407),PM6,Supporting,0.5 Points.,Strength
-KRAS (HGNC:6407),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-KRAS (HGNC:6407),PP1,Strong,≥7 informative meioses.,Strength
-KRAS (HGNC:6407),PP1,Moderate,≥5 informative meioses.,Strength
-KRAS (HGNC:6407),PP1,Supporting,≥3 informative meioses.,Disease-specific
-KRAS (HGNC:6407),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-KRAS (HGNC:6407),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-KRAS (HGNC:6407),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-KRAS (HGNC:6407),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-KRAS (HGNC:6407),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-KRAS (HGNC:6407),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-KRAS (HGNC:6407),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-KRAS (HGNC:6407),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-KRAS (HGNC:6407),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-KRAS (HGNC:6407),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-KRAS (HGNC:6407),BS2,Strong,-4 Points.,Strength
-KRAS (HGNC:6407),BS2,Supporting,-1 Point.,Strength
-KRAS (HGNC:6407),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-KRAS (HGNC:6407),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-KRAS (HGNC:6407),BS4,Strong,Requires only one informative meiosis.,General recommendation
-KRAS (HGNC:6407),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-KRAS (HGNC:6407),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-KRAS (HGNC:6407),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-KRAS (HGNC:6407),BP2,Strong,≥ (-4) Points.,Strength
-KRAS (HGNC:6407),BP2,Moderate,≥ (-2) Points.,Strength
-KRAS (HGNC:6407),BP2,Supporting,≥ (-1) Point.,None
-KRAS (HGNC:6407),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-KRAS (HGNC:6407),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-KRAS (HGNC:6407),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-KRAS (HGNC:6407),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-KRAS (HGNC:6407),BP5,Strong,≥ (-4) Points.,Strength
-KRAS (HGNC:6407),BP5,Moderate,≥ (-2) Points.,Strength
-KRAS (HGNC:6407),BP5,Supporting,≥ (-1) Point.,None
-KRAS (HGNC:6407),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-KRAS (HGNC:6407),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-KRAS (HGNC:6407),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforLZTR1Version1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforLZTR1Version1.0.0_version=1.0.0.csv
deleted file mode 100644
index 3b1f466328e2c06bd7fc1032f76f9a1c7e96337f..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforLZTR1Version1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,94 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-LZTR1 (HGNC:6742),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-LZTR1 (HGNC:6742),PVS1,Very Strong,Null variant in a gene where loss of function is a known mechanism of disease.,"Disease-specific,Gene-specific"
-LZTR1 (HGNC:6742),PVS1,Strong,Null variant in a gene where loss of function is a known mechanism of disease.,"Disease-specific,Gene-specific,Strength"
-LZTR1 (HGNC:6742),PVS1,Moderate,Null variant in a gene where loss of function is a known mechanism of disease.,"Disease-specific,Gene-specific,Strength"
-LZTR1 (HGNC:6742),PVS1,Supporting,Null variant in a gene where loss of function is a known mechanism of disease.,"Disease-specific,Gene-specific,Strength"
-LZTR1 (HGNC:6742),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-LZTR1 (HGNC:6742),PS1,Strong,"Same amino acid change as a previously established pathogenic variant in 
-LZTR1
- regardless of nucleotide change.",No change
-LZTR1 (HGNC:6742),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-LZTR1 (HGNC:6742),PS2,Very Strong,4 Points.,Strength
-LZTR1 (HGNC:6742),PS2,Strong,2 Points.,None
-LZTR1 (HGNC:6742),PS2,Moderate,1 Point.,Strength
-LZTR1 (HGNC:6742),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-LZTR1 (HGNC:6742),PS3,Moderate,Two or more different approved assays.,"Gene-specific,Strength"
-LZTR1 (HGNC:6742),PS3,Supporting,One approved assay.,"Gene-specific,Strength"
-LZTR1 (HGNC:6742),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-LZTR1 (HGNC:6742),PS4,Strong,≥5 points.,Disease-specific
-LZTR1 (HGNC:6742),PS4,Moderate,≥3 points.,Strength
-LZTR1 (HGNC:6742),PS4,Supporting,≥1 points.,Strength
-LZTR1 (HGNC:6742),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-LZTR1 (HGNC:6742),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-LZTR1 (HGNC:6742),PM2,Supporting,"The variant must be absent from controls (gnomAD). For variants in 
-LZTR1
-, PM2_P ≤0.0025% may be applied to support AR disease.","Disease-specific,Gene-specific,Strength"
-LZTR1 (HGNC:6742),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-LZTR1 (HGNC:6742),PM3,Very Strong,≥4 points.,"Disease-specific,Gene-specific,Strength"
-LZTR1 (HGNC:6742),PM3,Strong,≥2 points.,"Disease-specific,Gene-specific,Strength"
-LZTR1 (HGNC:6742),PM3,Moderate,≥1 points.,"Disease-specific,Gene-specific"
-LZTR1 (HGNC:6742),PM3,Supporting,≥0.5 points.,"Disease-specific,Gene-specific,Strength"
-LZTR1 (HGNC:6742),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-LZTR1 (HGNC:6742),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-LZTR1 (HGNC:6742),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-LZTR1 (HGNC:6742),PM5,Strong,≥2 different [likely] pathogenic residue changes at the same codon observed in ≥5 probands.,Strength
-LZTR1 (HGNC:6742),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,Disease-specific
-LZTR1 (HGNC:6742),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-LZTR1 (HGNC:6742),PM6,Strong,2 Points.,Strength
-LZTR1 (HGNC:6742),PM6,Moderate,1 Point.,None
-LZTR1 (HGNC:6742),PM6,Supporting,0.5 Points.,Strength
-LZTR1 (HGNC:6742),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-LZTR1 (HGNC:6742),PP1,Strong,≥7 informative meioses.,Strength
-LZTR1 (HGNC:6742),PP1,Moderate,≥5 informative meioses.,Strength
-LZTR1 (HGNC:6742),PP1,Supporting,≥3 informative meioses.,Disease-specific
-LZTR1 (HGNC:6742),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-LZTR1 (HGNC:6742),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-LZTR1 (HGNC:6742),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-LZTR1 (HGNC:6742),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-LZTR1 (HGNC:6742),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-LZTR1 (HGNC:6742),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-LZTR1 (HGNC:6742),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-LZTR1 (HGNC:6742),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-LZTR1 (HGNC:6742),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-LZTR1 (HGNC:6742),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-LZTR1 (HGNC:6742),BS2,Strong,-4 Points.,Strength
-LZTR1 (HGNC:6742),BS2,Supporting,-1 Point.,Strength
-LZTR1 (HGNC:6742),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-LZTR1 (HGNC:6742),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-LZTR1 (HGNC:6742),BS4,Strong,Requires only one informative meiosis.,General recommendation
-LZTR1 (HGNC:6742),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-LZTR1 (HGNC:6742),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-LZTR1 (HGNC:6742),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-LZTR1 (HGNC:6742),BP2,Strong,≥ (-4) Points.,Strength
-LZTR1 (HGNC:6742),BP2,Moderate,≥ (-2) Points.,Strength
-LZTR1 (HGNC:6742),BP2,Supporting,≥ (-1) Point.,None
-LZTR1 (HGNC:6742),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-LZTR1 (HGNC:6742),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-LZTR1 (HGNC:6742),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-LZTR1 (HGNC:6742),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-LZTR1 (HGNC:6742),BP5,Strong,≥ (-4) Points.,Strength
-LZTR1 (HGNC:6742),BP5,Moderate,≥ (-2) Points.,Strength
-LZTR1 (HGNC:6742),BP5,Supporting,≥ (-1) Point.,None
-LZTR1 (HGNC:6742),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-LZTR1 (HGNC:6742),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-LZTR1 (HGNC:6742),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforLZTR1Version1.1.0_version=1.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforLZTR1Version1.1.0_version=1.1.0.csv
deleted file mode 100644
index a560968f4fba7e06d5d96b3b9c6c1678e3ac5cbb..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforLZTR1Version1.1.0_version=1.1.0.csv
+++ /dev/null
@@ -1,93 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-LZTR1 (HGNC:6742),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-LZTR1 (HGNC:6742),PVS1,Very Strong,Null variant in a gene where loss of function is a known mechanism of disease.,"Disease-specific,Gene-specific"
-LZTR1 (HGNC:6742),PVS1,Strong,Null variant in a gene where loss of function is a known mechanism of disease.,"Disease-specific,Gene-specific,Strength"
-LZTR1 (HGNC:6742),PVS1,Moderate,Null variant in a gene where loss of function is a known mechanism of disease.,"Disease-specific,Gene-specific,Strength"
-LZTR1 (HGNC:6742),PVS1,Supporting,Null variant in a gene where loss of function is a known mechanism of disease.,"Disease-specific,Gene-specific,Strength"
-LZTR1 (HGNC:6742),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-LZTR1 (HGNC:6742),PS1,Strong,"Same amino acid change as a previously established pathogenic variant in 
-LZTR1
- regardless of nucleotide change.",No change
-LZTR1 (HGNC:6742),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-LZTR1 (HGNC:6742),PS2,Very Strong,4 Points.,Strength
-LZTR1 (HGNC:6742),PS2,Strong,2 Points.,None
-LZTR1 (HGNC:6742),PS2,Moderate,1 Point.,Strength
-LZTR1 (HGNC:6742),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-LZTR1 (HGNC:6742),PS3,Moderate,Two or more different approved assays.,"Gene-specific,Strength"
-LZTR1 (HGNC:6742),PS3,Supporting,One approved assay.,"Gene-specific,Strength"
-LZTR1 (HGNC:6742),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-LZTR1 (HGNC:6742),PS4,Strong,≥5 points.,Disease-specific
-LZTR1 (HGNC:6742),PS4,Moderate,≥3 points.,Strength
-LZTR1 (HGNC:6742),PS4,Supporting,≥1 points.,Strength
-LZTR1 (HGNC:6742),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-LZTR1 (HGNC:6742),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-LZTR1 (HGNC:6742),PM2,Supporting,"The variant must be absent from controls (gnomAD). For variants in 
-LZTR1
-, PM2_P ≤0.0025% may be applied to support AR disease.","Disease-specific,Gene-specific,Strength"
-LZTR1 (HGNC:6742),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-LZTR1 (HGNC:6742),PM3,Very Strong,≥4 points.,"Disease-specific,Gene-specific,Strength"
-LZTR1 (HGNC:6742),PM3,Strong,≥2 points.,"Disease-specific,Gene-specific,Strength"
-LZTR1 (HGNC:6742),PM3,Moderate,≥1 points.,"Disease-specific,Gene-specific"
-LZTR1 (HGNC:6742),PM3,Supporting,≥0.5 points.,"Disease-specific,Gene-specific,Strength"
-LZTR1 (HGNC:6742),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-LZTR1 (HGNC:6742),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-LZTR1 (HGNC:6742),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-LZTR1 (HGNC:6742),PM5,Strong,≥2 different [likely] pathogenic residue changes at the same codon observed in ≥5 probands.,Strength
-LZTR1 (HGNC:6742),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,Disease-specific
-LZTR1 (HGNC:6742),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-LZTR1 (HGNC:6742),PM6,Strong,2 Points.,Strength
-LZTR1 (HGNC:6742),PM6,Moderate,1 Point.,None
-LZTR1 (HGNC:6742),PM6,Supporting,0.5 Points.,Strength
-LZTR1 (HGNC:6742),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-LZTR1 (HGNC:6742),PP1,Strong,≥7 informative meioses.,Strength
-LZTR1 (HGNC:6742),PP1,Moderate,≥5 informative meioses.,Strength
-LZTR1 (HGNC:6742),PP1,Supporting,≥3 informative meioses.,Disease-specific
-LZTR1 (HGNC:6742),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-LZTR1 (HGNC:6742),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-LZTR1 (HGNC:6742),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-LZTR1 (HGNC:6742),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-LZTR1 (HGNC:6742),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-LZTR1 (HGNC:6742),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-LZTR1 (HGNC:6742),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-LZTR1 (HGNC:6742),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-LZTR1 (HGNC:6742),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-LZTR1 (HGNC:6742),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-LZTR1 (HGNC:6742),BS2,Strong,-4 Points.,Strength
-LZTR1 (HGNC:6742),BS2,Supporting,-1 Point.,Strength
-LZTR1 (HGNC:6742),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-LZTR1 (HGNC:6742),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-LZTR1 (HGNC:6742),BS4,Strong,Requires only one informative meiosis.,General recommendation
-LZTR1 (HGNC:6742),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-LZTR1 (HGNC:6742),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-LZTR1 (HGNC:6742),BP2,Strong,≥ (-4) Points.,Strength
-LZTR1 (HGNC:6742),BP2,Moderate,≥ (-2) Points.,Strength
-LZTR1 (HGNC:6742),BP2,Supporting,≥ (-1) Point.,None
-LZTR1 (HGNC:6742),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-LZTR1 (HGNC:6742),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-LZTR1 (HGNC:6742),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-LZTR1 (HGNC:6742),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-LZTR1 (HGNC:6742),BP5,Strong,≥ (-4) Points.,Strength
-LZTR1 (HGNC:6742),BP5,Moderate,≥ (-2) Points.,Strength
-LZTR1 (HGNC:6742),BP5,Supporting,≥ (-1) Point.,None
-LZTR1 (HGNC:6742),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-LZTR1 (HGNC:6742),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-LZTR1 (HGNC:6742),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforLZTR1Version1.2.0_version=1.2.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforLZTR1Version1.2.0_version=1.2.0.csv
deleted file mode 100644
index a560968f4fba7e06d5d96b3b9c6c1678e3ac5cbb..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforLZTR1Version1.2.0_version=1.2.0.csv
+++ /dev/null
@@ -1,93 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-LZTR1 (HGNC:6742),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-LZTR1 (HGNC:6742),PVS1,Very Strong,Null variant in a gene where loss of function is a known mechanism of disease.,"Disease-specific,Gene-specific"
-LZTR1 (HGNC:6742),PVS1,Strong,Null variant in a gene where loss of function is a known mechanism of disease.,"Disease-specific,Gene-specific,Strength"
-LZTR1 (HGNC:6742),PVS1,Moderate,Null variant in a gene where loss of function is a known mechanism of disease.,"Disease-specific,Gene-specific,Strength"
-LZTR1 (HGNC:6742),PVS1,Supporting,Null variant in a gene where loss of function is a known mechanism of disease.,"Disease-specific,Gene-specific,Strength"
-LZTR1 (HGNC:6742),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-LZTR1 (HGNC:6742),PS1,Strong,"Same amino acid change as a previously established pathogenic variant in 
-LZTR1
- regardless of nucleotide change.",No change
-LZTR1 (HGNC:6742),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-LZTR1 (HGNC:6742),PS2,Very Strong,4 Points.,Strength
-LZTR1 (HGNC:6742),PS2,Strong,2 Points.,None
-LZTR1 (HGNC:6742),PS2,Moderate,1 Point.,Strength
-LZTR1 (HGNC:6742),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-LZTR1 (HGNC:6742),PS3,Moderate,Two or more different approved assays.,"Gene-specific,Strength"
-LZTR1 (HGNC:6742),PS3,Supporting,One approved assay.,"Gene-specific,Strength"
-LZTR1 (HGNC:6742),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-LZTR1 (HGNC:6742),PS4,Strong,≥5 points.,Disease-specific
-LZTR1 (HGNC:6742),PS4,Moderate,≥3 points.,Strength
-LZTR1 (HGNC:6742),PS4,Supporting,≥1 points.,Strength
-LZTR1 (HGNC:6742),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-LZTR1 (HGNC:6742),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-LZTR1 (HGNC:6742),PM2,Supporting,"The variant must be absent from controls (gnomAD). For variants in 
-LZTR1
-, PM2_P ≤0.0025% may be applied to support AR disease.","Disease-specific,Gene-specific,Strength"
-LZTR1 (HGNC:6742),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-LZTR1 (HGNC:6742),PM3,Very Strong,≥4 points.,"Disease-specific,Gene-specific,Strength"
-LZTR1 (HGNC:6742),PM3,Strong,≥2 points.,"Disease-specific,Gene-specific,Strength"
-LZTR1 (HGNC:6742),PM3,Moderate,≥1 points.,"Disease-specific,Gene-specific"
-LZTR1 (HGNC:6742),PM3,Supporting,≥0.5 points.,"Disease-specific,Gene-specific,Strength"
-LZTR1 (HGNC:6742),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-LZTR1 (HGNC:6742),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-LZTR1 (HGNC:6742),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-LZTR1 (HGNC:6742),PM5,Strong,≥2 different [likely] pathogenic residue changes at the same codon observed in ≥5 probands.,Strength
-LZTR1 (HGNC:6742),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,Disease-specific
-LZTR1 (HGNC:6742),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-LZTR1 (HGNC:6742),PM6,Strong,2 Points.,Strength
-LZTR1 (HGNC:6742),PM6,Moderate,1 Point.,None
-LZTR1 (HGNC:6742),PM6,Supporting,0.5 Points.,Strength
-LZTR1 (HGNC:6742),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-LZTR1 (HGNC:6742),PP1,Strong,≥7 informative meioses.,Strength
-LZTR1 (HGNC:6742),PP1,Moderate,≥5 informative meioses.,Strength
-LZTR1 (HGNC:6742),PP1,Supporting,≥3 informative meioses.,Disease-specific
-LZTR1 (HGNC:6742),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-LZTR1 (HGNC:6742),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-LZTR1 (HGNC:6742),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-LZTR1 (HGNC:6742),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-LZTR1 (HGNC:6742),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-LZTR1 (HGNC:6742),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-LZTR1 (HGNC:6742),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-LZTR1 (HGNC:6742),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-LZTR1 (HGNC:6742),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-LZTR1 (HGNC:6742),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-LZTR1 (HGNC:6742),BS2,Strong,-4 Points.,Strength
-LZTR1 (HGNC:6742),BS2,Supporting,-1 Point.,Strength
-LZTR1 (HGNC:6742),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-LZTR1 (HGNC:6742),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-LZTR1 (HGNC:6742),BS4,Strong,Requires only one informative meiosis.,General recommendation
-LZTR1 (HGNC:6742),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-LZTR1 (HGNC:6742),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-LZTR1 (HGNC:6742),BP2,Strong,≥ (-4) Points.,Strength
-LZTR1 (HGNC:6742),BP2,Moderate,≥ (-2) Points.,Strength
-LZTR1 (HGNC:6742),BP2,Supporting,≥ (-1) Point.,None
-LZTR1 (HGNC:6742),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-LZTR1 (HGNC:6742),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-LZTR1 (HGNC:6742),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-LZTR1 (HGNC:6742),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-LZTR1 (HGNC:6742),BP5,Strong,≥ (-4) Points.,Strength
-LZTR1 (HGNC:6742),BP5,Moderate,≥ (-2) Points.,Strength
-LZTR1 (HGNC:6742),BP5,Supporting,≥ (-1) Point.,None
-LZTR1 (HGNC:6742),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-LZTR1 (HGNC:6742),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-LZTR1 (HGNC:6742),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforLZTR1Version1.3.0_version=1.3.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforLZTR1Version1.3.0_version=1.3.0.csv
deleted file mode 100644
index 873869882e8cbcc18e0bfce1bd5b1e5ebf9935a5..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforLZTR1Version1.3.0_version=1.3.0.csv
+++ /dev/null
@@ -1,93 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-LZTR1 (HGNC:6742),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-LZTR1 (HGNC:6742),PVS1,Very Strong,Null variant in a gene where loss of function is a known mechanism of disease.,"Disease-specific,Gene-specific"
-LZTR1 (HGNC:6742),PVS1,Strong,Null variant in a gene where loss of function is a known mechanism of disease.,"Disease-specific,Gene-specific,Strength"
-LZTR1 (HGNC:6742),PVS1,Moderate,Null variant in a gene where loss of function is a known mechanism of disease.,"Disease-specific,Gene-specific,Strength"
-LZTR1 (HGNC:6742),PVS1,Supporting,Null variant in a gene where loss of function is a known mechanism of disease.,"Disease-specific,Gene-specific,Strength"
-LZTR1 (HGNC:6742),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-LZTR1 (HGNC:6742),PS1,Strong,"Same amino acid change as a previously established pathogenic variant in 
-LZTR1
- regardless of nucleotide change.",No change
-LZTR1 (HGNC:6742),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-LZTR1 (HGNC:6742),PS2,Very Strong,4 Points.,Strength
-LZTR1 (HGNC:6742),PS2,Strong,2 Points.,None
-LZTR1 (HGNC:6742),PS2,Moderate,1 Point.,Strength
-LZTR1 (HGNC:6742),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-LZTR1 (HGNC:6742),PS3,Moderate,Two or more different approved assays.,"Gene-specific,Strength"
-LZTR1 (HGNC:6742),PS3,Supporting,One approved assay.,"Gene-specific,Strength"
-LZTR1 (HGNC:6742),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-LZTR1 (HGNC:6742),PS4,Strong,≥5 points.,Disease-specific
-LZTR1 (HGNC:6742),PS4,Moderate,≥3 points.,Strength
-LZTR1 (HGNC:6742),PS4,Supporting,≥1 points.,Strength
-LZTR1 (HGNC:6742),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-LZTR1 (HGNC:6742),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-LZTR1 (HGNC:6742),PM2,Supporting,"The variant must be absent from controls (gnomAD). For variants in 
-LZTR1
-, PM2_P ≤0.0025% may be applied to support AR disease.","Disease-specific,Gene-specific,Strength"
-LZTR1 (HGNC:6742),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-LZTR1 (HGNC:6742),PM3,Very Strong,≥4 points.,"Disease-specific,Gene-specific,Strength"
-LZTR1 (HGNC:6742),PM3,Strong,≥2 points.,"Disease-specific,Gene-specific,Strength"
-LZTR1 (HGNC:6742),PM3,Moderate,≥1 points.,"Disease-specific,Gene-specific"
-LZTR1 (HGNC:6742),PM3,Supporting,≥0.5 points.,"Disease-specific,Gene-specific,Strength"
-LZTR1 (HGNC:6742),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-LZTR1 (HGNC:6742),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-LZTR1 (HGNC:6742),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-LZTR1 (HGNC:6742),PM5,Strong,≥2 different [likely] pathogenic residue changes at the same codon observed in ≥5 probands.,Strength
-LZTR1 (HGNC:6742),PM5,Moderate,1 [likely] pathogenic residue change at the same codon.,Disease-specific
-LZTR1 (HGNC:6742),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-LZTR1 (HGNC:6742),PM6,Strong,2 Points.,Strength
-LZTR1 (HGNC:6742),PM6,Moderate,1 Point.,None
-LZTR1 (HGNC:6742),PM6,Supporting,0.5 Points.,Strength
-LZTR1 (HGNC:6742),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-LZTR1 (HGNC:6742),PP1,Strong,≥7 informative meioses.,Strength
-LZTR1 (HGNC:6742),PP1,Moderate,≥5 informative meioses.,Strength
-LZTR1 (HGNC:6742),PP1,Supporting,≥3 informative meioses.,Disease-specific
-LZTR1 (HGNC:6742),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-LZTR1 (HGNC:6742),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-LZTR1 (HGNC:6742),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-LZTR1 (HGNC:6742),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-LZTR1 (HGNC:6742),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-LZTR1 (HGNC:6742),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-LZTR1 (HGNC:6742),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-LZTR1 (HGNC:6742),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-LZTR1 (HGNC:6742),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-LZTR1 (HGNC:6742),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-LZTR1 (HGNC:6742),BS2,Strong,-4 Points.,Strength
-LZTR1 (HGNC:6742),BS2,Supporting,-1 Point.,Strength
-LZTR1 (HGNC:6742),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-LZTR1 (HGNC:6742),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-LZTR1 (HGNC:6742),BS4,Strong,Requires only one informative meiosis.,General recommendation
-LZTR1 (HGNC:6742),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-LZTR1 (HGNC:6742),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-LZTR1 (HGNC:6742),BP2,Strong,≥ (-4) Points.,Strength
-LZTR1 (HGNC:6742),BP2,Moderate,≥ (-2) Points.,Strength
-LZTR1 (HGNC:6742),BP2,Supporting,≥ (-1) Point.,None
-LZTR1 (HGNC:6742),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-LZTR1 (HGNC:6742),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-LZTR1 (HGNC:6742),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-LZTR1 (HGNC:6742),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-LZTR1 (HGNC:6742),BP5,Strong,≥ (-4) Points.,Strength
-LZTR1 (HGNC:6742),BP5,Moderate,≥ (-2) Points.,Strength
-LZTR1 (HGNC:6742),BP5,Supporting,≥ (-1) Point.,None
-LZTR1 (HGNC:6742),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-LZTR1 (HGNC:6742),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-LZTR1 (HGNC:6742),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K1Version2.0.0_version=2.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K1Version2.0.0_version=2.0.0.csv
deleted file mode 100644
index 12eab9eba7d1e24ca03cd3b64cf5c8ead3466dd2..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K1Version2.0.0_version=2.0.0.csv
+++ /dev/null
@@ -1,88 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-MAP2K1 (HGNC:6840),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-MAP2K1 (HGNC:6840),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MAP2K1 (HGNC:6840),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-MAP2K1
- and 
-MAP2K2
-.",Analogous Gene
-MAP2K1 (HGNC:6840),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-MAP2K1 (HGNC:6840),PS2,Very Strong,4 Points.,Strength
-MAP2K1 (HGNC:6840),PS2,Strong,2 Points.,None
-MAP2K1 (HGNC:6840),PS2,Moderate,1 Point.,Strength
-MAP2K1 (HGNC:6840),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-MAP2K1 (HGNC:6840),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-MAP2K1 (HGNC:6840),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-MAP2K1 (HGNC:6840),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-MAP2K1 (HGNC:6840),PS4,Strong,≥5 points.,Disease-specific
-MAP2K1 (HGNC:6840),PS4,Moderate,≥3 points.,Strength
-MAP2K1 (HGNC:6840),PS4,Supporting,≥1 points.,Strength
-MAP2K1 (HGNC:6840),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-MAP2K1 (HGNC:6840),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (AA 43-61, AA 124-134). Not applicable to specific amino acid residues (see BP5).",Gene-specific
-MAP2K1 (HGNC:6840),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-MAP2K1 (HGNC:6840),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-MAP2K1 (HGNC:6840),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-MAP2K1 (HGNC:6840),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-MAP2K1 (HGNC:6840),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-MAP2K1 (HGNC:6840),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MAP2K1 (HGNC:6840),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-MAP2K1 (HGNC:6840),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,"Analogous Gene,Disease-specific"
-MAP2K1 (HGNC:6840),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-MAP2K1 (HGNC:6840),PM6,Strong,2 Points.,Strength
-MAP2K1 (HGNC:6840),PM6,Moderate,1 Point.,None
-MAP2K1 (HGNC:6840),PM6,Supporting,0.5 Points.,Strength
-MAP2K1 (HGNC:6840),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-MAP2K1 (HGNC:6840),PP1,Strong,≥7 informative meioses.,Strength
-MAP2K1 (HGNC:6840),PP1,Moderate,≥5 informative meioses.,Strength
-MAP2K1 (HGNC:6840),PP1,Supporting,≥3 informative meioses.,Disease-specific
-MAP2K1 (HGNC:6840),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,
-MAP2K1 (HGNC:6840),PP2,Supporting,Missense z score is >3.09 in gnomAD.,Gene-specific
-MAP2K1 (HGNC:6840),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-MAP2K1 (HGNC:6840),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-MAP2K1 (HGNC:6840),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-MAP2K1 (HGNC:6840),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MAP2K1 (HGNC:6840),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-MAP2K1 (HGNC:6840),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-MAP2K1 (HGNC:6840),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-MAP2K1 (HGNC:6840),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-MAP2K1 (HGNC:6840),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-MAP2K1 (HGNC:6840),BS2,Strong,-4 Points.,Strength
-MAP2K1 (HGNC:6840),BS2,Supporting,-1 Point.,Strength
-MAP2K1 (HGNC:6840),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-MAP2K1 (HGNC:6840),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-MAP2K1 (HGNC:6840),BS4,Strong,Requires only one informative meiosis.,General recommendation
-MAP2K1 (HGNC:6840),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-MAP2K1 (HGNC:6840),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-MAP2K1 (HGNC:6840),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-MAP2K1 (HGNC:6840),BP2,Strong,≥ (-4) Points.,Strength
-MAP2K1 (HGNC:6840),BP2,Moderate,≥ (-2) Points.,Strength
-MAP2K1 (HGNC:6840),BP2,Supporting,≥ (-1) Point.,None
-MAP2K1 (HGNC:6840),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-MAP2K1 (HGNC:6840),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-MAP2K1 (HGNC:6840),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-MAP2K1 (HGNC:6840),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-MAP2K1 (HGNC:6840),BP5,Strong,≥ (-4) Points.,Strength
-MAP2K1 (HGNC:6840),BP5,Moderate,≥ (-2) Points.,Strength
-MAP2K1 (HGNC:6840),BP5,Supporting,≥ (-1) Point.,None
-MAP2K1 (HGNC:6840),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MAP2K1 (HGNC:6840),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-MAP2K1 (HGNC:6840),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K1Version2.1.0_version=2.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K1Version2.1.0_version=2.1.0.csv
deleted file mode 100644
index 82fa2195b8a168f807ba46a58b6fbc0c02fa9db3..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K1Version2.1.0_version=2.1.0.csv
+++ /dev/null
@@ -1,88 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-MAP2K1 (HGNC:6840),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-MAP2K1 (HGNC:6840),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MAP2K1 (HGNC:6840),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-MAP2K1
- and 
-MAP2K2
-.",Analogous Gene
-MAP2K1 (HGNC:6840),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-MAP2K1 (HGNC:6840),PS2,Very Strong,4 Points.,Strength
-MAP2K1 (HGNC:6840),PS2,Strong,2 Points.,None
-MAP2K1 (HGNC:6840),PS2,Moderate,1 Point.,Strength
-MAP2K1 (HGNC:6840),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-MAP2K1 (HGNC:6840),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-MAP2K1 (HGNC:6840),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-MAP2K1 (HGNC:6840),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-MAP2K1 (HGNC:6840),PS4,Strong,≥5 points.,Disease-specific
-MAP2K1 (HGNC:6840),PS4,Moderate,≥3 points.,Strength
-MAP2K1 (HGNC:6840),PS4,Supporting,≥1 points.,Strength
-MAP2K1 (HGNC:6840),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-MAP2K1 (HGNC:6840),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (AA 43-61, AA 124-134). Not applicable to specific amino acid residues (see PM5).",Gene-specific
-MAP2K1 (HGNC:6840),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-MAP2K1 (HGNC:6840),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-MAP2K1 (HGNC:6840),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-MAP2K1 (HGNC:6840),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-MAP2K1 (HGNC:6840),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-MAP2K1 (HGNC:6840),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MAP2K1 (HGNC:6840),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-MAP2K1 (HGNC:6840),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,"Analogous Gene,Disease-specific"
-MAP2K1 (HGNC:6840),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-MAP2K1 (HGNC:6840),PM6,Strong,2 Points.,Strength
-MAP2K1 (HGNC:6840),PM6,Moderate,1 Point.,None
-MAP2K1 (HGNC:6840),PM6,Supporting,0.5 Points.,Strength
-MAP2K1 (HGNC:6840),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-MAP2K1 (HGNC:6840),PP1,Strong,≥7 informative meioses.,Strength
-MAP2K1 (HGNC:6840),PP1,Moderate,≥5 informative meioses.,Strength
-MAP2K1 (HGNC:6840),PP1,Supporting,≥3 informative meioses.,Disease-specific
-MAP2K1 (HGNC:6840),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,
-MAP2K1 (HGNC:6840),PP2,Supporting,Missense z score is >3.09 in gnomAD.,Gene-specific
-MAP2K1 (HGNC:6840),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-MAP2K1 (HGNC:6840),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-MAP2K1 (HGNC:6840),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-MAP2K1 (HGNC:6840),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MAP2K1 (HGNC:6840),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-MAP2K1 (HGNC:6840),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-MAP2K1 (HGNC:6840),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-MAP2K1 (HGNC:6840),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-MAP2K1 (HGNC:6840),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-MAP2K1 (HGNC:6840),BS2,Strong,-4 Points.,Strength
-MAP2K1 (HGNC:6840),BS2,Supporting,-1 Point.,Strength
-MAP2K1 (HGNC:6840),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-MAP2K1 (HGNC:6840),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-MAP2K1 (HGNC:6840),BS4,Strong,Requires only one informative meiosis.,General recommendation
-MAP2K1 (HGNC:6840),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-MAP2K1 (HGNC:6840),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-MAP2K1 (HGNC:6840),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-MAP2K1 (HGNC:6840),BP2,Strong,≥ (-4) Points.,Strength
-MAP2K1 (HGNC:6840),BP2,Moderate,≥ (-2) Points.,Strength
-MAP2K1 (HGNC:6840),BP2,Supporting,≥ (-1) Point.,None
-MAP2K1 (HGNC:6840),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-MAP2K1 (HGNC:6840),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-MAP2K1 (HGNC:6840),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-MAP2K1 (HGNC:6840),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-MAP2K1 (HGNC:6840),BP5,Strong,≥ (-4) Points.,Strength
-MAP2K1 (HGNC:6840),BP5,Moderate,≥ (-2) Points.,Strength
-MAP2K1 (HGNC:6840),BP5,Supporting,≥ (-1) Point.,None
-MAP2K1 (HGNC:6840),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MAP2K1 (HGNC:6840),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-MAP2K1 (HGNC:6840),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K1Version2.2.0_version=2.2.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K1Version2.2.0_version=2.2.0.csv
deleted file mode 100644
index 82fa2195b8a168f807ba46a58b6fbc0c02fa9db3..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K1Version2.2.0_version=2.2.0.csv
+++ /dev/null
@@ -1,88 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-MAP2K1 (HGNC:6840),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-MAP2K1 (HGNC:6840),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MAP2K1 (HGNC:6840),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-MAP2K1
- and 
-MAP2K2
-.",Analogous Gene
-MAP2K1 (HGNC:6840),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-MAP2K1 (HGNC:6840),PS2,Very Strong,4 Points.,Strength
-MAP2K1 (HGNC:6840),PS2,Strong,2 Points.,None
-MAP2K1 (HGNC:6840),PS2,Moderate,1 Point.,Strength
-MAP2K1 (HGNC:6840),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-MAP2K1 (HGNC:6840),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-MAP2K1 (HGNC:6840),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-MAP2K1 (HGNC:6840),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-MAP2K1 (HGNC:6840),PS4,Strong,≥5 points.,Disease-specific
-MAP2K1 (HGNC:6840),PS4,Moderate,≥3 points.,Strength
-MAP2K1 (HGNC:6840),PS4,Supporting,≥1 points.,Strength
-MAP2K1 (HGNC:6840),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-MAP2K1 (HGNC:6840),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (AA 43-61, AA 124-134). Not applicable to specific amino acid residues (see PM5).",Gene-specific
-MAP2K1 (HGNC:6840),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-MAP2K1 (HGNC:6840),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-MAP2K1 (HGNC:6840),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-MAP2K1 (HGNC:6840),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-MAP2K1 (HGNC:6840),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-MAP2K1 (HGNC:6840),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MAP2K1 (HGNC:6840),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-MAP2K1 (HGNC:6840),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,"Analogous Gene,Disease-specific"
-MAP2K1 (HGNC:6840),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-MAP2K1 (HGNC:6840),PM6,Strong,2 Points.,Strength
-MAP2K1 (HGNC:6840),PM6,Moderate,1 Point.,None
-MAP2K1 (HGNC:6840),PM6,Supporting,0.5 Points.,Strength
-MAP2K1 (HGNC:6840),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-MAP2K1 (HGNC:6840),PP1,Strong,≥7 informative meioses.,Strength
-MAP2K1 (HGNC:6840),PP1,Moderate,≥5 informative meioses.,Strength
-MAP2K1 (HGNC:6840),PP1,Supporting,≥3 informative meioses.,Disease-specific
-MAP2K1 (HGNC:6840),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,
-MAP2K1 (HGNC:6840),PP2,Supporting,Missense z score is >3.09 in gnomAD.,Gene-specific
-MAP2K1 (HGNC:6840),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-MAP2K1 (HGNC:6840),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-MAP2K1 (HGNC:6840),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-MAP2K1 (HGNC:6840),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MAP2K1 (HGNC:6840),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-MAP2K1 (HGNC:6840),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-MAP2K1 (HGNC:6840),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-MAP2K1 (HGNC:6840),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-MAP2K1 (HGNC:6840),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-MAP2K1 (HGNC:6840),BS2,Strong,-4 Points.,Strength
-MAP2K1 (HGNC:6840),BS2,Supporting,-1 Point.,Strength
-MAP2K1 (HGNC:6840),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-MAP2K1 (HGNC:6840),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-MAP2K1 (HGNC:6840),BS4,Strong,Requires only one informative meiosis.,General recommendation
-MAP2K1 (HGNC:6840),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-MAP2K1 (HGNC:6840),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-MAP2K1 (HGNC:6840),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-MAP2K1 (HGNC:6840),BP2,Strong,≥ (-4) Points.,Strength
-MAP2K1 (HGNC:6840),BP2,Moderate,≥ (-2) Points.,Strength
-MAP2K1 (HGNC:6840),BP2,Supporting,≥ (-1) Point.,None
-MAP2K1 (HGNC:6840),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-MAP2K1 (HGNC:6840),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-MAP2K1 (HGNC:6840),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-MAP2K1 (HGNC:6840),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-MAP2K1 (HGNC:6840),BP5,Strong,≥ (-4) Points.,Strength
-MAP2K1 (HGNC:6840),BP5,Moderate,≥ (-2) Points.,Strength
-MAP2K1 (HGNC:6840),BP5,Supporting,≥ (-1) Point.,None
-MAP2K1 (HGNC:6840),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MAP2K1 (HGNC:6840),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-MAP2K1 (HGNC:6840),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K1Version2.3.0_version=2.3.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K1Version2.3.0_version=2.3.0.csv
deleted file mode 100644
index 0797ddd85e7614ed4aaf93a1d7c15ed34c7d1adc..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K1Version2.3.0_version=2.3.0.csv
+++ /dev/null
@@ -1,88 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-MAP2K1 (HGNC:6840),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-MAP2K1 (HGNC:6840),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MAP2K1 (HGNC:6840),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-MAP2K1
- and 
-MAP2K2
-.",Analogous Gene
-MAP2K1 (HGNC:6840),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-MAP2K1 (HGNC:6840),PS2,Very Strong,4 Points.,Strength
-MAP2K1 (HGNC:6840),PS2,Strong,2 Points.,None
-MAP2K1 (HGNC:6840),PS2,Moderate,1 Point.,Strength
-MAP2K1 (HGNC:6840),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-MAP2K1 (HGNC:6840),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-MAP2K1 (HGNC:6840),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-MAP2K1 (HGNC:6840),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-MAP2K1 (HGNC:6840),PS4,Strong,≥5 points.,Disease-specific
-MAP2K1 (HGNC:6840),PS4,Moderate,≥3 points.,Strength
-MAP2K1 (HGNC:6840),PS4,Supporting,≥1 points.,Strength
-MAP2K1 (HGNC:6840),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-MAP2K1 (HGNC:6840),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (AA 43-61, AA 124-134). Not applicable to specific amino acid residues (see PM5).",Gene-specific
-MAP2K1 (HGNC:6840),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-MAP2K1 (HGNC:6840),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-MAP2K1 (HGNC:6840),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-MAP2K1 (HGNC:6840),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-MAP2K1 (HGNC:6840),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-MAP2K1 (HGNC:6840),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MAP2K1 (HGNC:6840),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-MAP2K1 (HGNC:6840),PM5,Moderate,1 [likely] pathogenic residue change at the same codon.,"Analogous Gene,Disease-specific"
-MAP2K1 (HGNC:6840),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-MAP2K1 (HGNC:6840),PM6,Strong,2 Points.,Strength
-MAP2K1 (HGNC:6840),PM6,Moderate,1 Point.,None
-MAP2K1 (HGNC:6840),PM6,Supporting,0.5 Points.,Strength
-MAP2K1 (HGNC:6840),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-MAP2K1 (HGNC:6840),PP1,Strong,≥7 informative meioses.,Strength
-MAP2K1 (HGNC:6840),PP1,Moderate,≥5 informative meioses.,Strength
-MAP2K1 (HGNC:6840),PP1,Supporting,≥3 informative meioses.,Disease-specific
-MAP2K1 (HGNC:6840),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,
-MAP2K1 (HGNC:6840),PP2,Supporting,Missense z score is >3.09 in gnomAD.,Gene-specific
-MAP2K1 (HGNC:6840),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-MAP2K1 (HGNC:6840),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-MAP2K1 (HGNC:6840),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-MAP2K1 (HGNC:6840),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MAP2K1 (HGNC:6840),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-MAP2K1 (HGNC:6840),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-MAP2K1 (HGNC:6840),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-MAP2K1 (HGNC:6840),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-MAP2K1 (HGNC:6840),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-MAP2K1 (HGNC:6840),BS2,Strong,-4 Points.,Strength
-MAP2K1 (HGNC:6840),BS2,Supporting,-1 Point.,Strength
-MAP2K1 (HGNC:6840),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-MAP2K1 (HGNC:6840),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-MAP2K1 (HGNC:6840),BS4,Strong,Requires only one informative meiosis.,General recommendation
-MAP2K1 (HGNC:6840),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-MAP2K1 (HGNC:6840),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-MAP2K1 (HGNC:6840),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-MAP2K1 (HGNC:6840),BP2,Strong,≥ (-4) Points.,Strength
-MAP2K1 (HGNC:6840),BP2,Moderate,≥ (-2) Points.,Strength
-MAP2K1 (HGNC:6840),BP2,Supporting,≥ (-1) Point.,None
-MAP2K1 (HGNC:6840),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-MAP2K1 (HGNC:6840),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-MAP2K1 (HGNC:6840),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-MAP2K1 (HGNC:6840),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-MAP2K1 (HGNC:6840),BP5,Strong,≥ (-4) Points.,Strength
-MAP2K1 (HGNC:6840),BP5,Moderate,≥ (-2) Points.,Strength
-MAP2K1 (HGNC:6840),BP5,Supporting,≥ (-1) Point.,None
-MAP2K1 (HGNC:6840),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MAP2K1 (HGNC:6840),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-MAP2K1 (HGNC:6840),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K2Version2.0.0_version=2.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K2Version2.0.0_version=2.0.0.csv
deleted file mode 100644
index 94c4455c54dda9b7b82c7b3d440c22523f188a5e..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K2Version2.0.0_version=2.0.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-MAP2K2 (HGNC:6842),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-MAP2K2 (HGNC:6842),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MAP2K2 (HGNC:6842),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-MAP2K1
- and 
-MAP2K2.",Analogous Gene
-MAP2K2 (HGNC:6842),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-MAP2K2 (HGNC:6842),PS2,Very Strong,4 Points.,Strength
-MAP2K2 (HGNC:6842),PS2,Strong,2 Points.,None
-MAP2K2 (HGNC:6842),PS2,Moderate,1 Point.,Strength
-MAP2K2 (HGNC:6842),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-MAP2K2 (HGNC:6842),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-MAP2K2 (HGNC:6842),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-MAP2K2 (HGNC:6842),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-MAP2K2 (HGNC:6842),PS4,Strong,≥5 points.,Disease-specific
-MAP2K2 (HGNC:6842),PS4,Moderate,≥3 points.,Strength
-MAP2K2 (HGNC:6842),PS4,Supporting,≥1 points.,Strength
-MAP2K2 (HGNC:6842),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-MAP2K2 (HGNC:6842),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (AA 47-65, AA 128-138). Not applicable to specific amino acid residues (see BP5).",Gene-specific
-MAP2K2 (HGNC:6842),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-MAP2K2 (HGNC:6842),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-MAP2K2 (HGNC:6842),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-MAP2K2 (HGNC:6842),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-MAP2K2 (HGNC:6842),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-MAP2K2 (HGNC:6842),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MAP2K2 (HGNC:6842),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-MAP2K2 (HGNC:6842),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,"Analogous Gene,Disease-specific"
-MAP2K2 (HGNC:6842),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-MAP2K2 (HGNC:6842),PM6,Strong,2 Points.,Strength
-MAP2K2 (HGNC:6842),PM6,Moderate,1 Point.,None
-MAP2K2 (HGNC:6842),PM6,Supporting,0.5 Points.,Strength
-MAP2K2 (HGNC:6842),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-MAP2K2 (HGNC:6842),PP1,Strong,≥7 informative meioses.,Strength
-MAP2K2 (HGNC:6842),PP1,Moderate,≥5 informative meioses.,Strength
-MAP2K2 (HGNC:6842),PP1,Supporting,≥3 informative meioses.,Disease-specific
-MAP2K2 (HGNC:6842),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-MAP2K2 (HGNC:6842),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-MAP2K2 (HGNC:6842),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-MAP2K2 (HGNC:6842),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-MAP2K2 (HGNC:6842),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MAP2K2 (HGNC:6842),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-MAP2K2 (HGNC:6842),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-MAP2K2 (HGNC:6842),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-MAP2K2 (HGNC:6842),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-MAP2K2 (HGNC:6842),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-MAP2K2 (HGNC:6842),BS2,Strong,-4 Points.,Strength
-MAP2K2 (HGNC:6842),BS2,Supporting,-1 Point.,Strength
-MAP2K2 (HGNC:6842),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-MAP2K2 (HGNC:6842),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-MAP2K2 (HGNC:6842),BS4,Strong,Requires only one informative meiosis.,General recommendation
-MAP2K2 (HGNC:6842),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-MAP2K2 (HGNC:6842),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-MAP2K2 (HGNC:6842),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-MAP2K2 (HGNC:6842),BP2,Strong,≥ (-4) Points.,Strength
-MAP2K2 (HGNC:6842),BP2,Moderate,≥ (-2) Points.,Strength
-MAP2K2 (HGNC:6842),BP2,Supporting,≥ (-1) Point.,None
-MAP2K2 (HGNC:6842),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-MAP2K2 (HGNC:6842),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-MAP2K2 (HGNC:6842),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-MAP2K2 (HGNC:6842),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-MAP2K2 (HGNC:6842),BP5,Strong,≥ (-4) Points.,Strength
-MAP2K2 (HGNC:6842),BP5,Moderate,≥ (-2) Points.,Strength
-MAP2K2 (HGNC:6842),BP5,Supporting,≥ (-1) Point.,None
-MAP2K2 (HGNC:6842),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MAP2K2 (HGNC:6842),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-MAP2K2 (HGNC:6842),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K2Version2.1.0_version=2.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K2Version2.1.0_version=2.1.0.csv
deleted file mode 100644
index cd3b9e22d475a115dfcb53555a1e8aa5dd384daf..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K2Version2.1.0_version=2.1.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-MAP2K2 (HGNC:6842),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-MAP2K2 (HGNC:6842),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MAP2K2 (HGNC:6842),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-MAP2K1
- and 
-MAP2K2.",Analogous Gene
-MAP2K2 (HGNC:6842),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-MAP2K2 (HGNC:6842),PS2,Very Strong,4 Points.,Strength
-MAP2K2 (HGNC:6842),PS2,Strong,2 Points.,None
-MAP2K2 (HGNC:6842),PS2,Moderate,1 Point.,Strength
-MAP2K2 (HGNC:6842),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-MAP2K2 (HGNC:6842),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-MAP2K2 (HGNC:6842),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-MAP2K2 (HGNC:6842),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-MAP2K2 (HGNC:6842),PS4,Strong,≥5 points.,Disease-specific
-MAP2K2 (HGNC:6842),PS4,Moderate,≥3 points.,Strength
-MAP2K2 (HGNC:6842),PS4,Supporting,≥1 points.,Strength
-MAP2K2 (HGNC:6842),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-MAP2K2 (HGNC:6842),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (AA 47-65, AA 128-138). Not applicable to specific amino acid residues (see PM5).",Gene-specific
-MAP2K2 (HGNC:6842),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-MAP2K2 (HGNC:6842),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-MAP2K2 (HGNC:6842),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-MAP2K2 (HGNC:6842),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-MAP2K2 (HGNC:6842),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-MAP2K2 (HGNC:6842),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MAP2K2 (HGNC:6842),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-MAP2K2 (HGNC:6842),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,"Analogous Gene,Disease-specific"
-MAP2K2 (HGNC:6842),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-MAP2K2 (HGNC:6842),PM6,Strong,2 Points.,Strength
-MAP2K2 (HGNC:6842),PM6,Moderate,1 Point.,None
-MAP2K2 (HGNC:6842),PM6,Supporting,0.5 Points.,Strength
-MAP2K2 (HGNC:6842),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-MAP2K2 (HGNC:6842),PP1,Strong,≥7 informative meioses.,Strength
-MAP2K2 (HGNC:6842),PP1,Moderate,≥5 informative meioses.,Strength
-MAP2K2 (HGNC:6842),PP1,Supporting,≥3 informative meioses.,Disease-specific
-MAP2K2 (HGNC:6842),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-MAP2K2 (HGNC:6842),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-MAP2K2 (HGNC:6842),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-MAP2K2 (HGNC:6842),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-MAP2K2 (HGNC:6842),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MAP2K2 (HGNC:6842),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-MAP2K2 (HGNC:6842),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-MAP2K2 (HGNC:6842),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-MAP2K2 (HGNC:6842),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-MAP2K2 (HGNC:6842),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-MAP2K2 (HGNC:6842),BS2,Strong,-4 Points.,Strength
-MAP2K2 (HGNC:6842),BS2,Supporting,-1 Point.,Strength
-MAP2K2 (HGNC:6842),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-MAP2K2 (HGNC:6842),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-MAP2K2 (HGNC:6842),BS4,Strong,Requires only one informative meiosis.,General recommendation
-MAP2K2 (HGNC:6842),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-MAP2K2 (HGNC:6842),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-MAP2K2 (HGNC:6842),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-MAP2K2 (HGNC:6842),BP2,Strong,≥ (-4) Points.,Strength
-MAP2K2 (HGNC:6842),BP2,Moderate,≥ (-2) Points.,Strength
-MAP2K2 (HGNC:6842),BP2,Supporting,≥ (-1) Point.,None
-MAP2K2 (HGNC:6842),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-MAP2K2 (HGNC:6842),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-MAP2K2 (HGNC:6842),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-MAP2K2 (HGNC:6842),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-MAP2K2 (HGNC:6842),BP5,Strong,≥ (-4) Points.,Strength
-MAP2K2 (HGNC:6842),BP5,Moderate,≥ (-2) Points.,Strength
-MAP2K2 (HGNC:6842),BP5,Supporting,≥ (-1) Point.,None
-MAP2K2 (HGNC:6842),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MAP2K2 (HGNC:6842),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-MAP2K2 (HGNC:6842),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K2Version2.2.0_version=2.2.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K2Version2.2.0_version=2.2.0.csv
deleted file mode 100644
index cd3b9e22d475a115dfcb53555a1e8aa5dd384daf..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K2Version2.2.0_version=2.2.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-MAP2K2 (HGNC:6842),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-MAP2K2 (HGNC:6842),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MAP2K2 (HGNC:6842),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-MAP2K1
- and 
-MAP2K2.",Analogous Gene
-MAP2K2 (HGNC:6842),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-MAP2K2 (HGNC:6842),PS2,Very Strong,4 Points.,Strength
-MAP2K2 (HGNC:6842),PS2,Strong,2 Points.,None
-MAP2K2 (HGNC:6842),PS2,Moderate,1 Point.,Strength
-MAP2K2 (HGNC:6842),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-MAP2K2 (HGNC:6842),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-MAP2K2 (HGNC:6842),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-MAP2K2 (HGNC:6842),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-MAP2K2 (HGNC:6842),PS4,Strong,≥5 points.,Disease-specific
-MAP2K2 (HGNC:6842),PS4,Moderate,≥3 points.,Strength
-MAP2K2 (HGNC:6842),PS4,Supporting,≥1 points.,Strength
-MAP2K2 (HGNC:6842),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-MAP2K2 (HGNC:6842),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (AA 47-65, AA 128-138). Not applicable to specific amino acid residues (see PM5).",Gene-specific
-MAP2K2 (HGNC:6842),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-MAP2K2 (HGNC:6842),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-MAP2K2 (HGNC:6842),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-MAP2K2 (HGNC:6842),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-MAP2K2 (HGNC:6842),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-MAP2K2 (HGNC:6842),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MAP2K2 (HGNC:6842),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-MAP2K2 (HGNC:6842),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,"Analogous Gene,Disease-specific"
-MAP2K2 (HGNC:6842),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-MAP2K2 (HGNC:6842),PM6,Strong,2 Points.,Strength
-MAP2K2 (HGNC:6842),PM6,Moderate,1 Point.,None
-MAP2K2 (HGNC:6842),PM6,Supporting,0.5 Points.,Strength
-MAP2K2 (HGNC:6842),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-MAP2K2 (HGNC:6842),PP1,Strong,≥7 informative meioses.,Strength
-MAP2K2 (HGNC:6842),PP1,Moderate,≥5 informative meioses.,Strength
-MAP2K2 (HGNC:6842),PP1,Supporting,≥3 informative meioses.,Disease-specific
-MAP2K2 (HGNC:6842),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-MAP2K2 (HGNC:6842),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-MAP2K2 (HGNC:6842),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-MAP2K2 (HGNC:6842),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-MAP2K2 (HGNC:6842),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MAP2K2 (HGNC:6842),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-MAP2K2 (HGNC:6842),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-MAP2K2 (HGNC:6842),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-MAP2K2 (HGNC:6842),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-MAP2K2 (HGNC:6842),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-MAP2K2 (HGNC:6842),BS2,Strong,-4 Points.,Strength
-MAP2K2 (HGNC:6842),BS2,Supporting,-1 Point.,Strength
-MAP2K2 (HGNC:6842),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-MAP2K2 (HGNC:6842),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-MAP2K2 (HGNC:6842),BS4,Strong,Requires only one informative meiosis.,General recommendation
-MAP2K2 (HGNC:6842),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-MAP2K2 (HGNC:6842),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-MAP2K2 (HGNC:6842),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-MAP2K2 (HGNC:6842),BP2,Strong,≥ (-4) Points.,Strength
-MAP2K2 (HGNC:6842),BP2,Moderate,≥ (-2) Points.,Strength
-MAP2K2 (HGNC:6842),BP2,Supporting,≥ (-1) Point.,None
-MAP2K2 (HGNC:6842),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-MAP2K2 (HGNC:6842),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-MAP2K2 (HGNC:6842),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-MAP2K2 (HGNC:6842),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-MAP2K2 (HGNC:6842),BP5,Strong,≥ (-4) Points.,Strength
-MAP2K2 (HGNC:6842),BP5,Moderate,≥ (-2) Points.,Strength
-MAP2K2 (HGNC:6842),BP5,Supporting,≥ (-1) Point.,None
-MAP2K2 (HGNC:6842),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MAP2K2 (HGNC:6842),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-MAP2K2 (HGNC:6842),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K2Version2.3.0_version=2.3.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K2Version2.3.0_version=2.3.0.csv
deleted file mode 100644
index 083f75f68f4d67c7d7aeb40beefefb94cb36ccc6..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMAP2K2Version2.3.0_version=2.3.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-MAP2K2 (HGNC:6842),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-MAP2K2 (HGNC:6842),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MAP2K2 (HGNC:6842),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-MAP2K1
- and 
-MAP2K2.",Analogous Gene
-MAP2K2 (HGNC:6842),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-MAP2K2 (HGNC:6842),PS2,Very Strong,4 Points.,Strength
-MAP2K2 (HGNC:6842),PS2,Strong,2 Points.,None
-MAP2K2 (HGNC:6842),PS2,Moderate,1 Point.,Strength
-MAP2K2 (HGNC:6842),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-MAP2K2 (HGNC:6842),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-MAP2K2 (HGNC:6842),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-MAP2K2 (HGNC:6842),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-MAP2K2 (HGNC:6842),PS4,Strong,≥5 points.,Disease-specific
-MAP2K2 (HGNC:6842),PS4,Moderate,≥3 points.,Strength
-MAP2K2 (HGNC:6842),PS4,Supporting,≥1 points.,Strength
-MAP2K2 (HGNC:6842),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-MAP2K2 (HGNC:6842),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (AA 47-65, AA 128-138). Not applicable to specific amino acid residues (see PM5).",Gene-specific
-MAP2K2 (HGNC:6842),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-MAP2K2 (HGNC:6842),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-MAP2K2 (HGNC:6842),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-MAP2K2 (HGNC:6842),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-MAP2K2 (HGNC:6842),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-MAP2K2 (HGNC:6842),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MAP2K2 (HGNC:6842),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-MAP2K2 (HGNC:6842),PM5,Moderate,1 [likely] pathogenic residue change at the same codon.,"Analogous Gene,Disease-specific"
-MAP2K2 (HGNC:6842),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-MAP2K2 (HGNC:6842),PM6,Strong,2 Points.,Strength
-MAP2K2 (HGNC:6842),PM6,Moderate,1 Point.,None
-MAP2K2 (HGNC:6842),PM6,Supporting,0.5 Points.,Strength
-MAP2K2 (HGNC:6842),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-MAP2K2 (HGNC:6842),PP1,Strong,≥7 informative meioses.,Strength
-MAP2K2 (HGNC:6842),PP1,Moderate,≥5 informative meioses.,Strength
-MAP2K2 (HGNC:6842),PP1,Supporting,≥3 informative meioses.,Disease-specific
-MAP2K2 (HGNC:6842),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-MAP2K2 (HGNC:6842),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-MAP2K2 (HGNC:6842),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-MAP2K2 (HGNC:6842),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-MAP2K2 (HGNC:6842),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MAP2K2 (HGNC:6842),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-MAP2K2 (HGNC:6842),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-MAP2K2 (HGNC:6842),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-MAP2K2 (HGNC:6842),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-MAP2K2 (HGNC:6842),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-MAP2K2 (HGNC:6842),BS2,Strong,-4 Points.,Strength
-MAP2K2 (HGNC:6842),BS2,Supporting,-1 Point.,Strength
-MAP2K2 (HGNC:6842),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-MAP2K2 (HGNC:6842),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-MAP2K2 (HGNC:6842),BS4,Strong,Requires only one informative meiosis.,General recommendation
-MAP2K2 (HGNC:6842),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-MAP2K2 (HGNC:6842),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-MAP2K2 (HGNC:6842),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-MAP2K2 (HGNC:6842),BP2,Strong,≥ (-4) Points.,Strength
-MAP2K2 (HGNC:6842),BP2,Moderate,≥ (-2) Points.,Strength
-MAP2K2 (HGNC:6842),BP2,Supporting,≥ (-1) Point.,None
-MAP2K2 (HGNC:6842),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-MAP2K2 (HGNC:6842),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-MAP2K2 (HGNC:6842),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-MAP2K2 (HGNC:6842),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-MAP2K2 (HGNC:6842),BP5,Strong,≥ (-4) Points.,Strength
-MAP2K2 (HGNC:6842),BP5,Moderate,≥ (-2) Points.,Strength
-MAP2K2 (HGNC:6842),BP5,Supporting,≥ (-1) Point.,None
-MAP2K2 (HGNC:6842),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MAP2K2 (HGNC:6842),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-MAP2K2 (HGNC:6842),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMRASVersion1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMRASVersion1.0.0_version=1.0.0.csv
deleted file mode 100644
index 62c0fce5add5f01b7676485da84bc67c80795b40..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMRASVersion1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-MRAS (HGNC:7227),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-MRAS (HGNC:7227),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MRAS (HGNC:7227),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-HRAS, KRAS, MRAS, NRAS, RIT1,
- and 
-RRAS2.",Analogous Gene
-MRAS (HGNC:7227),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-MRAS (HGNC:7227),PS2,Very Strong,4 Points.,Strength
-MRAS (HGNC:7227),PS2,Strong,2 Points.,None
-MRAS (HGNC:7227),PS2,Moderate,1 Point.,Strength
-MRAS (HGNC:7227),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-MRAS (HGNC:7227),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-MRAS (HGNC:7227),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-MRAS (HGNC:7227),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-MRAS (HGNC:7227),PS4,Strong,≥5 points.,Disease-specific
-MRAS (HGNC:7227),PS4,Moderate,≥3 points.,Strength
-MRAS (HGNC:7227),PS4,Supporting,≥1 points.,Strength
-MRAS (HGNC:7227),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-MRAS (HGNC:7227),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (P-loop [AA 20-27], SW1 [AA 35-50], SW2 [AA 67-74], no SAK). Not applicable to specific amino acid residues (see BP5).",Gene-specific
-MRAS (HGNC:7227),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-MRAS (HGNC:7227),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-MRAS (HGNC:7227),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-MRAS (HGNC:7227),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-MRAS (HGNC:7227),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-MRAS (HGNC:7227),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MRAS (HGNC:7227),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-MRAS (HGNC:7227),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,"Analogous Gene,Disease-specific"
-MRAS (HGNC:7227),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-MRAS (HGNC:7227),PM6,Strong,2 Points.,Strength
-MRAS (HGNC:7227),PM6,Moderate,1 Point.,None
-MRAS (HGNC:7227),PM6,Supporting,0.5 Points.,Strength
-MRAS (HGNC:7227),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-MRAS (HGNC:7227),PP1,Strong,≥7 informative meioses.,Strength
-MRAS (HGNC:7227),PP1,Moderate,≥5 informative meioses.,Strength
-MRAS (HGNC:7227),PP1,Supporting,≥3 informative meioses.,Disease-specific
-MRAS (HGNC:7227),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-MRAS (HGNC:7227),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-MRAS (HGNC:7227),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-MRAS (HGNC:7227),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-MRAS (HGNC:7227),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MRAS (HGNC:7227),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-MRAS (HGNC:7227),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-MRAS (HGNC:7227),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-MRAS (HGNC:7227),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-MRAS (HGNC:7227),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-MRAS (HGNC:7227),BS2,Strong,-4 Points.,Strength
-MRAS (HGNC:7227),BS2,Supporting,-1 Point.,Strength
-MRAS (HGNC:7227),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-MRAS (HGNC:7227),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-MRAS (HGNC:7227),BS4,Strong,Requires only one informative meiosis.,General recommendation
-MRAS (HGNC:7227),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-MRAS (HGNC:7227),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-MRAS (HGNC:7227),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-MRAS (HGNC:7227),BP2,Strong,≥ (-4) Points.,Strength
-MRAS (HGNC:7227),BP2,Moderate,≥ (-2) Points.,Strength
-MRAS (HGNC:7227),BP2,Supporting,≥ (-1) Point.,None
-MRAS (HGNC:7227),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-MRAS (HGNC:7227),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-MRAS (HGNC:7227),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-MRAS (HGNC:7227),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-MRAS (HGNC:7227),BP5,Strong,≥ (-4) Points.,Strength
-MRAS (HGNC:7227),BP5,Moderate,≥ (-2) Points.,Strength
-MRAS (HGNC:7227),BP5,Supporting,≥ (-1) Point.,None
-MRAS (HGNC:7227),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MRAS (HGNC:7227),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-MRAS (HGNC:7227),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMRASVersion1.1.0_version=1.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMRASVersion1.1.0_version=1.1.0.csv
deleted file mode 100644
index 690de50289bbe430d6e2a745d3edf18a9c3ef767..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMRASVersion1.1.0_version=1.1.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-MRAS (HGNC:7227),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-MRAS (HGNC:7227),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MRAS (HGNC:7227),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-HRAS, KRAS, MRAS, NRAS, RIT1,
- and 
-RRAS2.",Analogous Gene
-MRAS (HGNC:7227),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-MRAS (HGNC:7227),PS2,Very Strong,4 Points.,Strength
-MRAS (HGNC:7227),PS2,Strong,2 Points.,None
-MRAS (HGNC:7227),PS2,Moderate,1 Point.,Strength
-MRAS (HGNC:7227),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-MRAS (HGNC:7227),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-MRAS (HGNC:7227),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-MRAS (HGNC:7227),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-MRAS (HGNC:7227),PS4,Strong,≥5 points.,Disease-specific
-MRAS (HGNC:7227),PS4,Moderate,≥3 points.,Strength
-MRAS (HGNC:7227),PS4,Supporting,≥1 points.,Strength
-MRAS (HGNC:7227),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-MRAS (HGNC:7227),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (P-loop [AA 20-27], SW1 [AA 35-50], SW2 [AA 67-74], no SAK). Not applicable to specific amino acid residues (see PM5).",Gene-specific
-MRAS (HGNC:7227),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-MRAS (HGNC:7227),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-MRAS (HGNC:7227),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-MRAS (HGNC:7227),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-MRAS (HGNC:7227),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-MRAS (HGNC:7227),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MRAS (HGNC:7227),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-MRAS (HGNC:7227),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,"Analogous Gene,Disease-specific"
-MRAS (HGNC:7227),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-MRAS (HGNC:7227),PM6,Strong,2 Points.,Strength
-MRAS (HGNC:7227),PM6,Moderate,1 Point.,None
-MRAS (HGNC:7227),PM6,Supporting,0.5 Points.,Strength
-MRAS (HGNC:7227),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-MRAS (HGNC:7227),PP1,Strong,≥7 informative meioses.,Strength
-MRAS (HGNC:7227),PP1,Moderate,≥5 informative meioses.,Strength
-MRAS (HGNC:7227),PP1,Supporting,≥3 informative meioses.,Disease-specific
-MRAS (HGNC:7227),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-MRAS (HGNC:7227),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-MRAS (HGNC:7227),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-MRAS (HGNC:7227),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-MRAS (HGNC:7227),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MRAS (HGNC:7227),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-MRAS (HGNC:7227),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-MRAS (HGNC:7227),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-MRAS (HGNC:7227),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-MRAS (HGNC:7227),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-MRAS (HGNC:7227),BS2,Strong,-4 Points.,Strength
-MRAS (HGNC:7227),BS2,Supporting,-1 Point.,Strength
-MRAS (HGNC:7227),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-MRAS (HGNC:7227),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-MRAS (HGNC:7227),BS4,Strong,Requires only one informative meiosis.,General recommendation
-MRAS (HGNC:7227),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-MRAS (HGNC:7227),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-MRAS (HGNC:7227),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-MRAS (HGNC:7227),BP2,Strong,≥ (-4) Points.,Strength
-MRAS (HGNC:7227),BP2,Moderate,≥ (-2) Points.,Strength
-MRAS (HGNC:7227),BP2,Supporting,≥ (-1) Point.,None
-MRAS (HGNC:7227),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-MRAS (HGNC:7227),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-MRAS (HGNC:7227),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-MRAS (HGNC:7227),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-MRAS (HGNC:7227),BP5,Strong,≥ (-4) Points.,Strength
-MRAS (HGNC:7227),BP5,Moderate,≥ (-2) Points.,Strength
-MRAS (HGNC:7227),BP5,Supporting,≥ (-1) Point.,None
-MRAS (HGNC:7227),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MRAS (HGNC:7227),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-MRAS (HGNC:7227),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMRASVersion1.2.0_version=1.2.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMRASVersion1.2.0_version=1.2.0.csv
deleted file mode 100644
index 690de50289bbe430d6e2a745d3edf18a9c3ef767..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMRASVersion1.2.0_version=1.2.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-MRAS (HGNC:7227),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-MRAS (HGNC:7227),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MRAS (HGNC:7227),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-HRAS, KRAS, MRAS, NRAS, RIT1,
- and 
-RRAS2.",Analogous Gene
-MRAS (HGNC:7227),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-MRAS (HGNC:7227),PS2,Very Strong,4 Points.,Strength
-MRAS (HGNC:7227),PS2,Strong,2 Points.,None
-MRAS (HGNC:7227),PS2,Moderate,1 Point.,Strength
-MRAS (HGNC:7227),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-MRAS (HGNC:7227),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-MRAS (HGNC:7227),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-MRAS (HGNC:7227),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-MRAS (HGNC:7227),PS4,Strong,≥5 points.,Disease-specific
-MRAS (HGNC:7227),PS4,Moderate,≥3 points.,Strength
-MRAS (HGNC:7227),PS4,Supporting,≥1 points.,Strength
-MRAS (HGNC:7227),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-MRAS (HGNC:7227),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (P-loop [AA 20-27], SW1 [AA 35-50], SW2 [AA 67-74], no SAK). Not applicable to specific amino acid residues (see PM5).",Gene-specific
-MRAS (HGNC:7227),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-MRAS (HGNC:7227),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-MRAS (HGNC:7227),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-MRAS (HGNC:7227),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-MRAS (HGNC:7227),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-MRAS (HGNC:7227),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MRAS (HGNC:7227),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-MRAS (HGNC:7227),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,"Analogous Gene,Disease-specific"
-MRAS (HGNC:7227),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-MRAS (HGNC:7227),PM6,Strong,2 Points.,Strength
-MRAS (HGNC:7227),PM6,Moderate,1 Point.,None
-MRAS (HGNC:7227),PM6,Supporting,0.5 Points.,Strength
-MRAS (HGNC:7227),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-MRAS (HGNC:7227),PP1,Strong,≥7 informative meioses.,Strength
-MRAS (HGNC:7227),PP1,Moderate,≥5 informative meioses.,Strength
-MRAS (HGNC:7227),PP1,Supporting,≥3 informative meioses.,Disease-specific
-MRAS (HGNC:7227),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-MRAS (HGNC:7227),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-MRAS (HGNC:7227),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-MRAS (HGNC:7227),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-MRAS (HGNC:7227),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MRAS (HGNC:7227),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-MRAS (HGNC:7227),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-MRAS (HGNC:7227),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-MRAS (HGNC:7227),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-MRAS (HGNC:7227),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-MRAS (HGNC:7227),BS2,Strong,-4 Points.,Strength
-MRAS (HGNC:7227),BS2,Supporting,-1 Point.,Strength
-MRAS (HGNC:7227),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-MRAS (HGNC:7227),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-MRAS (HGNC:7227),BS4,Strong,Requires only one informative meiosis.,General recommendation
-MRAS (HGNC:7227),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-MRAS (HGNC:7227),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-MRAS (HGNC:7227),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-MRAS (HGNC:7227),BP2,Strong,≥ (-4) Points.,Strength
-MRAS (HGNC:7227),BP2,Moderate,≥ (-2) Points.,Strength
-MRAS (HGNC:7227),BP2,Supporting,≥ (-1) Point.,None
-MRAS (HGNC:7227),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-MRAS (HGNC:7227),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-MRAS (HGNC:7227),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-MRAS (HGNC:7227),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-MRAS (HGNC:7227),BP5,Strong,≥ (-4) Points.,Strength
-MRAS (HGNC:7227),BP5,Moderate,≥ (-2) Points.,Strength
-MRAS (HGNC:7227),BP5,Supporting,≥ (-1) Point.,None
-MRAS (HGNC:7227),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MRAS (HGNC:7227),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-MRAS (HGNC:7227),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMRASVersion1.3.0_version=1.3.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMRASVersion1.3.0_version=1.3.0.csv
deleted file mode 100644
index af48384054aad91a28d458d1d068bd8058064fef..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMRASVersion1.3.0_version=1.3.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-MRAS (HGNC:7227),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-MRAS (HGNC:7227),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MRAS (HGNC:7227),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-HRAS, KRAS, MRAS, NRAS, RIT1,
- and 
-RRAS2.",Analogous Gene
-MRAS (HGNC:7227),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-MRAS (HGNC:7227),PS2,Very Strong,4 Points.,Strength
-MRAS (HGNC:7227),PS2,Strong,2 Points.,None
-MRAS (HGNC:7227),PS2,Moderate,1 Point.,Strength
-MRAS (HGNC:7227),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-MRAS (HGNC:7227),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-MRAS (HGNC:7227),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-MRAS (HGNC:7227),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-MRAS (HGNC:7227),PS4,Strong,≥5 points.,Disease-specific
-MRAS (HGNC:7227),PS4,Moderate,≥3 points.,Strength
-MRAS (HGNC:7227),PS4,Supporting,≥1 points.,Strength
-MRAS (HGNC:7227),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-MRAS (HGNC:7227),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (P-loop [AA 20-27], SW1 [AA 35-50], SW2 [AA 67-74], no SAK). Not applicable to specific amino acid residues (see PM5).",Gene-specific
-MRAS (HGNC:7227),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-MRAS (HGNC:7227),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-MRAS (HGNC:7227),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-MRAS (HGNC:7227),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-MRAS (HGNC:7227),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-MRAS (HGNC:7227),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MRAS (HGNC:7227),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-MRAS (HGNC:7227),PM5,Moderate,1 [likely] pathogenic residue change at the same codon.,"Analogous Gene,Disease-specific"
-MRAS (HGNC:7227),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-MRAS (HGNC:7227),PM6,Strong,2 Points.,Strength
-MRAS (HGNC:7227),PM6,Moderate,1 Point.,None
-MRAS (HGNC:7227),PM6,Supporting,0.5 Points.,Strength
-MRAS (HGNC:7227),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-MRAS (HGNC:7227),PP1,Strong,≥7 informative meioses.,Strength
-MRAS (HGNC:7227),PP1,Moderate,≥5 informative meioses.,Strength
-MRAS (HGNC:7227),PP1,Supporting,≥3 informative meioses.,Disease-specific
-MRAS (HGNC:7227),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-MRAS (HGNC:7227),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-MRAS (HGNC:7227),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-MRAS (HGNC:7227),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-MRAS (HGNC:7227),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MRAS (HGNC:7227),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-MRAS (HGNC:7227),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-MRAS (HGNC:7227),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-MRAS (HGNC:7227),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-MRAS (HGNC:7227),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-MRAS (HGNC:7227),BS2,Strong,-4 Points.,Strength
-MRAS (HGNC:7227),BS2,Supporting,-1 Point.,Strength
-MRAS (HGNC:7227),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-MRAS (HGNC:7227),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-MRAS (HGNC:7227),BS4,Strong,Requires only one informative meiosis.,General recommendation
-MRAS (HGNC:7227),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-MRAS (HGNC:7227),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-MRAS (HGNC:7227),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-MRAS (HGNC:7227),BP2,Strong,≥ (-4) Points.,Strength
-MRAS (HGNC:7227),BP2,Moderate,≥ (-2) Points.,Strength
-MRAS (HGNC:7227),BP2,Supporting,≥ (-1) Point.,None
-MRAS (HGNC:7227),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-MRAS (HGNC:7227),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-MRAS (HGNC:7227),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-MRAS (HGNC:7227),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-MRAS (HGNC:7227),BP5,Strong,≥ (-4) Points.,Strength
-MRAS (HGNC:7227),BP5,Moderate,≥ (-2) Points.,Strength
-MRAS (HGNC:7227),BP5,Supporting,≥ (-1) Point.,None
-MRAS (HGNC:7227),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MRAS (HGNC:7227),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-MRAS (HGNC:7227),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMRASVersion1.4.0_version=1.4.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMRASVersion1.4.0_version=1.4.0.csv
deleted file mode 100644
index af48384054aad91a28d458d1d068bd8058064fef..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMRASVersion1.4.0_version=1.4.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-MRAS (HGNC:7227),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-MRAS (HGNC:7227),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MRAS (HGNC:7227),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-HRAS, KRAS, MRAS, NRAS, RIT1,
- and 
-RRAS2.",Analogous Gene
-MRAS (HGNC:7227),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-MRAS (HGNC:7227),PS2,Very Strong,4 Points.,Strength
-MRAS (HGNC:7227),PS2,Strong,2 Points.,None
-MRAS (HGNC:7227),PS2,Moderate,1 Point.,Strength
-MRAS (HGNC:7227),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-MRAS (HGNC:7227),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-MRAS (HGNC:7227),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-MRAS (HGNC:7227),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-MRAS (HGNC:7227),PS4,Strong,≥5 points.,Disease-specific
-MRAS (HGNC:7227),PS4,Moderate,≥3 points.,Strength
-MRAS (HGNC:7227),PS4,Supporting,≥1 points.,Strength
-MRAS (HGNC:7227),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-MRAS (HGNC:7227),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (P-loop [AA 20-27], SW1 [AA 35-50], SW2 [AA 67-74], no SAK). Not applicable to specific amino acid residues (see PM5).",Gene-specific
-MRAS (HGNC:7227),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-MRAS (HGNC:7227),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-MRAS (HGNC:7227),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-MRAS (HGNC:7227),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-MRAS (HGNC:7227),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-MRAS (HGNC:7227),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MRAS (HGNC:7227),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-MRAS (HGNC:7227),PM5,Moderate,1 [likely] pathogenic residue change at the same codon.,"Analogous Gene,Disease-specific"
-MRAS (HGNC:7227),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-MRAS (HGNC:7227),PM6,Strong,2 Points.,Strength
-MRAS (HGNC:7227),PM6,Moderate,1 Point.,None
-MRAS (HGNC:7227),PM6,Supporting,0.5 Points.,Strength
-MRAS (HGNC:7227),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-MRAS (HGNC:7227),PP1,Strong,≥7 informative meioses.,Strength
-MRAS (HGNC:7227),PP1,Moderate,≥5 informative meioses.,Strength
-MRAS (HGNC:7227),PP1,Supporting,≥3 informative meioses.,Disease-specific
-MRAS (HGNC:7227),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-MRAS (HGNC:7227),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-MRAS (HGNC:7227),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-MRAS (HGNC:7227),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-MRAS (HGNC:7227),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MRAS (HGNC:7227),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-MRAS (HGNC:7227),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-MRAS (HGNC:7227),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-MRAS (HGNC:7227),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-MRAS (HGNC:7227),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-MRAS (HGNC:7227),BS2,Strong,-4 Points.,Strength
-MRAS (HGNC:7227),BS2,Supporting,-1 Point.,Strength
-MRAS (HGNC:7227),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-MRAS (HGNC:7227),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-MRAS (HGNC:7227),BS4,Strong,Requires only one informative meiosis.,General recommendation
-MRAS (HGNC:7227),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-MRAS (HGNC:7227),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-MRAS (HGNC:7227),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-MRAS (HGNC:7227),BP2,Strong,≥ (-4) Points.,Strength
-MRAS (HGNC:7227),BP2,Moderate,≥ (-2) Points.,Strength
-MRAS (HGNC:7227),BP2,Supporting,≥ (-1) Point.,None
-MRAS (HGNC:7227),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-MRAS (HGNC:7227),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-MRAS (HGNC:7227),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-MRAS (HGNC:7227),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-MRAS (HGNC:7227),BP5,Strong,≥ (-4) Points.,Strength
-MRAS (HGNC:7227),BP5,Moderate,≥ (-2) Points.,Strength
-MRAS (HGNC:7227),BP5,Supporting,≥ (-1) Point.,None
-MRAS (HGNC:7227),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MRAS (HGNC:7227),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-MRAS (HGNC:7227),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforNRASVersion2.0.0_version=2.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforNRASVersion2.0.0_version=2.0.0.csv
deleted file mode 100644
index d39e989106ba4d3cce54ec66d475f477997a17e7..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforNRASVersion2.0.0_version=2.0.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-NRAS (HGNC:7989),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-NRAS (HGNC:7989),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-NRAS (HGNC:7989),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous pathogenic residue positions in 
-HRAS, KRAS, MRAS, NRAS, RIT1,
- and 
-RRAS2.",Analogous Gene
-NRAS (HGNC:7989),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-NRAS (HGNC:7989),PS2,Very Strong,4 Points.,Strength
-NRAS (HGNC:7989),PS2,Strong,2 Points.,None
-NRAS (HGNC:7989),PS2,Moderate,1 Point.,Strength
-NRAS (HGNC:7989),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-NRAS (HGNC:7989),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-NRAS (HGNC:7989),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-NRAS (HGNC:7989),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-NRAS (HGNC:7989),PS4,Strong,≥5 points.,Disease-specific
-NRAS (HGNC:7989),PS4,Moderate,≥3 points.,Strength
-NRAS (HGNC:7989),PS4,Supporting,≥1 points.,Strength
-NRAS (HGNC:7989),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-NRAS (HGNC:7989),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (P-loop [AA 10-17], SW1 [AA 25-40], SW2 [AA 57-64], SAK [AA 145-156]). Not applicable to specific amino acid residues (see BP5).",Gene-specific
-NRAS (HGNC:7989),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-NRAS (HGNC:7989),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-NRAS (HGNC:7989),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-NRAS (HGNC:7989),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-NRAS (HGNC:7989),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-NRAS (HGNC:7989),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-NRAS (HGNC:7989),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-NRAS (HGNC:7989),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,"Analogous Gene,Disease-specific"
-NRAS (HGNC:7989),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-NRAS (HGNC:7989),PM6,Strong,2 Points.,Strength
-NRAS (HGNC:7989),PM6,Moderate,1 Point.,None
-NRAS (HGNC:7989),PM6,Supporting,0.5 Points.,Strength
-NRAS (HGNC:7989),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-NRAS (HGNC:7989),PP1,Strong,≥7 informative meioses.,Strength
-NRAS (HGNC:7989),PP1,Moderate,≥5 informative meioses.,Strength
-NRAS (HGNC:7989),PP1,Supporting,≥3 informative meioses.,Disease-specific
-NRAS (HGNC:7989),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-NRAS (HGNC:7989),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-NRAS (HGNC:7989),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-NRAS (HGNC:7989),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-NRAS (HGNC:7989),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-NRAS (HGNC:7989),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-NRAS (HGNC:7989),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-NRAS (HGNC:7989),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-NRAS (HGNC:7989),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-NRAS (HGNC:7989),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-NRAS (HGNC:7989),BS2,Strong,-4 Points.,Strength
-NRAS (HGNC:7989),BS2,Supporting,-1 Point.,Strength
-NRAS (HGNC:7989),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-NRAS (HGNC:7989),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-NRAS (HGNC:7989),BS4,Strong,Requires only one informative meiosis.,General recommendation
-NRAS (HGNC:7989),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-NRAS (HGNC:7989),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-NRAS (HGNC:7989),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-NRAS (HGNC:7989),BP2,Strong,≥ (-4) Points.,Strength
-NRAS (HGNC:7989),BP2,Moderate,≥ (-2) Points.,Strength
-NRAS (HGNC:7989),BP2,Supporting,≥ (-1) Point.,None
-NRAS (HGNC:7989),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-NRAS (HGNC:7989),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-NRAS (HGNC:7989),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-NRAS (HGNC:7989),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-NRAS (HGNC:7989),BP5,Strong,≥ (-4) Points.,Strength
-NRAS (HGNC:7989),BP5,Moderate,≥ (-2) Points.,Strength
-NRAS (HGNC:7989),BP5,Supporting,≥ (-1) Point.,None
-NRAS (HGNC:7989),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-NRAS (HGNC:7989),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-NRAS (HGNC:7989),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforNRASVersion2.1.0_version=2.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforNRASVersion2.1.0_version=2.1.0.csv
deleted file mode 100644
index 016277c2309a4aa248632c1444e3d23128e22920..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforNRASVersion2.1.0_version=2.1.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-NRAS (HGNC:7989),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-NRAS (HGNC:7989),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-NRAS (HGNC:7989),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous pathogenic residue positions in 
-HRAS, KRAS, MRAS, NRAS, RIT1,
- and 
-RRAS2.",Analogous Gene
-NRAS (HGNC:7989),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-NRAS (HGNC:7989),PS2,Very Strong,4 Points.,Strength
-NRAS (HGNC:7989),PS2,Strong,2 Points.,None
-NRAS (HGNC:7989),PS2,Moderate,1 Point.,Strength
-NRAS (HGNC:7989),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-NRAS (HGNC:7989),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-NRAS (HGNC:7989),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-NRAS (HGNC:7989),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-NRAS (HGNC:7989),PS4,Strong,≥5 points.,Disease-specific
-NRAS (HGNC:7989),PS4,Moderate,≥3 points.,Strength
-NRAS (HGNC:7989),PS4,Supporting,≥1 points.,Strength
-NRAS (HGNC:7989),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-NRAS (HGNC:7989),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (P-loop [AA 10-17], SW1 [AA 25-40], SW2 [AA 57-64], SAK [AA 145-156]). Not applicable to specific amino acid residues (see PM5).",Gene-specific
-NRAS (HGNC:7989),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-NRAS (HGNC:7989),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-NRAS (HGNC:7989),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-NRAS (HGNC:7989),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-NRAS (HGNC:7989),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-NRAS (HGNC:7989),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-NRAS (HGNC:7989),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-NRAS (HGNC:7989),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,"Analogous Gene,Disease-specific"
-NRAS (HGNC:7989),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-NRAS (HGNC:7989),PM6,Strong,2 Points.,Strength
-NRAS (HGNC:7989),PM6,Moderate,1 Point.,None
-NRAS (HGNC:7989),PM6,Supporting,0.5 Points.,Strength
-NRAS (HGNC:7989),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-NRAS (HGNC:7989),PP1,Strong,≥7 informative meioses.,Strength
-NRAS (HGNC:7989),PP1,Moderate,≥5 informative meioses.,Strength
-NRAS (HGNC:7989),PP1,Supporting,≥3 informative meioses.,Disease-specific
-NRAS (HGNC:7989),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-NRAS (HGNC:7989),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-NRAS (HGNC:7989),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-NRAS (HGNC:7989),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-NRAS (HGNC:7989),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-NRAS (HGNC:7989),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-NRAS (HGNC:7989),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-NRAS (HGNC:7989),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-NRAS (HGNC:7989),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-NRAS (HGNC:7989),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-NRAS (HGNC:7989),BS2,Strong,-4 Points.,Strength
-NRAS (HGNC:7989),BS2,Supporting,-1 Point.,Strength
-NRAS (HGNC:7989),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-NRAS (HGNC:7989),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-NRAS (HGNC:7989),BS4,Strong,Requires only one informative meiosis.,General recommendation
-NRAS (HGNC:7989),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-NRAS (HGNC:7989),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-NRAS (HGNC:7989),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-NRAS (HGNC:7989),BP2,Strong,≥ (-4) Points.,Strength
-NRAS (HGNC:7989),BP2,Moderate,≥ (-2) Points.,Strength
-NRAS (HGNC:7989),BP2,Supporting,≥ (-1) Point.,None
-NRAS (HGNC:7989),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-NRAS (HGNC:7989),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-NRAS (HGNC:7989),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-NRAS (HGNC:7989),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-NRAS (HGNC:7989),BP5,Strong,≥ (-4) Points.,Strength
-NRAS (HGNC:7989),BP5,Moderate,≥ (-2) Points.,Strength
-NRAS (HGNC:7989),BP5,Supporting,≥ (-1) Point.,None
-NRAS (HGNC:7989),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-NRAS (HGNC:7989),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-NRAS (HGNC:7989),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforNRASVersion2.2.0_version=2.2.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforNRASVersion2.2.0_version=2.2.0.csv
deleted file mode 100644
index 016277c2309a4aa248632c1444e3d23128e22920..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforNRASVersion2.2.0_version=2.2.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-NRAS (HGNC:7989),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-NRAS (HGNC:7989),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-NRAS (HGNC:7989),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous pathogenic residue positions in 
-HRAS, KRAS, MRAS, NRAS, RIT1,
- and 
-RRAS2.",Analogous Gene
-NRAS (HGNC:7989),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-NRAS (HGNC:7989),PS2,Very Strong,4 Points.,Strength
-NRAS (HGNC:7989),PS2,Strong,2 Points.,None
-NRAS (HGNC:7989),PS2,Moderate,1 Point.,Strength
-NRAS (HGNC:7989),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-NRAS (HGNC:7989),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-NRAS (HGNC:7989),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-NRAS (HGNC:7989),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-NRAS (HGNC:7989),PS4,Strong,≥5 points.,Disease-specific
-NRAS (HGNC:7989),PS4,Moderate,≥3 points.,Strength
-NRAS (HGNC:7989),PS4,Supporting,≥1 points.,Strength
-NRAS (HGNC:7989),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-NRAS (HGNC:7989),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (P-loop [AA 10-17], SW1 [AA 25-40], SW2 [AA 57-64], SAK [AA 145-156]). Not applicable to specific amino acid residues (see PM5).",Gene-specific
-NRAS (HGNC:7989),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-NRAS (HGNC:7989),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-NRAS (HGNC:7989),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-NRAS (HGNC:7989),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-NRAS (HGNC:7989),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-NRAS (HGNC:7989),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-NRAS (HGNC:7989),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-NRAS (HGNC:7989),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,"Analogous Gene,Disease-specific"
-NRAS (HGNC:7989),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-NRAS (HGNC:7989),PM6,Strong,2 Points.,Strength
-NRAS (HGNC:7989),PM6,Moderate,1 Point.,None
-NRAS (HGNC:7989),PM6,Supporting,0.5 Points.,Strength
-NRAS (HGNC:7989),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-NRAS (HGNC:7989),PP1,Strong,≥7 informative meioses.,Strength
-NRAS (HGNC:7989),PP1,Moderate,≥5 informative meioses.,Strength
-NRAS (HGNC:7989),PP1,Supporting,≥3 informative meioses.,Disease-specific
-NRAS (HGNC:7989),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-NRAS (HGNC:7989),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-NRAS (HGNC:7989),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-NRAS (HGNC:7989),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-NRAS (HGNC:7989),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-NRAS (HGNC:7989),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-NRAS (HGNC:7989),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-NRAS (HGNC:7989),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-NRAS (HGNC:7989),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-NRAS (HGNC:7989),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-NRAS (HGNC:7989),BS2,Strong,-4 Points.,Strength
-NRAS (HGNC:7989),BS2,Supporting,-1 Point.,Strength
-NRAS (HGNC:7989),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-NRAS (HGNC:7989),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-NRAS (HGNC:7989),BS4,Strong,Requires only one informative meiosis.,General recommendation
-NRAS (HGNC:7989),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-NRAS (HGNC:7989),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-NRAS (HGNC:7989),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-NRAS (HGNC:7989),BP2,Strong,≥ (-4) Points.,Strength
-NRAS (HGNC:7989),BP2,Moderate,≥ (-2) Points.,Strength
-NRAS (HGNC:7989),BP2,Supporting,≥ (-1) Point.,None
-NRAS (HGNC:7989),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-NRAS (HGNC:7989),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-NRAS (HGNC:7989),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-NRAS (HGNC:7989),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-NRAS (HGNC:7989),BP5,Strong,≥ (-4) Points.,Strength
-NRAS (HGNC:7989),BP5,Moderate,≥ (-2) Points.,Strength
-NRAS (HGNC:7989),BP5,Supporting,≥ (-1) Point.,None
-NRAS (HGNC:7989),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-NRAS (HGNC:7989),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-NRAS (HGNC:7989),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforNRASVersion2.3.0_version=2.3.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforNRASVersion2.3.0_version=2.3.0.csv
deleted file mode 100644
index 2a66cf529b278c7bd12c851516356a853fa64435..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforNRASVersion2.3.0_version=2.3.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-NRAS (HGNC:7989),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-NRAS (HGNC:7989),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-NRAS (HGNC:7989),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous pathogenic residue positions in 
-HRAS, KRAS, MRAS, NRAS, RIT1,
- and 
-RRAS2.",Analogous Gene
-NRAS (HGNC:7989),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-NRAS (HGNC:7989),PS2,Very Strong,4 Points.,Strength
-NRAS (HGNC:7989),PS2,Strong,2 Points.,None
-NRAS (HGNC:7989),PS2,Moderate,1 Point.,Strength
-NRAS (HGNC:7989),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-NRAS (HGNC:7989),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-NRAS (HGNC:7989),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-NRAS (HGNC:7989),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-NRAS (HGNC:7989),PS4,Strong,≥5 points.,Disease-specific
-NRAS (HGNC:7989),PS4,Moderate,≥3 points.,Strength
-NRAS (HGNC:7989),PS4,Supporting,≥1 points.,Strength
-NRAS (HGNC:7989),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-NRAS (HGNC:7989),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (P-loop [AA 10-17], SW1 [AA 25-40], SW2 [AA 57-64], SAK [AA 145-156]). Not applicable to specific amino acid residues (see PM5).",Gene-specific
-NRAS (HGNC:7989),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-NRAS (HGNC:7989),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-NRAS (HGNC:7989),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-NRAS (HGNC:7989),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-NRAS (HGNC:7989),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-NRAS (HGNC:7989),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-NRAS (HGNC:7989),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-NRAS (HGNC:7989),PM5,Moderate,1 [likely] pathogenic residue change at the same codon.,"Analogous Gene,Disease-specific"
-NRAS (HGNC:7989),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-NRAS (HGNC:7989),PM6,Strong,2 Points.,Strength
-NRAS (HGNC:7989),PM6,Moderate,1 Point.,None
-NRAS (HGNC:7989),PM6,Supporting,0.5 Points.,Strength
-NRAS (HGNC:7989),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-NRAS (HGNC:7989),PP1,Strong,≥7 informative meioses.,Strength
-NRAS (HGNC:7989),PP1,Moderate,≥5 informative meioses.,Strength
-NRAS (HGNC:7989),PP1,Supporting,≥3 informative meioses.,Disease-specific
-NRAS (HGNC:7989),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-NRAS (HGNC:7989),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-NRAS (HGNC:7989),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-NRAS (HGNC:7989),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-NRAS (HGNC:7989),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-NRAS (HGNC:7989),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-NRAS (HGNC:7989),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-NRAS (HGNC:7989),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-NRAS (HGNC:7989),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-NRAS (HGNC:7989),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-NRAS (HGNC:7989),BS2,Strong,-4 Points.,Strength
-NRAS (HGNC:7989),BS2,Supporting,-1 Point.,Strength
-NRAS (HGNC:7989),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-NRAS (HGNC:7989),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-NRAS (HGNC:7989),BS4,Strong,Requires only one informative meiosis.,General recommendation
-NRAS (HGNC:7989),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-NRAS (HGNC:7989),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-NRAS (HGNC:7989),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-NRAS (HGNC:7989),BP2,Strong,≥ (-4) Points.,Strength
-NRAS (HGNC:7989),BP2,Moderate,≥ (-2) Points.,Strength
-NRAS (HGNC:7989),BP2,Supporting,≥ (-1) Point.,None
-NRAS (HGNC:7989),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-NRAS (HGNC:7989),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-NRAS (HGNC:7989),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-NRAS (HGNC:7989),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-NRAS (HGNC:7989),BP5,Strong,≥ (-4) Points.,Strength
-NRAS (HGNC:7989),BP5,Moderate,≥ (-2) Points.,Strength
-NRAS (HGNC:7989),BP5,Supporting,≥ (-1) Point.,None
-NRAS (HGNC:7989),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-NRAS (HGNC:7989),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-NRAS (HGNC:7989),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPPP1CBVersion1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPPP1CBVersion1.0.0_version=1.0.0.csv
deleted file mode 100644
index 0700d0113a201195ed5d559f85cbecd273676bc9..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPPP1CBVersion1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,83 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-PPP1CB (HGNC:9282),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-PPP1CB (HGNC:9282),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-PPP1CB (HGNC:9282),PS1,Strong,"Same amino acid change as a previously established pathogenic variant in 
-PPP1CB
- regardless of nucleotide change.",Analogous Gene
-PPP1CB (HGNC:9282),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-PPP1CB (HGNC:9282),PS2,Very Strong,4 Points.,Strength
-PPP1CB (HGNC:9282),PS2,Strong,2 Points.,None
-PPP1CB (HGNC:9282),PS2,Moderate,1 Point.,Strength
-PPP1CB (HGNC:9282),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",NA
-PPP1CB (HGNC:9282),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-PPP1CB (HGNC:9282),PS4,Strong,≥5 points.,Disease-specific
-PPP1CB (HGNC:9282),PS4,Moderate,≥3 points.,Strength
-PPP1CB (HGNC:9282),PS4,Supporting,≥1 points.,Strength
-PPP1CB (HGNC:9282),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-PPP1CB (HGNC:9282),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-PPP1CB (HGNC:9282),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-PPP1CB (HGNC:9282),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-PPP1CB (HGNC:9282),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-PPP1CB (HGNC:9282),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-PPP1CB (HGNC:9282),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-PPP1CB (HGNC:9282),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,Strength
-PPP1CB (HGNC:9282),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,Disease-specific
-PPP1CB (HGNC:9282),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-PPP1CB (HGNC:9282),PM6,Strong,2 Points.,Strength
-PPP1CB (HGNC:9282),PM6,Moderate,1 Point.,None
-PPP1CB (HGNC:9282),PM6,Supporting,0.5 Points.,Strength
-PPP1CB (HGNC:9282),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-PPP1CB (HGNC:9282),PP1,Strong,≥7 informative meioses.,Strength
-PPP1CB (HGNC:9282),PP1,Moderate,≥5 informative meioses.,Strength
-PPP1CB (HGNC:9282),PP1,Supporting,≥3 informative meioses.,Disease-specific
-PPP1CB (HGNC:9282),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,
-PPP1CB (HGNC:9282),PP2,Supporting,Missense z score is <3.09 in gnomAD.,Gene-specific
-PPP1CB (HGNC:9282),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-PPP1CB (HGNC:9282),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-PPP1CB (HGNC:9282),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-PPP1CB (HGNC:9282),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-PPP1CB (HGNC:9282),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-PPP1CB (HGNC:9282),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-PPP1CB (HGNC:9282),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-PPP1CB (HGNC:9282),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-PPP1CB (HGNC:9282),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-PPP1CB (HGNC:9282),BS2,Strong,-4 Points.,Strength
-PPP1CB (HGNC:9282),BS2,Supporting,-1 Point.,Strength
-PPP1CB (HGNC:9282),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-PPP1CB (HGNC:9282),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-PPP1CB (HGNC:9282),BS4,Strong,Requires only one informative meiosis.,General recommendation
-PPP1CB (HGNC:9282),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-PPP1CB (HGNC:9282),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-PPP1CB (HGNC:9282),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-PPP1CB (HGNC:9282),BP2,Strong,≥ (-4) Points.,Strength
-PPP1CB (HGNC:9282),BP2,Moderate,≥ (-2) Points.,Strength
-PPP1CB (HGNC:9282),BP2,Supporting,≥ (-1) Point.,None
-PPP1CB (HGNC:9282),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-PPP1CB (HGNC:9282),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-PPP1CB (HGNC:9282),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-PPP1CB (HGNC:9282),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-PPP1CB (HGNC:9282),BP5,Strong,≥ (-4) Points.,Strength
-PPP1CB (HGNC:9282),BP5,Moderate,≥ (-2) Points.,Strength
-PPP1CB (HGNC:9282),BP5,Supporting,≥ (-1) Point.,None
-PPP1CB (HGNC:9282),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-PPP1CB (HGNC:9282),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-PPP1CB (HGNC:9282),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPPP1CBVersion1.1.0_version=1.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPPP1CBVersion1.1.0_version=1.1.0.csv
deleted file mode 100644
index 0700d0113a201195ed5d559f85cbecd273676bc9..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPPP1CBVersion1.1.0_version=1.1.0.csv
+++ /dev/null
@@ -1,83 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-PPP1CB (HGNC:9282),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-PPP1CB (HGNC:9282),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-PPP1CB (HGNC:9282),PS1,Strong,"Same amino acid change as a previously established pathogenic variant in 
-PPP1CB
- regardless of nucleotide change.",Analogous Gene
-PPP1CB (HGNC:9282),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-PPP1CB (HGNC:9282),PS2,Very Strong,4 Points.,Strength
-PPP1CB (HGNC:9282),PS2,Strong,2 Points.,None
-PPP1CB (HGNC:9282),PS2,Moderate,1 Point.,Strength
-PPP1CB (HGNC:9282),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",NA
-PPP1CB (HGNC:9282),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-PPP1CB (HGNC:9282),PS4,Strong,≥5 points.,Disease-specific
-PPP1CB (HGNC:9282),PS4,Moderate,≥3 points.,Strength
-PPP1CB (HGNC:9282),PS4,Supporting,≥1 points.,Strength
-PPP1CB (HGNC:9282),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-PPP1CB (HGNC:9282),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-PPP1CB (HGNC:9282),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-PPP1CB (HGNC:9282),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-PPP1CB (HGNC:9282),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-PPP1CB (HGNC:9282),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-PPP1CB (HGNC:9282),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-PPP1CB (HGNC:9282),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,Strength
-PPP1CB (HGNC:9282),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,Disease-specific
-PPP1CB (HGNC:9282),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-PPP1CB (HGNC:9282),PM6,Strong,2 Points.,Strength
-PPP1CB (HGNC:9282),PM6,Moderate,1 Point.,None
-PPP1CB (HGNC:9282),PM6,Supporting,0.5 Points.,Strength
-PPP1CB (HGNC:9282),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-PPP1CB (HGNC:9282),PP1,Strong,≥7 informative meioses.,Strength
-PPP1CB (HGNC:9282),PP1,Moderate,≥5 informative meioses.,Strength
-PPP1CB (HGNC:9282),PP1,Supporting,≥3 informative meioses.,Disease-specific
-PPP1CB (HGNC:9282),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,
-PPP1CB (HGNC:9282),PP2,Supporting,Missense z score is <3.09 in gnomAD.,Gene-specific
-PPP1CB (HGNC:9282),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-PPP1CB (HGNC:9282),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-PPP1CB (HGNC:9282),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-PPP1CB (HGNC:9282),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-PPP1CB (HGNC:9282),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-PPP1CB (HGNC:9282),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-PPP1CB (HGNC:9282),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-PPP1CB (HGNC:9282),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-PPP1CB (HGNC:9282),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-PPP1CB (HGNC:9282),BS2,Strong,-4 Points.,Strength
-PPP1CB (HGNC:9282),BS2,Supporting,-1 Point.,Strength
-PPP1CB (HGNC:9282),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-PPP1CB (HGNC:9282),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-PPP1CB (HGNC:9282),BS4,Strong,Requires only one informative meiosis.,General recommendation
-PPP1CB (HGNC:9282),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-PPP1CB (HGNC:9282),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-PPP1CB (HGNC:9282),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-PPP1CB (HGNC:9282),BP2,Strong,≥ (-4) Points.,Strength
-PPP1CB (HGNC:9282),BP2,Moderate,≥ (-2) Points.,Strength
-PPP1CB (HGNC:9282),BP2,Supporting,≥ (-1) Point.,None
-PPP1CB (HGNC:9282),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-PPP1CB (HGNC:9282),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-PPP1CB (HGNC:9282),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-PPP1CB (HGNC:9282),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-PPP1CB (HGNC:9282),BP5,Strong,≥ (-4) Points.,Strength
-PPP1CB (HGNC:9282),BP5,Moderate,≥ (-2) Points.,Strength
-PPP1CB (HGNC:9282),BP5,Supporting,≥ (-1) Point.,None
-PPP1CB (HGNC:9282),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-PPP1CB (HGNC:9282),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-PPP1CB (HGNC:9282),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPPP1CBVersion1.2.0_version=1.2.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPPP1CBVersion1.2.0_version=1.2.0.csv
deleted file mode 100644
index 7f497e2a6c3cc5204fe14eb7c9d901fb4b34c6be..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPPP1CBVersion1.2.0_version=1.2.0.csv
+++ /dev/null
@@ -1,83 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-PPP1CB (HGNC:9282),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-PPP1CB (HGNC:9282),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-PPP1CB (HGNC:9282),PS1,Strong,"Same amino acid change as a previously established pathogenic variant in 
-PPP1CB
- regardless of nucleotide change.",Analogous Gene
-PPP1CB (HGNC:9282),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-PPP1CB (HGNC:9282),PS2,Very Strong,4 Points.,Strength
-PPP1CB (HGNC:9282),PS2,Strong,2 Points.,None
-PPP1CB (HGNC:9282),PS2,Moderate,1 Point.,Strength
-PPP1CB (HGNC:9282),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",NA
-PPP1CB (HGNC:9282),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-PPP1CB (HGNC:9282),PS4,Strong,≥5 points.,Disease-specific
-PPP1CB (HGNC:9282),PS4,Moderate,≥3 points.,Strength
-PPP1CB (HGNC:9282),PS4,Supporting,≥1 points.,Strength
-PPP1CB (HGNC:9282),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-PPP1CB (HGNC:9282),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-PPP1CB (HGNC:9282),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-PPP1CB (HGNC:9282),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-PPP1CB (HGNC:9282),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-PPP1CB (HGNC:9282),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-PPP1CB (HGNC:9282),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-PPP1CB (HGNC:9282),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,Strength
-PPP1CB (HGNC:9282),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,Disease-specific
-PPP1CB (HGNC:9282),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-PPP1CB (HGNC:9282),PM6,Strong,2 Points.,Strength
-PPP1CB (HGNC:9282),PM6,Moderate,1 Point.,None
-PPP1CB (HGNC:9282),PM6,Supporting,0.5 Points.,Strength
-PPP1CB (HGNC:9282),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-PPP1CB (HGNC:9282),PP1,Strong,≥7 informative meioses.,Strength
-PPP1CB (HGNC:9282),PP1,Moderate,≥5 informative meioses.,Strength
-PPP1CB (HGNC:9282),PP1,Supporting,≥3 informative meioses.,Disease-specific
-PPP1CB (HGNC:9282),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,
-PPP1CB (HGNC:9282),PP2,Supporting,Missense z score is >3.09 in gnomAD.,Gene-specific
-PPP1CB (HGNC:9282),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-PPP1CB (HGNC:9282),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-PPP1CB (HGNC:9282),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-PPP1CB (HGNC:9282),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-PPP1CB (HGNC:9282),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-PPP1CB (HGNC:9282),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-PPP1CB (HGNC:9282),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-PPP1CB (HGNC:9282),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-PPP1CB (HGNC:9282),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-PPP1CB (HGNC:9282),BS2,Strong,-4 Points.,Strength
-PPP1CB (HGNC:9282),BS2,Supporting,-1 Point.,Strength
-PPP1CB (HGNC:9282),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-PPP1CB (HGNC:9282),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-PPP1CB (HGNC:9282),BS4,Strong,Requires only one informative meiosis.,General recommendation
-PPP1CB (HGNC:9282),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-PPP1CB (HGNC:9282),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-PPP1CB (HGNC:9282),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-PPP1CB (HGNC:9282),BP2,Strong,≥ (-4) Points.,Strength
-PPP1CB (HGNC:9282),BP2,Moderate,≥ (-2) Points.,Strength
-PPP1CB (HGNC:9282),BP2,Supporting,≥ (-1) Point.,None
-PPP1CB (HGNC:9282),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-PPP1CB (HGNC:9282),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-PPP1CB (HGNC:9282),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-PPP1CB (HGNC:9282),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-PPP1CB (HGNC:9282),BP5,Strong,≥ (-4) Points.,Strength
-PPP1CB (HGNC:9282),BP5,Moderate,≥ (-2) Points.,Strength
-PPP1CB (HGNC:9282),BP5,Supporting,≥ (-1) Point.,None
-PPP1CB (HGNC:9282),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-PPP1CB (HGNC:9282),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-PPP1CB (HGNC:9282),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPPP1CBVersion1.3.0_version=1.3.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPPP1CBVersion1.3.0_version=1.3.0.csv
deleted file mode 100644
index e1dbf77976b01eb78b660705a75a7e967877cd47..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPPP1CBVersion1.3.0_version=1.3.0.csv
+++ /dev/null
@@ -1,83 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-PPP1CB (HGNC:9282),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-PPP1CB (HGNC:9282),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-PPP1CB (HGNC:9282),PS1,Strong,"Same amino acid change as a previously established pathogenic variant in 
-PPP1CB
- regardless of nucleotide change.",Analogous Gene
-PPP1CB (HGNC:9282),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-PPP1CB (HGNC:9282),PS2,Very Strong,4 Points.,Strength
-PPP1CB (HGNC:9282),PS2,Strong,2 Points.,None
-PPP1CB (HGNC:9282),PS2,Moderate,1 Point.,Strength
-PPP1CB (HGNC:9282),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",NA
-PPP1CB (HGNC:9282),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-PPP1CB (HGNC:9282),PS4,Strong,≥5 points.,Disease-specific
-PPP1CB (HGNC:9282),PS4,Moderate,≥3 points.,Strength
-PPP1CB (HGNC:9282),PS4,Supporting,≥1 points.,Strength
-PPP1CB (HGNC:9282),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-PPP1CB (HGNC:9282),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-PPP1CB (HGNC:9282),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-PPP1CB (HGNC:9282),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-PPP1CB (HGNC:9282),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-PPP1CB (HGNC:9282),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-PPP1CB (HGNC:9282),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-PPP1CB (HGNC:9282),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,Strength
-PPP1CB (HGNC:9282),PM5,Moderate,1 [likely] pathogenic residue change at the same codon.,Disease-specific
-PPP1CB (HGNC:9282),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-PPP1CB (HGNC:9282),PM6,Strong,2 Points.,Strength
-PPP1CB (HGNC:9282),PM6,Moderate,1 Point.,None
-PPP1CB (HGNC:9282),PM6,Supporting,0.5 Points.,Strength
-PPP1CB (HGNC:9282),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-PPP1CB (HGNC:9282),PP1,Strong,≥7 informative meioses.,Strength
-PPP1CB (HGNC:9282),PP1,Moderate,≥5 informative meioses.,Strength
-PPP1CB (HGNC:9282),PP1,Supporting,≥3 informative meioses.,Disease-specific
-PPP1CB (HGNC:9282),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,
-PPP1CB (HGNC:9282),PP2,Supporting,Missense z score is >3.09 in gnomAD.,Gene-specific
-PPP1CB (HGNC:9282),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-PPP1CB (HGNC:9282),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-PPP1CB (HGNC:9282),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-PPP1CB (HGNC:9282),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-PPP1CB (HGNC:9282),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-PPP1CB (HGNC:9282),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-PPP1CB (HGNC:9282),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-PPP1CB (HGNC:9282),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-PPP1CB (HGNC:9282),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-PPP1CB (HGNC:9282),BS2,Strong,-4 Points.,Strength
-PPP1CB (HGNC:9282),BS2,Supporting,-1 Point.,Strength
-PPP1CB (HGNC:9282),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-PPP1CB (HGNC:9282),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-PPP1CB (HGNC:9282),BS4,Strong,Requires only one informative meiosis.,General recommendation
-PPP1CB (HGNC:9282),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-PPP1CB (HGNC:9282),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-PPP1CB (HGNC:9282),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-PPP1CB (HGNC:9282),BP2,Strong,≥ (-4) Points.,Strength
-PPP1CB (HGNC:9282),BP2,Moderate,≥ (-2) Points.,Strength
-PPP1CB (HGNC:9282),BP2,Supporting,≥ (-1) Point.,None
-PPP1CB (HGNC:9282),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-PPP1CB (HGNC:9282),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-PPP1CB (HGNC:9282),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-PPP1CB (HGNC:9282),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-PPP1CB (HGNC:9282),BP5,Strong,≥ (-4) Points.,Strength
-PPP1CB (HGNC:9282),BP5,Moderate,≥ (-2) Points.,Strength
-PPP1CB (HGNC:9282),BP5,Supporting,≥ (-1) Point.,None
-PPP1CB (HGNC:9282),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-PPP1CB (HGNC:9282),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-PPP1CB (HGNC:9282),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTPN11Version2.0.0_version=2.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTPN11Version2.0.0_version=2.0.0.csv
deleted file mode 100644
index 625688e01696ecd2009a4fe7761a6a055df37f98..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTPN11Version2.0.0_version=2.0.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-PTPN11 (HGNC:9644),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-PTPN11 (HGNC:9644),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-PTPN11 (HGNC:9644),PS1,Strong,"Same amino acid change as a previously established pathogenic variant in 
-PTPN11
- regardless of nucleotide change.",Gene-specific
-PTPN11 (HGNC:9644),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-PTPN11 (HGNC:9644),PS2,Very Strong,4 Points.,Strength
-PTPN11 (HGNC:9644),PS2,Strong,2 Points.,None
-PTPN11 (HGNC:9644),PS2,Moderate,1 Point.,Strength
-PTPN11 (HGNC:9644),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-PTPN11 (HGNC:9644),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-PTPN11 (HGNC:9644),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-PTPN11 (HGNC:9644),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-PTPN11 (HGNC:9644),PS4,Strong,≥5 points.,Disease-specific
-PTPN11 (HGNC:9644),PS4,Moderate,≥3 points.,Strength
-PTPN11 (HGNC:9644),PS4,Supporting,≥1 points.,Strength
-PTPN11 (HGNC:9644),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-PTPN11 (HGNC:9644),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (Directly interacting residues between N-SH2 and PTPN domains [AA 4, AA 7-9, AA 58-63, AA 69-77, AA 247, AA 251, AA 255, AA 256, AA 258, AA 261, AA 265, AA 278-281, AA 284]). Not applicable to specific amino acid residues (see BP5).",Gene-specific
-PTPN11 (HGNC:9644),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-PTPN11 (HGNC:9644),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-PTPN11 (HGNC:9644),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-PTPN11 (HGNC:9644),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-PTPN11 (HGNC:9644),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-PTPN11 (HGNC:9644),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-PTPN11 (HGNC:9644),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,Strength
-PTPN11 (HGNC:9644),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,Disease-specific
-PTPN11 (HGNC:9644),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-PTPN11 (HGNC:9644),PM6,Strong,2 Points.,Strength
-PTPN11 (HGNC:9644),PM6,Moderate,1 Point.,None
-PTPN11 (HGNC:9644),PM6,Supporting,0.5 Points.,Strength
-PTPN11 (HGNC:9644),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-PTPN11 (HGNC:9644),PP1,Strong,≥7 informative meioses.,Strength
-PTPN11 (HGNC:9644),PP1,Moderate,≥5 informative meioses.,Strength
-PTPN11 (HGNC:9644),PP1,Supporting,≥3 informative meioses.,Disease-specific
-PTPN11 (HGNC:9644),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,
-PTPN11 (HGNC:9644),PP2,Supporting,Missense z score is >3.09 in gnomAD.,Gene-specific
-PTPN11 (HGNC:9644),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-PTPN11 (HGNC:9644),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-PTPN11 (HGNC:9644),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-PTPN11 (HGNC:9644),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-PTPN11 (HGNC:9644),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-PTPN11 (HGNC:9644),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-PTPN11 (HGNC:9644),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-PTPN11 (HGNC:9644),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-PTPN11 (HGNC:9644),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-PTPN11 (HGNC:9644),BS2,Strong,-4 Points.,Strength
-PTPN11 (HGNC:9644),BS2,Supporting,-1 Point.,Strength
-PTPN11 (HGNC:9644),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-PTPN11 (HGNC:9644),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-PTPN11 (HGNC:9644),BS4,Strong,Requires only one informative meiosis.,General recommendation
-PTPN11 (HGNC:9644),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-PTPN11 (HGNC:9644),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-PTPN11 (HGNC:9644),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-PTPN11 (HGNC:9644),BP2,Strong,≥ (-4) Points.,Strength
-PTPN11 (HGNC:9644),BP2,Moderate,≥ (-2) Points.,Strength
-PTPN11 (HGNC:9644),BP2,Supporting,≥ (-1) Point.,None
-PTPN11 (HGNC:9644),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-PTPN11 (HGNC:9644),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-PTPN11 (HGNC:9644),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-PTPN11 (HGNC:9644),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-PTPN11 (HGNC:9644),BP5,Strong,≥ (-4) Points.,Strength
-PTPN11 (HGNC:9644),BP5,Moderate,≥ (-2) Points.,Strength
-PTPN11 (HGNC:9644),BP5,Supporting,≥ (-1) Point.,None
-PTPN11 (HGNC:9644),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-PTPN11 (HGNC:9644),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-PTPN11 (HGNC:9644),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTPN11Version2.1.0_version=2.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTPN11Version2.1.0_version=2.1.0.csv
deleted file mode 100644
index 7645130b3645e3505ff21e0e40312e7d2b7ceed1..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTPN11Version2.1.0_version=2.1.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-PTPN11 (HGNC:9644),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-PTPN11 (HGNC:9644),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-PTPN11 (HGNC:9644),PS1,Strong,"Same amino acid change as a previously established pathogenic variant in 
-PTPN11
- regardless of nucleotide change.",Gene-specific
-PTPN11 (HGNC:9644),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-PTPN11 (HGNC:9644),PS2,Very Strong,4 Points.,Strength
-PTPN11 (HGNC:9644),PS2,Strong,2 Points.,None
-PTPN11 (HGNC:9644),PS2,Moderate,1 Point.,Strength
-PTPN11 (HGNC:9644),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-PTPN11 (HGNC:9644),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-PTPN11 (HGNC:9644),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-PTPN11 (HGNC:9644),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-PTPN11 (HGNC:9644),PS4,Strong,≥5 points.,Disease-specific
-PTPN11 (HGNC:9644),PS4,Moderate,≥3 points.,Strength
-PTPN11 (HGNC:9644),PS4,Supporting,≥1 points.,Strength
-PTPN11 (HGNC:9644),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-PTPN11 (HGNC:9644),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (Directly interacting residues between N-SH2 and PTPN domains [AA 4, AA 7-9, AA 58-63, AA 69-77, AA 247, AA 251, AA 255, AA 256, AA 258, AA 261, AA 265, AA 278-281, AA 284]). Not applicable to specific amino acid residues (see PM5).",Gene-specific
-PTPN11 (HGNC:9644),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-PTPN11 (HGNC:9644),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-PTPN11 (HGNC:9644),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-PTPN11 (HGNC:9644),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-PTPN11 (HGNC:9644),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-PTPN11 (HGNC:9644),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-PTPN11 (HGNC:9644),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,Strength
-PTPN11 (HGNC:9644),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,Disease-specific
-PTPN11 (HGNC:9644),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-PTPN11 (HGNC:9644),PM6,Strong,2 Points.,Strength
-PTPN11 (HGNC:9644),PM6,Moderate,1 Point.,None
-PTPN11 (HGNC:9644),PM6,Supporting,0.5 Points.,Strength
-PTPN11 (HGNC:9644),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-PTPN11 (HGNC:9644),PP1,Strong,≥7 informative meioses.,Strength
-PTPN11 (HGNC:9644),PP1,Moderate,≥5 informative meioses.,Strength
-PTPN11 (HGNC:9644),PP1,Supporting,≥3 informative meioses.,Disease-specific
-PTPN11 (HGNC:9644),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,
-PTPN11 (HGNC:9644),PP2,Supporting,Missense z score is >3.09 in gnomAD.,Gene-specific
-PTPN11 (HGNC:9644),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-PTPN11 (HGNC:9644),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-PTPN11 (HGNC:9644),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-PTPN11 (HGNC:9644),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-PTPN11 (HGNC:9644),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-PTPN11 (HGNC:9644),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-PTPN11 (HGNC:9644),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-PTPN11 (HGNC:9644),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-PTPN11 (HGNC:9644),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-PTPN11 (HGNC:9644),BS2,Strong,-4 Points.,Strength
-PTPN11 (HGNC:9644),BS2,Supporting,-1 Point.,Strength
-PTPN11 (HGNC:9644),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-PTPN11 (HGNC:9644),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-PTPN11 (HGNC:9644),BS4,Strong,Requires only one informative meiosis.,General recommendation
-PTPN11 (HGNC:9644),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-PTPN11 (HGNC:9644),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-PTPN11 (HGNC:9644),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-PTPN11 (HGNC:9644),BP2,Strong,≥ (-4) Points.,Strength
-PTPN11 (HGNC:9644),BP2,Moderate,≥ (-2) Points.,Strength
-PTPN11 (HGNC:9644),BP2,Supporting,≥ (-1) Point.,None
-PTPN11 (HGNC:9644),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-PTPN11 (HGNC:9644),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-PTPN11 (HGNC:9644),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-PTPN11 (HGNC:9644),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-PTPN11 (HGNC:9644),BP5,Strong,≥ (-4) Points.,Strength
-PTPN11 (HGNC:9644),BP5,Moderate,≥ (-2) Points.,Strength
-PTPN11 (HGNC:9644),BP5,Supporting,≥ (-1) Point.,None
-PTPN11 (HGNC:9644),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-PTPN11 (HGNC:9644),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-PTPN11 (HGNC:9644),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTPN11Version2.2.0_version=2.2.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTPN11Version2.2.0_version=2.2.0.csv
deleted file mode 100644
index 7645130b3645e3505ff21e0e40312e7d2b7ceed1..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTPN11Version2.2.0_version=2.2.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-PTPN11 (HGNC:9644),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-PTPN11 (HGNC:9644),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-PTPN11 (HGNC:9644),PS1,Strong,"Same amino acid change as a previously established pathogenic variant in 
-PTPN11
- regardless of nucleotide change.",Gene-specific
-PTPN11 (HGNC:9644),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-PTPN11 (HGNC:9644),PS2,Very Strong,4 Points.,Strength
-PTPN11 (HGNC:9644),PS2,Strong,2 Points.,None
-PTPN11 (HGNC:9644),PS2,Moderate,1 Point.,Strength
-PTPN11 (HGNC:9644),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-PTPN11 (HGNC:9644),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-PTPN11 (HGNC:9644),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-PTPN11 (HGNC:9644),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-PTPN11 (HGNC:9644),PS4,Strong,≥5 points.,Disease-specific
-PTPN11 (HGNC:9644),PS4,Moderate,≥3 points.,Strength
-PTPN11 (HGNC:9644),PS4,Supporting,≥1 points.,Strength
-PTPN11 (HGNC:9644),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-PTPN11 (HGNC:9644),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (Directly interacting residues between N-SH2 and PTPN domains [AA 4, AA 7-9, AA 58-63, AA 69-77, AA 247, AA 251, AA 255, AA 256, AA 258, AA 261, AA 265, AA 278-281, AA 284]). Not applicable to specific amino acid residues (see PM5).",Gene-specific
-PTPN11 (HGNC:9644),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-PTPN11 (HGNC:9644),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-PTPN11 (HGNC:9644),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-PTPN11 (HGNC:9644),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-PTPN11 (HGNC:9644),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-PTPN11 (HGNC:9644),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-PTPN11 (HGNC:9644),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,Strength
-PTPN11 (HGNC:9644),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,Disease-specific
-PTPN11 (HGNC:9644),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-PTPN11 (HGNC:9644),PM6,Strong,2 Points.,Strength
-PTPN11 (HGNC:9644),PM6,Moderate,1 Point.,None
-PTPN11 (HGNC:9644),PM6,Supporting,0.5 Points.,Strength
-PTPN11 (HGNC:9644),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-PTPN11 (HGNC:9644),PP1,Strong,≥7 informative meioses.,Strength
-PTPN11 (HGNC:9644),PP1,Moderate,≥5 informative meioses.,Strength
-PTPN11 (HGNC:9644),PP1,Supporting,≥3 informative meioses.,Disease-specific
-PTPN11 (HGNC:9644),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,
-PTPN11 (HGNC:9644),PP2,Supporting,Missense z score is >3.09 in gnomAD.,Gene-specific
-PTPN11 (HGNC:9644),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-PTPN11 (HGNC:9644),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-PTPN11 (HGNC:9644),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-PTPN11 (HGNC:9644),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-PTPN11 (HGNC:9644),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-PTPN11 (HGNC:9644),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-PTPN11 (HGNC:9644),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-PTPN11 (HGNC:9644),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-PTPN11 (HGNC:9644),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-PTPN11 (HGNC:9644),BS2,Strong,-4 Points.,Strength
-PTPN11 (HGNC:9644),BS2,Supporting,-1 Point.,Strength
-PTPN11 (HGNC:9644),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-PTPN11 (HGNC:9644),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-PTPN11 (HGNC:9644),BS4,Strong,Requires only one informative meiosis.,General recommendation
-PTPN11 (HGNC:9644),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-PTPN11 (HGNC:9644),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-PTPN11 (HGNC:9644),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-PTPN11 (HGNC:9644),BP2,Strong,≥ (-4) Points.,Strength
-PTPN11 (HGNC:9644),BP2,Moderate,≥ (-2) Points.,Strength
-PTPN11 (HGNC:9644),BP2,Supporting,≥ (-1) Point.,None
-PTPN11 (HGNC:9644),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-PTPN11 (HGNC:9644),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-PTPN11 (HGNC:9644),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-PTPN11 (HGNC:9644),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-PTPN11 (HGNC:9644),BP5,Strong,≥ (-4) Points.,Strength
-PTPN11 (HGNC:9644),BP5,Moderate,≥ (-2) Points.,Strength
-PTPN11 (HGNC:9644),BP5,Supporting,≥ (-1) Point.,None
-PTPN11 (HGNC:9644),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-PTPN11 (HGNC:9644),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-PTPN11 (HGNC:9644),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTPN11Version2.3.0_version=2.3.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTPN11Version2.3.0_version=2.3.0.csv
deleted file mode 100644
index 068564492217b2143a7df85fc9497897a6e2b8f0..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTPN11Version2.3.0_version=2.3.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-PTPN11 (HGNC:9644),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-PTPN11 (HGNC:9644),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-PTPN11 (HGNC:9644),PS1,Strong,"Same amino acid change as a previously established pathogenic variant in 
-PTPN11
- regardless of nucleotide change.",Gene-specific
-PTPN11 (HGNC:9644),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-PTPN11 (HGNC:9644),PS2,Very Strong,4 Points.,Strength
-PTPN11 (HGNC:9644),PS2,Strong,2 Points.,None
-PTPN11 (HGNC:9644),PS2,Moderate,1 Point.,Strength
-PTPN11 (HGNC:9644),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-PTPN11 (HGNC:9644),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-PTPN11 (HGNC:9644),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-PTPN11 (HGNC:9644),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-PTPN11 (HGNC:9644),PS4,Strong,≥5 points.,Disease-specific
-PTPN11 (HGNC:9644),PS4,Moderate,≥3 points.,Strength
-PTPN11 (HGNC:9644),PS4,Supporting,≥1 points.,Strength
-PTPN11 (HGNC:9644),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-PTPN11 (HGNC:9644),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (Directly interacting residues between N-SH2 and PTPN domains [AA 4, AA 7-9, AA 58-63, AA 69-77, AA 247, AA 251, AA 255, AA 256, AA 258, AA 261, AA 265, AA 278-281, AA 284]). Not applicable to specific amino acid residues (see PM5).",Gene-specific
-PTPN11 (HGNC:9644),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-PTPN11 (HGNC:9644),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-PTPN11 (HGNC:9644),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-PTPN11 (HGNC:9644),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-PTPN11 (HGNC:9644),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-PTPN11 (HGNC:9644),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-PTPN11 (HGNC:9644),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,Strength
-PTPN11 (HGNC:9644),PM5,Moderate,1 [likely] pathogenic residue change at the same codon.,Disease-specific
-PTPN11 (HGNC:9644),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-PTPN11 (HGNC:9644),PM6,Strong,2 Points.,Strength
-PTPN11 (HGNC:9644),PM6,Moderate,1 Point.,None
-PTPN11 (HGNC:9644),PM6,Supporting,0.5 Points.,Strength
-PTPN11 (HGNC:9644),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-PTPN11 (HGNC:9644),PP1,Strong,≥7 informative meioses.,Strength
-PTPN11 (HGNC:9644),PP1,Moderate,≥5 informative meioses.,Strength
-PTPN11 (HGNC:9644),PP1,Supporting,≥3 informative meioses.,Disease-specific
-PTPN11 (HGNC:9644),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,
-PTPN11 (HGNC:9644),PP2,Supporting,Missense z score is >3.09 in gnomAD.,Gene-specific
-PTPN11 (HGNC:9644),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-PTPN11 (HGNC:9644),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-PTPN11 (HGNC:9644),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-PTPN11 (HGNC:9644),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-PTPN11 (HGNC:9644),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-PTPN11 (HGNC:9644),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-PTPN11 (HGNC:9644),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-PTPN11 (HGNC:9644),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-PTPN11 (HGNC:9644),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-PTPN11 (HGNC:9644),BS2,Strong,-4 Points.,Strength
-PTPN11 (HGNC:9644),BS2,Supporting,-1 Point.,Strength
-PTPN11 (HGNC:9644),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-PTPN11 (HGNC:9644),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-PTPN11 (HGNC:9644),BS4,Strong,Requires only one informative meiosis.,General recommendation
-PTPN11 (HGNC:9644),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-PTPN11 (HGNC:9644),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-PTPN11 (HGNC:9644),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-PTPN11 (HGNC:9644),BP2,Strong,≥ (-4) Points.,Strength
-PTPN11 (HGNC:9644),BP2,Moderate,≥ (-2) Points.,Strength
-PTPN11 (HGNC:9644),BP2,Supporting,≥ (-1) Point.,None
-PTPN11 (HGNC:9644),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-PTPN11 (HGNC:9644),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-PTPN11 (HGNC:9644),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-PTPN11 (HGNC:9644),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-PTPN11 (HGNC:9644),BP5,Strong,≥ (-4) Points.,Strength
-PTPN11 (HGNC:9644),BP5,Moderate,≥ (-2) Points.,Strength
-PTPN11 (HGNC:9644),BP5,Supporting,≥ (-1) Point.,None
-PTPN11 (HGNC:9644),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-PTPN11 (HGNC:9644),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-PTPN11 (HGNC:9644),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRAF1Version2.0.0_version=2.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRAF1Version2.0.0_version=2.0.0.csv
deleted file mode 100644
index 419c76e91851ad5bd90b1750e2179ab84ab7d37d..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRAF1Version2.0.0_version=2.0.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-RAF1 (HGNC:9829),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-RAF1 (HGNC:9829),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RAF1 (HGNC:9829),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-BRAF
- and 
-RAF1.",Analogous Gene
-RAF1 (HGNC:9829),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-RAF1 (HGNC:9829),PS2,Very Strong,4 Points.,Strength
-RAF1 (HGNC:9829),PS2,Strong,2 Points.,None
-RAF1 (HGNC:9829),PS2,Moderate,1 Point.,Strength
-RAF1 (HGNC:9829),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-RAF1 (HGNC:9829),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-RAF1 (HGNC:9829),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-RAF1 (HGNC:9829),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-RAF1 (HGNC:9829),PS4,Strong,≥5 points.,Disease-specific
-RAF1 (HGNC:9829),PS4,Moderate,≥3 points.,Strength
-RAF1 (HGNC:9829),PS4,Supporting,≥1 points.,Strength
-RAF1 (HGNC:9829),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-RAF1 (HGNC:9829),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (CR2 domain [AA 251-266/exon7], exon 14, exon 17). Not applicable to specific amino acid residues (see BP5).",Gene-specific
-RAF1 (HGNC:9829),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-RAF1 (HGNC:9829),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-RAF1 (HGNC:9829),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-RAF1 (HGNC:9829),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-RAF1 (HGNC:9829),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-RAF1 (HGNC:9829),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RAF1 (HGNC:9829),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-RAF1 (HGNC:9829),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,"Analogous Gene,Disease-specific"
-RAF1 (HGNC:9829),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-RAF1 (HGNC:9829),PM6,Strong,2 Points.,Strength
-RAF1 (HGNC:9829),PM6,Moderate,1 Point.,None
-RAF1 (HGNC:9829),PM6,Supporting,0.5 Points.,Strength
-RAF1 (HGNC:9829),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-RAF1 (HGNC:9829),PP1,Strong,≥7 informative meioses.,Strength
-RAF1 (HGNC:9829),PP1,Moderate,≥5 informative meioses.,Strength
-RAF1 (HGNC:9829),PP1,Supporting,≥3 informative meioses.,Disease-specific
-RAF1 (HGNC:9829),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-RAF1 (HGNC:9829),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-RAF1 (HGNC:9829),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-RAF1 (HGNC:9829),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-RAF1 (HGNC:9829),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RAF1 (HGNC:9829),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-RAF1 (HGNC:9829),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-RAF1 (HGNC:9829),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-RAF1 (HGNC:9829),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-RAF1 (HGNC:9829),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-RAF1 (HGNC:9829),BS2,Strong,-4 Points.,Strength
-RAF1 (HGNC:9829),BS2,Supporting,-1 Point.,Strength
-RAF1 (HGNC:9829),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-RAF1 (HGNC:9829),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-RAF1 (HGNC:9829),BS4,Strong,Requires only one informative meiosis.,General recommendation
-RAF1 (HGNC:9829),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-RAF1 (HGNC:9829),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-RAF1 (HGNC:9829),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-RAF1 (HGNC:9829),BP2,Strong,≥ (-4) Points.,Strength
-RAF1 (HGNC:9829),BP2,Moderate,≥ (-2) Points.,Strength
-RAF1 (HGNC:9829),BP2,Supporting,≥ (-1) Point.,None
-RAF1 (HGNC:9829),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-RAF1 (HGNC:9829),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-RAF1 (HGNC:9829),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-RAF1 (HGNC:9829),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-RAF1 (HGNC:9829),BP5,Strong,≥ (-4) Points.,Strength
-RAF1 (HGNC:9829),BP5,Moderate,≥ (-2) Points.,Strength
-RAF1 (HGNC:9829),BP5,Supporting,≥ (-1) Point.,None
-RAF1 (HGNC:9829),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RAF1 (HGNC:9829),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-RAF1 (HGNC:9829),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRAF1Version2.1.0_version=2.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRAF1Version2.1.0_version=2.1.0.csv
deleted file mode 100644
index 8eb8f1ed961c79654b6c28592f772227c087e808..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRAF1Version2.1.0_version=2.1.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-RAF1 (HGNC:9829),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-RAF1 (HGNC:9829),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RAF1 (HGNC:9829),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-BRAF
- and 
-RAF1.",Analogous Gene
-RAF1 (HGNC:9829),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-RAF1 (HGNC:9829),PS2,Very Strong,4 Points.,Strength
-RAF1 (HGNC:9829),PS2,Strong,2 Points.,None
-RAF1 (HGNC:9829),PS2,Moderate,1 Point.,Strength
-RAF1 (HGNC:9829),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-RAF1 (HGNC:9829),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-RAF1 (HGNC:9829),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-RAF1 (HGNC:9829),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-RAF1 (HGNC:9829),PS4,Strong,≥5 points.,Disease-specific
-RAF1 (HGNC:9829),PS4,Moderate,≥3 points.,Strength
-RAF1 (HGNC:9829),PS4,Supporting,≥1 points.,Strength
-RAF1 (HGNC:9829),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-RAF1 (HGNC:9829),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (CR2 domain [AA 251-266/exon7], exon 14, exon 17). Not applicable to specific amino acid residues (see PM5).",Gene-specific
-RAF1 (HGNC:9829),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-RAF1 (HGNC:9829),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-RAF1 (HGNC:9829),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-RAF1 (HGNC:9829),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-RAF1 (HGNC:9829),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-RAF1 (HGNC:9829),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RAF1 (HGNC:9829),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-RAF1 (HGNC:9829),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,"Analogous Gene,Disease-specific"
-RAF1 (HGNC:9829),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-RAF1 (HGNC:9829),PM6,Strong,2 Points.,Strength
-RAF1 (HGNC:9829),PM6,Moderate,1 Point.,None
-RAF1 (HGNC:9829),PM6,Supporting,0.5 Points.,Strength
-RAF1 (HGNC:9829),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-RAF1 (HGNC:9829),PP1,Strong,≥7 informative meioses.,Strength
-RAF1 (HGNC:9829),PP1,Moderate,≥5 informative meioses.,Strength
-RAF1 (HGNC:9829),PP1,Supporting,≥3 informative meioses.,Disease-specific
-RAF1 (HGNC:9829),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-RAF1 (HGNC:9829),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-RAF1 (HGNC:9829),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-RAF1 (HGNC:9829),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-RAF1 (HGNC:9829),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RAF1 (HGNC:9829),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-RAF1 (HGNC:9829),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-RAF1 (HGNC:9829),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-RAF1 (HGNC:9829),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-RAF1 (HGNC:9829),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-RAF1 (HGNC:9829),BS2,Strong,-4 Points.,Strength
-RAF1 (HGNC:9829),BS2,Supporting,-1 Point.,Strength
-RAF1 (HGNC:9829),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-RAF1 (HGNC:9829),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-RAF1 (HGNC:9829),BS4,Strong,Requires only one informative meiosis.,General recommendation
-RAF1 (HGNC:9829),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-RAF1 (HGNC:9829),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-RAF1 (HGNC:9829),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-RAF1 (HGNC:9829),BP2,Strong,≥ (-4) Points.,Strength
-RAF1 (HGNC:9829),BP2,Moderate,≥ (-2) Points.,Strength
-RAF1 (HGNC:9829),BP2,Supporting,≥ (-1) Point.,None
-RAF1 (HGNC:9829),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-RAF1 (HGNC:9829),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-RAF1 (HGNC:9829),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-RAF1 (HGNC:9829),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-RAF1 (HGNC:9829),BP5,Strong,≥ (-4) Points.,Strength
-RAF1 (HGNC:9829),BP5,Moderate,≥ (-2) Points.,Strength
-RAF1 (HGNC:9829),BP5,Supporting,≥ (-1) Point.,None
-RAF1 (HGNC:9829),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RAF1 (HGNC:9829),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-RAF1 (HGNC:9829),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRAF1Version2.2.0_version=2.2.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRAF1Version2.2.0_version=2.2.0.csv
deleted file mode 100644
index 8eb8f1ed961c79654b6c28592f772227c087e808..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRAF1Version2.2.0_version=2.2.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-RAF1 (HGNC:9829),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-RAF1 (HGNC:9829),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RAF1 (HGNC:9829),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-BRAF
- and 
-RAF1.",Analogous Gene
-RAF1 (HGNC:9829),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-RAF1 (HGNC:9829),PS2,Very Strong,4 Points.,Strength
-RAF1 (HGNC:9829),PS2,Strong,2 Points.,None
-RAF1 (HGNC:9829),PS2,Moderate,1 Point.,Strength
-RAF1 (HGNC:9829),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-RAF1 (HGNC:9829),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-RAF1 (HGNC:9829),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-RAF1 (HGNC:9829),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-RAF1 (HGNC:9829),PS4,Strong,≥5 points.,Disease-specific
-RAF1 (HGNC:9829),PS4,Moderate,≥3 points.,Strength
-RAF1 (HGNC:9829),PS4,Supporting,≥1 points.,Strength
-RAF1 (HGNC:9829),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-RAF1 (HGNC:9829),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (CR2 domain [AA 251-266/exon7], exon 14, exon 17). Not applicable to specific amino acid residues (see PM5).",Gene-specific
-RAF1 (HGNC:9829),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-RAF1 (HGNC:9829),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-RAF1 (HGNC:9829),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-RAF1 (HGNC:9829),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-RAF1 (HGNC:9829),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-RAF1 (HGNC:9829),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RAF1 (HGNC:9829),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-RAF1 (HGNC:9829),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,"Analogous Gene,Disease-specific"
-RAF1 (HGNC:9829),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-RAF1 (HGNC:9829),PM6,Strong,2 Points.,Strength
-RAF1 (HGNC:9829),PM6,Moderate,1 Point.,None
-RAF1 (HGNC:9829),PM6,Supporting,0.5 Points.,Strength
-RAF1 (HGNC:9829),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-RAF1 (HGNC:9829),PP1,Strong,≥7 informative meioses.,Strength
-RAF1 (HGNC:9829),PP1,Moderate,≥5 informative meioses.,Strength
-RAF1 (HGNC:9829),PP1,Supporting,≥3 informative meioses.,Disease-specific
-RAF1 (HGNC:9829),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-RAF1 (HGNC:9829),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-RAF1 (HGNC:9829),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-RAF1 (HGNC:9829),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-RAF1 (HGNC:9829),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RAF1 (HGNC:9829),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-RAF1 (HGNC:9829),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-RAF1 (HGNC:9829),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-RAF1 (HGNC:9829),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-RAF1 (HGNC:9829),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-RAF1 (HGNC:9829),BS2,Strong,-4 Points.,Strength
-RAF1 (HGNC:9829),BS2,Supporting,-1 Point.,Strength
-RAF1 (HGNC:9829),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-RAF1 (HGNC:9829),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-RAF1 (HGNC:9829),BS4,Strong,Requires only one informative meiosis.,General recommendation
-RAF1 (HGNC:9829),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-RAF1 (HGNC:9829),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-RAF1 (HGNC:9829),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-RAF1 (HGNC:9829),BP2,Strong,≥ (-4) Points.,Strength
-RAF1 (HGNC:9829),BP2,Moderate,≥ (-2) Points.,Strength
-RAF1 (HGNC:9829),BP2,Supporting,≥ (-1) Point.,None
-RAF1 (HGNC:9829),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-RAF1 (HGNC:9829),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-RAF1 (HGNC:9829),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-RAF1 (HGNC:9829),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-RAF1 (HGNC:9829),BP5,Strong,≥ (-4) Points.,Strength
-RAF1 (HGNC:9829),BP5,Moderate,≥ (-2) Points.,Strength
-RAF1 (HGNC:9829),BP5,Supporting,≥ (-1) Point.,None
-RAF1 (HGNC:9829),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RAF1 (HGNC:9829),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-RAF1 (HGNC:9829),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRAF1Version2.3.0_version=2.3.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRAF1Version2.3.0_version=2.3.0.csv
deleted file mode 100644
index e5d0d950f4fd0942aa3034a4d1c64beb5e7e10ec..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRAF1Version2.3.0_version=2.3.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-RAF1 (HGNC:9829),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-RAF1 (HGNC:9829),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RAF1 (HGNC:9829),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-BRAF
- and 
-RAF1.",Analogous Gene
-RAF1 (HGNC:9829),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-RAF1 (HGNC:9829),PS2,Very Strong,4 Points.,Strength
-RAF1 (HGNC:9829),PS2,Strong,2 Points.,None
-RAF1 (HGNC:9829),PS2,Moderate,1 Point.,Strength
-RAF1 (HGNC:9829),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-RAF1 (HGNC:9829),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-RAF1 (HGNC:9829),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-RAF1 (HGNC:9829),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-RAF1 (HGNC:9829),PS4,Strong,≥5 points.,Disease-specific
-RAF1 (HGNC:9829),PS4,Moderate,≥3 points.,Strength
-RAF1 (HGNC:9829),PS4,Supporting,≥1 points.,Strength
-RAF1 (HGNC:9829),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-RAF1 (HGNC:9829),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (CR2 domain [AA 251-266/exon7], exon 14, exon 17). Not applicable to specific amino acid residues (see PM5).",Gene-specific
-RAF1 (HGNC:9829),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-RAF1 (HGNC:9829),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-RAF1 (HGNC:9829),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-RAF1 (HGNC:9829),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-RAF1 (HGNC:9829),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-RAF1 (HGNC:9829),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RAF1 (HGNC:9829),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-RAF1 (HGNC:9829),PM5,Moderate,1 [likely] pathogenic residue change at the same codon.,"Analogous Gene,Disease-specific"
-RAF1 (HGNC:9829),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-RAF1 (HGNC:9829),PM6,Strong,2 Points.,Strength
-RAF1 (HGNC:9829),PM6,Moderate,1 Point.,None
-RAF1 (HGNC:9829),PM6,Supporting,0.5 Points.,Strength
-RAF1 (HGNC:9829),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-RAF1 (HGNC:9829),PP1,Strong,≥7 informative meioses.,Strength
-RAF1 (HGNC:9829),PP1,Moderate,≥5 informative meioses.,Strength
-RAF1 (HGNC:9829),PP1,Supporting,≥3 informative meioses.,Disease-specific
-RAF1 (HGNC:9829),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-RAF1 (HGNC:9829),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-RAF1 (HGNC:9829),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-RAF1 (HGNC:9829),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-RAF1 (HGNC:9829),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RAF1 (HGNC:9829),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-RAF1 (HGNC:9829),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-RAF1 (HGNC:9829),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-RAF1 (HGNC:9829),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-RAF1 (HGNC:9829),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-RAF1 (HGNC:9829),BS2,Strong,-4 Points.,Strength
-RAF1 (HGNC:9829),BS2,Supporting,-1 Point.,Strength
-RAF1 (HGNC:9829),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-RAF1 (HGNC:9829),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-RAF1 (HGNC:9829),BS4,Strong,Requires only one informative meiosis.,General recommendation
-RAF1 (HGNC:9829),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-RAF1 (HGNC:9829),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-RAF1 (HGNC:9829),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-RAF1 (HGNC:9829),BP2,Strong,≥ (-4) Points.,Strength
-RAF1 (HGNC:9829),BP2,Moderate,≥ (-2) Points.,Strength
-RAF1 (HGNC:9829),BP2,Supporting,≥ (-1) Point.,None
-RAF1 (HGNC:9829),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-RAF1 (HGNC:9829),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-RAF1 (HGNC:9829),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-RAF1 (HGNC:9829),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-RAF1 (HGNC:9829),BP5,Strong,≥ (-4) Points.,Strength
-RAF1 (HGNC:9829),BP5,Moderate,≥ (-2) Points.,Strength
-RAF1 (HGNC:9829),BP5,Supporting,≥ (-1) Point.,None
-RAF1 (HGNC:9829),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RAF1 (HGNC:9829),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-RAF1 (HGNC:9829),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRIT1Version2.0.0_version=2.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRIT1Version2.0.0_version=2.0.0.csv
deleted file mode 100644
index 8d84a568fa2b065ef7de789b8e480219fc7a6772..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRIT1Version2.0.0_version=2.0.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-RIT1 (HGNC:10023),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-RIT1 (HGNC:10023),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RIT1 (HGNC:10023),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-HRAS, KRAS, MRAS, NRAS, RIT1,
- and 
-RRAS2.",Analogous Gene
-RIT1 (HGNC:10023),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-RIT1 (HGNC:10023),PS2,Very Strong,4 Points.,Strength
-RIT1 (HGNC:10023),PS2,Strong,2 Points.,None
-RIT1 (HGNC:10023),PS2,Moderate,1 Point.,Strength
-RIT1 (HGNC:10023),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-RIT1 (HGNC:10023),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-RIT1 (HGNC:10023),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-RIT1 (HGNC:10023),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-RIT1 (HGNC:10023),PS4,Strong,≥5 points.,Disease-specific
-RIT1 (HGNC:10023),PS4,Moderate,≥3 points.,Strength
-RIT1 (HGNC:10023),PS4,Supporting,≥1 point.,Strength
-RIT1 (HGNC:10023),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-RIT1 (HGNC:10023),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (P-loop [AA 28-35], SW1 [AA 43-58], SW2 [AA 75-82], no SAK). Not applicable to specific amino acid residues (see BP5).",Gene-specific
-RIT1 (HGNC:10023),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-RIT1 (HGNC:10023),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-RIT1 (HGNC:10023),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-RIT1 (HGNC:10023),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-RIT1 (HGNC:10023),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-RIT1 (HGNC:10023),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RIT1 (HGNC:10023),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-RIT1 (HGNC:10023),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,"Analogous Gene,Disease-specific"
-RIT1 (HGNC:10023),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-RIT1 (HGNC:10023),PM6,Strong,2 Points.,Strength
-RIT1 (HGNC:10023),PM6,Moderate,1 Point.,None
-RIT1 (HGNC:10023),PM6,Supporting,0.5 Points.,Strength
-RIT1 (HGNC:10023),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-RIT1 (HGNC:10023),PP1,Strong,≥7 informative meioses.,Strength
-RIT1 (HGNC:10023),PP1,Moderate,≥5 informative meioses.,Strength
-RIT1 (HGNC:10023),PP1,Supporting,≥3 informative meioses.,Disease-specific
-RIT1 (HGNC:10023),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-RIT1 (HGNC:10023),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-RIT1 (HGNC:10023),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-RIT1 (HGNC:10023),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-RIT1 (HGNC:10023),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RIT1 (HGNC:10023),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-RIT1 (HGNC:10023),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-RIT1 (HGNC:10023),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-RIT1 (HGNC:10023),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-RIT1 (HGNC:10023),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-RIT1 (HGNC:10023),BS2,Strong,-4 Points.,Strength
-RIT1 (HGNC:10023),BS2,Supporting,-1 Point.,Strength
-RIT1 (HGNC:10023),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-RIT1 (HGNC:10023),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-RIT1 (HGNC:10023),BS4,Strong,Requires only one informative meiosis.,General recommendation
-RIT1 (HGNC:10023),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-RIT1 (HGNC:10023),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-RIT1 (HGNC:10023),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-RIT1 (HGNC:10023),BP2,Strong,≥ (-4) Points.,Strength
-RIT1 (HGNC:10023),BP2,Moderate,≥ (-2) Points.,Strength
-RIT1 (HGNC:10023),BP2,Supporting,≥ (-1) Point.,None
-RIT1 (HGNC:10023),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-RIT1 (HGNC:10023),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-RIT1 (HGNC:10023),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-RIT1 (HGNC:10023),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-RIT1 (HGNC:10023),BP5,Strong,≥ (-4) Points.,Strength
-RIT1 (HGNC:10023),BP5,Moderate,≥ (-2) Points.,Strength
-RIT1 (HGNC:10023),BP5,Supporting,≥ (-1) Point.,None
-RIT1 (HGNC:10023),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RIT1 (HGNC:10023),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-RIT1 (HGNC:10023),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRIT1Version2.1.0_version=2.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRIT1Version2.1.0_version=2.1.0.csv
deleted file mode 100644
index d3e3a25b5106e499a62bf53401ac32ee9a4facc7..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRIT1Version2.1.0_version=2.1.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-RIT1 (HGNC:10023),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-RIT1 (HGNC:10023),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RIT1 (HGNC:10023),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-HRAS, KRAS, MRAS, NRAS, RIT1,
- and 
-RRAS2.",Analogous Gene
-RIT1 (HGNC:10023),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-RIT1 (HGNC:10023),PS2,Very Strong,4 Points.,Strength
-RIT1 (HGNC:10023),PS2,Strong,2 Points.,None
-RIT1 (HGNC:10023),PS2,Moderate,1 Point.,Strength
-RIT1 (HGNC:10023),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-RIT1 (HGNC:10023),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-RIT1 (HGNC:10023),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-RIT1 (HGNC:10023),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-RIT1 (HGNC:10023),PS4,Strong,≥5 points.,Disease-specific
-RIT1 (HGNC:10023),PS4,Moderate,≥3 points.,Strength
-RIT1 (HGNC:10023),PS4,Supporting,≥1 point.,Strength
-RIT1 (HGNC:10023),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-RIT1 (HGNC:10023),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (P-loop [AA 28-35], SW1 [AA 43-58], SW2 [AA 75-82], no SAK). Not applicable to specific amino acid residues (see PM5).",Gene-specific
-RIT1 (HGNC:10023),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-RIT1 (HGNC:10023),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-RIT1 (HGNC:10023),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-RIT1 (HGNC:10023),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-RIT1 (HGNC:10023),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-RIT1 (HGNC:10023),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RIT1 (HGNC:10023),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-RIT1 (HGNC:10023),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,"Analogous Gene,Disease-specific"
-RIT1 (HGNC:10023),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-RIT1 (HGNC:10023),PM6,Strong,2 Points.,Strength
-RIT1 (HGNC:10023),PM6,Moderate,1 Point.,None
-RIT1 (HGNC:10023),PM6,Supporting,0.5 Points.,Strength
-RIT1 (HGNC:10023),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-RIT1 (HGNC:10023),PP1,Strong,≥7 informative meioses.,Strength
-RIT1 (HGNC:10023),PP1,Moderate,≥5 informative meioses.,Strength
-RIT1 (HGNC:10023),PP1,Supporting,≥3 informative meioses.,Disease-specific
-RIT1 (HGNC:10023),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-RIT1 (HGNC:10023),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-RIT1 (HGNC:10023),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-RIT1 (HGNC:10023),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-RIT1 (HGNC:10023),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RIT1 (HGNC:10023),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-RIT1 (HGNC:10023),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-RIT1 (HGNC:10023),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-RIT1 (HGNC:10023),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-RIT1 (HGNC:10023),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-RIT1 (HGNC:10023),BS2,Strong,-4 Points.,Strength
-RIT1 (HGNC:10023),BS2,Supporting,-1 Point.,Strength
-RIT1 (HGNC:10023),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-RIT1 (HGNC:10023),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-RIT1 (HGNC:10023),BS4,Strong,Requires only one informative meiosis.,General recommendation
-RIT1 (HGNC:10023),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-RIT1 (HGNC:10023),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-RIT1 (HGNC:10023),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-RIT1 (HGNC:10023),BP2,Strong,≥ (-4) Points.,Strength
-RIT1 (HGNC:10023),BP2,Moderate,≥ (-2) Points.,Strength
-RIT1 (HGNC:10023),BP2,Supporting,≥ (-1) Point.,None
-RIT1 (HGNC:10023),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-RIT1 (HGNC:10023),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-RIT1 (HGNC:10023),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-RIT1 (HGNC:10023),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-RIT1 (HGNC:10023),BP5,Strong,≥ (-4) Points.,Strength
-RIT1 (HGNC:10023),BP5,Moderate,≥ (-2) Points.,Strength
-RIT1 (HGNC:10023),BP5,Supporting,≥ (-1) Point.,None
-RIT1 (HGNC:10023),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RIT1 (HGNC:10023),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-RIT1 (HGNC:10023),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRIT1Version2.2.0_version=2.2.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRIT1Version2.2.0_version=2.2.0.csv
deleted file mode 100644
index d3e3a25b5106e499a62bf53401ac32ee9a4facc7..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRIT1Version2.2.0_version=2.2.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-RIT1 (HGNC:10023),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-RIT1 (HGNC:10023),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RIT1 (HGNC:10023),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-HRAS, KRAS, MRAS, NRAS, RIT1,
- and 
-RRAS2.",Analogous Gene
-RIT1 (HGNC:10023),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-RIT1 (HGNC:10023),PS2,Very Strong,4 Points.,Strength
-RIT1 (HGNC:10023),PS2,Strong,2 Points.,None
-RIT1 (HGNC:10023),PS2,Moderate,1 Point.,Strength
-RIT1 (HGNC:10023),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-RIT1 (HGNC:10023),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-RIT1 (HGNC:10023),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-RIT1 (HGNC:10023),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-RIT1 (HGNC:10023),PS4,Strong,≥5 points.,Disease-specific
-RIT1 (HGNC:10023),PS4,Moderate,≥3 points.,Strength
-RIT1 (HGNC:10023),PS4,Supporting,≥1 point.,Strength
-RIT1 (HGNC:10023),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-RIT1 (HGNC:10023),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (P-loop [AA 28-35], SW1 [AA 43-58], SW2 [AA 75-82], no SAK). Not applicable to specific amino acid residues (see PM5).",Gene-specific
-RIT1 (HGNC:10023),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-RIT1 (HGNC:10023),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-RIT1 (HGNC:10023),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-RIT1 (HGNC:10023),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-RIT1 (HGNC:10023),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-RIT1 (HGNC:10023),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RIT1 (HGNC:10023),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-RIT1 (HGNC:10023),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,"Analogous Gene,Disease-specific"
-RIT1 (HGNC:10023),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-RIT1 (HGNC:10023),PM6,Strong,2 Points.,Strength
-RIT1 (HGNC:10023),PM6,Moderate,1 Point.,None
-RIT1 (HGNC:10023),PM6,Supporting,0.5 Points.,Strength
-RIT1 (HGNC:10023),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-RIT1 (HGNC:10023),PP1,Strong,≥7 informative meioses.,Strength
-RIT1 (HGNC:10023),PP1,Moderate,≥5 informative meioses.,Strength
-RIT1 (HGNC:10023),PP1,Supporting,≥3 informative meioses.,Disease-specific
-RIT1 (HGNC:10023),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-RIT1 (HGNC:10023),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-RIT1 (HGNC:10023),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-RIT1 (HGNC:10023),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-RIT1 (HGNC:10023),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RIT1 (HGNC:10023),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-RIT1 (HGNC:10023),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-RIT1 (HGNC:10023),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-RIT1 (HGNC:10023),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-RIT1 (HGNC:10023),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-RIT1 (HGNC:10023),BS2,Strong,-4 Points.,Strength
-RIT1 (HGNC:10023),BS2,Supporting,-1 Point.,Strength
-RIT1 (HGNC:10023),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-RIT1 (HGNC:10023),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-RIT1 (HGNC:10023),BS4,Strong,Requires only one informative meiosis.,General recommendation
-RIT1 (HGNC:10023),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-RIT1 (HGNC:10023),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-RIT1 (HGNC:10023),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-RIT1 (HGNC:10023),BP2,Strong,≥ (-4) Points.,Strength
-RIT1 (HGNC:10023),BP2,Moderate,≥ (-2) Points.,Strength
-RIT1 (HGNC:10023),BP2,Supporting,≥ (-1) Point.,None
-RIT1 (HGNC:10023),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-RIT1 (HGNC:10023),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-RIT1 (HGNC:10023),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-RIT1 (HGNC:10023),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-RIT1 (HGNC:10023),BP5,Strong,≥ (-4) Points.,Strength
-RIT1 (HGNC:10023),BP5,Moderate,≥ (-2) Points.,Strength
-RIT1 (HGNC:10023),BP5,Supporting,≥ (-1) Point.,None
-RIT1 (HGNC:10023),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RIT1 (HGNC:10023),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-RIT1 (HGNC:10023),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRIT1Version2.3.0_version=2.3.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRIT1Version2.3.0_version=2.3.0.csv
deleted file mode 100644
index 185b4f963fe634ce6efa850a4191c5240d57dd53..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRIT1Version2.3.0_version=2.3.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-RIT1 (HGNC:10023),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-RIT1 (HGNC:10023),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RIT1 (HGNC:10023),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-HRAS, KRAS, MRAS, NRAS, RIT1,
- and 
-RRAS2.",Analogous Gene
-RIT1 (HGNC:10023),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-RIT1 (HGNC:10023),PS2,Very Strong,4 Points.,Strength
-RIT1 (HGNC:10023),PS2,Strong,2 Points.,None
-RIT1 (HGNC:10023),PS2,Moderate,1 Point.,Strength
-RIT1 (HGNC:10023),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-RIT1 (HGNC:10023),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-RIT1 (HGNC:10023),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-RIT1 (HGNC:10023),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-RIT1 (HGNC:10023),PS4,Strong,≥5 points.,Disease-specific
-RIT1 (HGNC:10023),PS4,Moderate,≥3 points.,Strength
-RIT1 (HGNC:10023),PS4,Supporting,≥1 point.,Strength
-RIT1 (HGNC:10023),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-RIT1 (HGNC:10023),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (P-loop [AA 28-35], SW1 [AA 43-58], SW2 [AA 75-82], no SAK). Not applicable to specific amino acid residues (see PM5).",Gene-specific
-RIT1 (HGNC:10023),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-RIT1 (HGNC:10023),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-RIT1 (HGNC:10023),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-RIT1 (HGNC:10023),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-RIT1 (HGNC:10023),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-RIT1 (HGNC:10023),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RIT1 (HGNC:10023),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-RIT1 (HGNC:10023),PM5,Moderate,1 [likely] pathogenic residue change at the same codon.,"Analogous Gene,Disease-specific"
-RIT1 (HGNC:10023),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-RIT1 (HGNC:10023),PM6,Strong,2 Points.,Strength
-RIT1 (HGNC:10023),PM6,Moderate,1 Point.,None
-RIT1 (HGNC:10023),PM6,Supporting,0.5 Points.,Strength
-RIT1 (HGNC:10023),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-RIT1 (HGNC:10023),PP1,Strong,≥7 informative meioses.,Strength
-RIT1 (HGNC:10023),PP1,Moderate,≥5 informative meioses.,Strength
-RIT1 (HGNC:10023),PP1,Supporting,≥3 informative meioses.,Disease-specific
-RIT1 (HGNC:10023),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-RIT1 (HGNC:10023),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-RIT1 (HGNC:10023),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-RIT1 (HGNC:10023),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-RIT1 (HGNC:10023),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RIT1 (HGNC:10023),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-RIT1 (HGNC:10023),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-RIT1 (HGNC:10023),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-RIT1 (HGNC:10023),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-RIT1 (HGNC:10023),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-RIT1 (HGNC:10023),BS2,Strong,-4 Points.,Strength
-RIT1 (HGNC:10023),BS2,Supporting,-1 Point.,Strength
-RIT1 (HGNC:10023),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-RIT1 (HGNC:10023),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-RIT1 (HGNC:10023),BS4,Strong,Requires only one informative meiosis.,General recommendation
-RIT1 (HGNC:10023),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-RIT1 (HGNC:10023),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-RIT1 (HGNC:10023),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-RIT1 (HGNC:10023),BP2,Strong,≥ (-4) Points.,Strength
-RIT1 (HGNC:10023),BP2,Moderate,≥ (-2) Points.,Strength
-RIT1 (HGNC:10023),BP2,Supporting,≥ (-1) Point.,None
-RIT1 (HGNC:10023),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-RIT1 (HGNC:10023),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-RIT1 (HGNC:10023),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-RIT1 (HGNC:10023),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-RIT1 (HGNC:10023),BP5,Strong,≥ (-4) Points.,Strength
-RIT1 (HGNC:10023),BP5,Moderate,≥ (-2) Points.,Strength
-RIT1 (HGNC:10023),BP5,Supporting,≥ (-1) Point.,None
-RIT1 (HGNC:10023),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RIT1 (HGNC:10023),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-RIT1 (HGNC:10023),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRRAS2Version1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRRAS2Version1.0.0_version=1.0.0.csv
deleted file mode 100644
index 19b986b0f811ed29e9361123014c181882ff0161..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRRAS2Version1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,87 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-RRAS2 (HGNC:17271),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-RRAS2 (HGNC:17271),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RRAS2 (HGNC:17271),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-HRAS, KRAS, MRAS, NRAS, RIT1,
- and 
-RRAS2.",Analogous Gene
-RRAS2 (HGNC:17271),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-RRAS2 (HGNC:17271),PS2,Very Strong,4 Points.,Strength
-RRAS2 (HGNC:17271),PS2,Strong,2 Points.,None
-RRAS2 (HGNC:17271),PS2,Moderate,1 Point.,Strength
-RRAS2 (HGNC:17271),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-RRAS2 (HGNC:17271),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-RRAS2 (HGNC:17271),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-RRAS2 (HGNC:17271),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-RRAS2 (HGNC:17271),PS4,Strong,≥5 points.,Disease-specific
-RRAS2 (HGNC:17271),PS4,Moderate,≥3 points.,Strength
-RRAS2 (HGNC:17271),PS4,Supporting,≥1 points.,Strength
-RRAS2 (HGNC:17271),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-RRAS2 (HGNC:17271),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (P-loop [AA 21-28], SW1 [AA 36-51], SW2 [AA 68-75], no SAK). Not applicable to specific amino acid residues (see BP5).",Gene-specific
-RRAS2 (HGNC:17271),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-RRAS2 (HGNC:17271),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-RRAS2 (HGNC:17271),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-RRAS2 (HGNC:17271),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-RRAS2 (HGNC:17271),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-RRAS2 (HGNC:17271),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RRAS2 (HGNC:17271),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-RRAS2 (HGNC:17271),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,"Analogous Gene,Disease-specific"
-RRAS2 (HGNC:17271),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-RRAS2 (HGNC:17271),PM6,Strong,2 Points.,Strength
-RRAS2 (HGNC:17271),PM6,Moderate,1 Point.,None
-RRAS2 (HGNC:17271),PM6,Supporting,0.5 Points.,Strength
-RRAS2 (HGNC:17271),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-RRAS2 (HGNC:17271),PP1,Strong,≥7 informative meioses.,Strength
-RRAS2 (HGNC:17271),PP1,Moderate,≥5 informative meioses.,Strength
-RRAS2 (HGNC:17271),PP1,Supporting,≥3 informative meioses.,Disease-specific
-RRAS2 (HGNC:17271),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-RRAS2 (HGNC:17271),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-RRAS2 (HGNC:17271),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-RRAS2 (HGNC:17271),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-RRAS2 (HGNC:17271),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RRAS2 (HGNC:17271),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-RRAS2 (HGNC:17271),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-RRAS2 (HGNC:17271),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-RRAS2 (HGNC:17271),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-RRAS2 (HGNC:17271),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-RRAS2 (HGNC:17271),BS2,Strong,-4 Points.,Strength
-RRAS2 (HGNC:17271),BS2,Supporting,-1 Point.,Strength
-RRAS2 (HGNC:17271),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-RRAS2 (HGNC:17271),BS3,Supporting,Assays approved by the VCEP sufficiently evaluate the functional impact of a given variant for the application of PS3_Supporting.,"Disease-specific,Strength"
-RRAS2 (HGNC:17271),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-RRAS2 (HGNC:17271),BS4,Strong,Requires only one informative meiosis.,General recommendation
-RRAS2 (HGNC:17271),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-RRAS2 (HGNC:17271),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-RRAS2 (HGNC:17271),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-RRAS2 (HGNC:17271),BP2,Strong,≥ (-4) Points.,Strength
-RRAS2 (HGNC:17271),BP2,Moderate,≥ (-2) Points.,Strength
-RRAS2 (HGNC:17271),BP2,Supporting,≥ (-1) Point.,None
-RRAS2 (HGNC:17271),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-RRAS2 (HGNC:17271),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-RRAS2 (HGNC:17271),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-RRAS2 (HGNC:17271),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-RRAS2 (HGNC:17271),BP5,Strong,≥ (-4) Points.,Strength
-RRAS2 (HGNC:17271),BP5,Moderate,≥ (-2) Points.,Strength
-RRAS2 (HGNC:17271),BP5,Supporting,≥ (-1) Point.,None
-RRAS2 (HGNC:17271),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RRAS2 (HGNC:17271),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-RRAS2 (HGNC:17271),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRRAS2Version1.1.0_version=1.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRRAS2Version1.1.0_version=1.1.0.csv
deleted file mode 100644
index ba87244693235f38d5496bce9e9ed769e7108d93..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRRAS2Version1.1.0_version=1.1.0.csv
+++ /dev/null
@@ -1,87 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-RRAS2 (HGNC:17271),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-RRAS2 (HGNC:17271),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RRAS2 (HGNC:17271),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-HRAS, KRAS, MRAS, NRAS, RIT1,
- and 
-RRAS2.",Analogous Gene
-RRAS2 (HGNC:17271),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-RRAS2 (HGNC:17271),PS2,Very Strong,4 Points.,Strength
-RRAS2 (HGNC:17271),PS2,Strong,2 Points.,None
-RRAS2 (HGNC:17271),PS2,Moderate,1 Point.,Strength
-RRAS2 (HGNC:17271),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-RRAS2 (HGNC:17271),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-RRAS2 (HGNC:17271),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-RRAS2 (HGNC:17271),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-RRAS2 (HGNC:17271),PS4,Strong,≥5 points.,Disease-specific
-RRAS2 (HGNC:17271),PS4,Moderate,≥3 points.,Strength
-RRAS2 (HGNC:17271),PS4,Supporting,≥1 points.,Strength
-RRAS2 (HGNC:17271),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-RRAS2 (HGNC:17271),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (P-loop [AA 21-28], SW1 [AA 36-51], SW2 [AA 68-75], no SAK). Not applicable to specific amino acid residues (see PM5).",Gene-specific
-RRAS2 (HGNC:17271),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-RRAS2 (HGNC:17271),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-RRAS2 (HGNC:17271),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-RRAS2 (HGNC:17271),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-RRAS2 (HGNC:17271),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-RRAS2 (HGNC:17271),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RRAS2 (HGNC:17271),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-RRAS2 (HGNC:17271),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,"Analogous Gene,Disease-specific"
-RRAS2 (HGNC:17271),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-RRAS2 (HGNC:17271),PM6,Strong,2 Points.,Strength
-RRAS2 (HGNC:17271),PM6,Moderate,1 Point.,None
-RRAS2 (HGNC:17271),PM6,Supporting,0.5 Points.,Strength
-RRAS2 (HGNC:17271),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-RRAS2 (HGNC:17271),PP1,Strong,≥7 informative meioses.,Strength
-RRAS2 (HGNC:17271),PP1,Moderate,≥5 informative meioses.,Strength
-RRAS2 (HGNC:17271),PP1,Supporting,≥3 informative meioses.,Disease-specific
-RRAS2 (HGNC:17271),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-RRAS2 (HGNC:17271),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-RRAS2 (HGNC:17271),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-RRAS2 (HGNC:17271),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-RRAS2 (HGNC:17271),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RRAS2 (HGNC:17271),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-RRAS2 (HGNC:17271),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-RRAS2 (HGNC:17271),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-RRAS2 (HGNC:17271),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-RRAS2 (HGNC:17271),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-RRAS2 (HGNC:17271),BS2,Strong,-4 Points.,Strength
-RRAS2 (HGNC:17271),BS2,Supporting,-1 Point.,Strength
-RRAS2 (HGNC:17271),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-RRAS2 (HGNC:17271),BS3,Supporting,Assays approved by the VCEP sufficiently evaluate the functional impact of a given variant for the application of PS3_Supporting.,"Disease-specific,Strength"
-RRAS2 (HGNC:17271),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-RRAS2 (HGNC:17271),BS4,Strong,Requires only one informative meiosis.,General recommendation
-RRAS2 (HGNC:17271),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-RRAS2 (HGNC:17271),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-RRAS2 (HGNC:17271),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-RRAS2 (HGNC:17271),BP2,Strong,≥ (-4) Points.,Strength
-RRAS2 (HGNC:17271),BP2,Moderate,≥ (-2) Points.,Strength
-RRAS2 (HGNC:17271),BP2,Supporting,≥ (-1) Point.,None
-RRAS2 (HGNC:17271),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-RRAS2 (HGNC:17271),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-RRAS2 (HGNC:17271),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-RRAS2 (HGNC:17271),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-RRAS2 (HGNC:17271),BP5,Strong,≥ (-4) Points.,Strength
-RRAS2 (HGNC:17271),BP5,Moderate,≥ (-2) Points.,Strength
-RRAS2 (HGNC:17271),BP5,Supporting,≥ (-1) Point.,None
-RRAS2 (HGNC:17271),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RRAS2 (HGNC:17271),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-RRAS2 (HGNC:17271),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRRAS2Version1.2.0_version=1.2.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRRAS2Version1.2.0_version=1.2.0.csv
deleted file mode 100644
index ba87244693235f38d5496bce9e9ed769e7108d93..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRRAS2Version1.2.0_version=1.2.0.csv
+++ /dev/null
@@ -1,87 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-RRAS2 (HGNC:17271),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-RRAS2 (HGNC:17271),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RRAS2 (HGNC:17271),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-HRAS, KRAS, MRAS, NRAS, RIT1,
- and 
-RRAS2.",Analogous Gene
-RRAS2 (HGNC:17271),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-RRAS2 (HGNC:17271),PS2,Very Strong,4 Points.,Strength
-RRAS2 (HGNC:17271),PS2,Strong,2 Points.,None
-RRAS2 (HGNC:17271),PS2,Moderate,1 Point.,Strength
-RRAS2 (HGNC:17271),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-RRAS2 (HGNC:17271),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-RRAS2 (HGNC:17271),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-RRAS2 (HGNC:17271),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-RRAS2 (HGNC:17271),PS4,Strong,≥5 points.,Disease-specific
-RRAS2 (HGNC:17271),PS4,Moderate,≥3 points.,Strength
-RRAS2 (HGNC:17271),PS4,Supporting,≥1 points.,Strength
-RRAS2 (HGNC:17271),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-RRAS2 (HGNC:17271),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (P-loop [AA 21-28], SW1 [AA 36-51], SW2 [AA 68-75], no SAK). Not applicable to specific amino acid residues (see PM5).",Gene-specific
-RRAS2 (HGNC:17271),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-RRAS2 (HGNC:17271),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-RRAS2 (HGNC:17271),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-RRAS2 (HGNC:17271),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-RRAS2 (HGNC:17271),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-RRAS2 (HGNC:17271),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RRAS2 (HGNC:17271),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-RRAS2 (HGNC:17271),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,"Analogous Gene,Disease-specific"
-RRAS2 (HGNC:17271),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-RRAS2 (HGNC:17271),PM6,Strong,2 Points.,Strength
-RRAS2 (HGNC:17271),PM6,Moderate,1 Point.,None
-RRAS2 (HGNC:17271),PM6,Supporting,0.5 Points.,Strength
-RRAS2 (HGNC:17271),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-RRAS2 (HGNC:17271),PP1,Strong,≥7 informative meioses.,Strength
-RRAS2 (HGNC:17271),PP1,Moderate,≥5 informative meioses.,Strength
-RRAS2 (HGNC:17271),PP1,Supporting,≥3 informative meioses.,Disease-specific
-RRAS2 (HGNC:17271),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-RRAS2 (HGNC:17271),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-RRAS2 (HGNC:17271),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-RRAS2 (HGNC:17271),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-RRAS2 (HGNC:17271),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RRAS2 (HGNC:17271),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-RRAS2 (HGNC:17271),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-RRAS2 (HGNC:17271),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-RRAS2 (HGNC:17271),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-RRAS2 (HGNC:17271),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-RRAS2 (HGNC:17271),BS2,Strong,-4 Points.,Strength
-RRAS2 (HGNC:17271),BS2,Supporting,-1 Point.,Strength
-RRAS2 (HGNC:17271),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-RRAS2 (HGNC:17271),BS3,Supporting,Assays approved by the VCEP sufficiently evaluate the functional impact of a given variant for the application of PS3_Supporting.,"Disease-specific,Strength"
-RRAS2 (HGNC:17271),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-RRAS2 (HGNC:17271),BS4,Strong,Requires only one informative meiosis.,General recommendation
-RRAS2 (HGNC:17271),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-RRAS2 (HGNC:17271),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-RRAS2 (HGNC:17271),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-RRAS2 (HGNC:17271),BP2,Strong,≥ (-4) Points.,Strength
-RRAS2 (HGNC:17271),BP2,Moderate,≥ (-2) Points.,Strength
-RRAS2 (HGNC:17271),BP2,Supporting,≥ (-1) Point.,None
-RRAS2 (HGNC:17271),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-RRAS2 (HGNC:17271),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-RRAS2 (HGNC:17271),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-RRAS2 (HGNC:17271),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-RRAS2 (HGNC:17271),BP5,Strong,≥ (-4) Points.,Strength
-RRAS2 (HGNC:17271),BP5,Moderate,≥ (-2) Points.,Strength
-RRAS2 (HGNC:17271),BP5,Supporting,≥ (-1) Point.,None
-RRAS2 (HGNC:17271),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RRAS2 (HGNC:17271),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-RRAS2 (HGNC:17271),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRRAS2Version1.3.0_version=1.3.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRRAS2Version1.3.0_version=1.3.0.csv
deleted file mode 100644
index dacefa80651882751fffc253ce67d123db99fb3f..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRRAS2Version1.3.0_version=1.3.0.csv
+++ /dev/null
@@ -1,87 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-RRAS2 (HGNC:17271),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-RRAS2 (HGNC:17271),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RRAS2 (HGNC:17271),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-HRAS, KRAS, MRAS, NRAS, RIT1,
- and 
-RRAS2.",Analogous Gene
-RRAS2 (HGNC:17271),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-RRAS2 (HGNC:17271),PS2,Very Strong,4 Points.,Strength
-RRAS2 (HGNC:17271),PS2,Strong,2 Points.,None
-RRAS2 (HGNC:17271),PS2,Moderate,1 Point.,Strength
-RRAS2 (HGNC:17271),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-RRAS2 (HGNC:17271),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-RRAS2 (HGNC:17271),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-RRAS2 (HGNC:17271),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-RRAS2 (HGNC:17271),PS4,Strong,≥5 points.,Disease-specific
-RRAS2 (HGNC:17271),PS4,Moderate,≥3 points.,Strength
-RRAS2 (HGNC:17271),PS4,Supporting,≥1 points.,Strength
-RRAS2 (HGNC:17271),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-RRAS2 (HGNC:17271),PM1,Moderate,"Applicable only to critical and well-established functional domains available in the supplementary table (P-loop [AA 21-28], SW1 [AA 36-51], SW2 [AA 68-75], no SAK). Not applicable to specific amino acid residues (see PM5).",Gene-specific
-RRAS2 (HGNC:17271),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-RRAS2 (HGNC:17271),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-RRAS2 (HGNC:17271),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-RRAS2 (HGNC:17271),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-RRAS2 (HGNC:17271),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-RRAS2 (HGNC:17271),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RRAS2 (HGNC:17271),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-RRAS2 (HGNC:17271),PM5,Moderate,1 [likely] pathogenic residue change at the same codon.,"Analogous Gene,Disease-specific"
-RRAS2 (HGNC:17271),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-RRAS2 (HGNC:17271),PM6,Strong,2 Points.,Strength
-RRAS2 (HGNC:17271),PM6,Moderate,1 Point.,None
-RRAS2 (HGNC:17271),PM6,Supporting,0.5 Points.,Strength
-RRAS2 (HGNC:17271),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-RRAS2 (HGNC:17271),PP1,Strong,≥7 informative meioses.,Strength
-RRAS2 (HGNC:17271),PP1,Moderate,≥5 informative meioses.,Strength
-RRAS2 (HGNC:17271),PP1,Supporting,≥3 informative meioses.,Disease-specific
-RRAS2 (HGNC:17271),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-RRAS2 (HGNC:17271),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-RRAS2 (HGNC:17271),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-RRAS2 (HGNC:17271),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-RRAS2 (HGNC:17271),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RRAS2 (HGNC:17271),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-RRAS2 (HGNC:17271),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-RRAS2 (HGNC:17271),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-RRAS2 (HGNC:17271),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-RRAS2 (HGNC:17271),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-RRAS2 (HGNC:17271),BS2,Strong,-4 Points.,Strength
-RRAS2 (HGNC:17271),BS2,Supporting,-1 Point.,Strength
-RRAS2 (HGNC:17271),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-RRAS2 (HGNC:17271),BS3,Supporting,Assays approved by the VCEP sufficiently evaluate the functional impact of a given variant for the application of PS3_Supporting.,"Disease-specific,Strength"
-RRAS2 (HGNC:17271),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-RRAS2 (HGNC:17271),BS4,Strong,Requires only one informative meiosis.,General recommendation
-RRAS2 (HGNC:17271),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-RRAS2 (HGNC:17271),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-RRAS2 (HGNC:17271),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-RRAS2 (HGNC:17271),BP2,Strong,≥ (-4) Points.,Strength
-RRAS2 (HGNC:17271),BP2,Moderate,≥ (-2) Points.,Strength
-RRAS2 (HGNC:17271),BP2,Supporting,≥ (-1) Point.,None
-RRAS2 (HGNC:17271),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-RRAS2 (HGNC:17271),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-RRAS2 (HGNC:17271),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-RRAS2 (HGNC:17271),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-RRAS2 (HGNC:17271),BP5,Strong,≥ (-4) Points.,Strength
-RRAS2 (HGNC:17271),BP5,Moderate,≥ (-2) Points.,Strength
-RRAS2 (HGNC:17271),BP5,Supporting,≥ (-1) Point.,None
-RRAS2 (HGNC:17271),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RRAS2 (HGNC:17271),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-RRAS2 (HGNC:17271),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSHOC2Version2.0.0_version=2.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSHOC2Version2.0.0_version=2.0.0.csv
deleted file mode 100644
index d40f27848fa1504fef59f302071112fd7dd63bd8..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSHOC2Version2.0.0_version=2.0.0.csv
+++ /dev/null
@@ -1,82 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-SHOC2 (HGNC:15454),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-SHOC2 (HGNC:15454),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SHOC2 (HGNC:15454),PS1,Strong,"Same amino acid change as a previously established pathogenic variant in 
-SHOC2
- regardless of nucleotide change.",Gene-specific
-SHOC2 (HGNC:15454),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-SHOC2 (HGNC:15454),PS2,Very Strong,4 Points.,Strength
-SHOC2 (HGNC:15454),PS2,Strong,2 Points.,None
-SHOC2 (HGNC:15454),PS2,Moderate,1 Point.,Strength
-SHOC2 (HGNC:15454),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",NA
-SHOC2 (HGNC:15454),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-SHOC2 (HGNC:15454),PS4,Strong,≥5 points.,Disease-specific
-SHOC2 (HGNC:15454),PS4,Moderate,≥3 points.,Strength
-SHOC2 (HGNC:15454),PS4,Supporting,≥1 points.,Strength
-SHOC2 (HGNC:15454),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-SHOC2 (HGNC:15454),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-SHOC2 (HGNC:15454),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-SHOC2 (HGNC:15454),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-SHOC2 (HGNC:15454),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-SHOC2 (HGNC:15454),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-SHOC2 (HGNC:15454),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SHOC2 (HGNC:15454),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,Strength
-SHOC2 (HGNC:15454),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,Disease-specific
-SHOC2 (HGNC:15454),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-SHOC2 (HGNC:15454),PM6,Strong,2 Points.,Strength
-SHOC2 (HGNC:15454),PM6,Moderate,1 Point.,None
-SHOC2 (HGNC:15454),PM6,Supporting,0.5 Points.,Strength
-SHOC2 (HGNC:15454),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-SHOC2 (HGNC:15454),PP1,Strong,≥7 informative meioses.,Strength
-SHOC2 (HGNC:15454),PP1,Moderate,≥5 informative meioses.,Strength
-SHOC2 (HGNC:15454),PP1,Supporting,≥3 informative meioses.,Disease-specific
-SHOC2 (HGNC:15454),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-SHOC2 (HGNC:15454),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-SHOC2 (HGNC:15454),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-SHOC2 (HGNC:15454),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-SHOC2 (HGNC:15454),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SHOC2 (HGNC:15454),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-SHOC2 (HGNC:15454),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-SHOC2 (HGNC:15454),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-SHOC2 (HGNC:15454),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-SHOC2 (HGNC:15454),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-SHOC2 (HGNC:15454),BS2,Strong,-4 Points.,Strength
-SHOC2 (HGNC:15454),BS2,Supporting,-1 Point.,Strength
-SHOC2 (HGNC:15454),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-SHOC2 (HGNC:15454),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-SHOC2 (HGNC:15454),BS4,Strong,Requires only one informative meiosis.,General recommendation
-SHOC2 (HGNC:15454),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-SHOC2 (HGNC:15454),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-SHOC2 (HGNC:15454),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-SHOC2 (HGNC:15454),BP2,Strong,≥ (-4) Points.,Strength
-SHOC2 (HGNC:15454),BP2,Moderate,≥ (-2) Points.,Strength
-SHOC2 (HGNC:15454),BP2,Supporting,≥ (-1) Point.,None
-SHOC2 (HGNC:15454),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-SHOC2 (HGNC:15454),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SHOC2 (HGNC:15454),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-SHOC2 (HGNC:15454),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-SHOC2 (HGNC:15454),BP5,Strong,≥ (-4) Points.,Strength
-SHOC2 (HGNC:15454),BP5,Moderate,≥ (-2) Points.,Strength
-SHOC2 (HGNC:15454),BP5,Supporting,≥ (-1) Point.,None
-SHOC2 (HGNC:15454),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SHOC2 (HGNC:15454),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-SHOC2 (HGNC:15454),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSHOC2Version2.1.0_version=2.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSHOC2Version2.1.0_version=2.1.0.csv
deleted file mode 100644
index d40f27848fa1504fef59f302071112fd7dd63bd8..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSHOC2Version2.1.0_version=2.1.0.csv
+++ /dev/null
@@ -1,82 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-SHOC2 (HGNC:15454),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-SHOC2 (HGNC:15454),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SHOC2 (HGNC:15454),PS1,Strong,"Same amino acid change as a previously established pathogenic variant in 
-SHOC2
- regardless of nucleotide change.",Gene-specific
-SHOC2 (HGNC:15454),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-SHOC2 (HGNC:15454),PS2,Very Strong,4 Points.,Strength
-SHOC2 (HGNC:15454),PS2,Strong,2 Points.,None
-SHOC2 (HGNC:15454),PS2,Moderate,1 Point.,Strength
-SHOC2 (HGNC:15454),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",NA
-SHOC2 (HGNC:15454),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-SHOC2 (HGNC:15454),PS4,Strong,≥5 points.,Disease-specific
-SHOC2 (HGNC:15454),PS4,Moderate,≥3 points.,Strength
-SHOC2 (HGNC:15454),PS4,Supporting,≥1 points.,Strength
-SHOC2 (HGNC:15454),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-SHOC2 (HGNC:15454),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-SHOC2 (HGNC:15454),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-SHOC2 (HGNC:15454),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-SHOC2 (HGNC:15454),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-SHOC2 (HGNC:15454),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-SHOC2 (HGNC:15454),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SHOC2 (HGNC:15454),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,Strength
-SHOC2 (HGNC:15454),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,Disease-specific
-SHOC2 (HGNC:15454),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-SHOC2 (HGNC:15454),PM6,Strong,2 Points.,Strength
-SHOC2 (HGNC:15454),PM6,Moderate,1 Point.,None
-SHOC2 (HGNC:15454),PM6,Supporting,0.5 Points.,Strength
-SHOC2 (HGNC:15454),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-SHOC2 (HGNC:15454),PP1,Strong,≥7 informative meioses.,Strength
-SHOC2 (HGNC:15454),PP1,Moderate,≥5 informative meioses.,Strength
-SHOC2 (HGNC:15454),PP1,Supporting,≥3 informative meioses.,Disease-specific
-SHOC2 (HGNC:15454),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-SHOC2 (HGNC:15454),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-SHOC2 (HGNC:15454),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-SHOC2 (HGNC:15454),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-SHOC2 (HGNC:15454),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SHOC2 (HGNC:15454),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-SHOC2 (HGNC:15454),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-SHOC2 (HGNC:15454),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-SHOC2 (HGNC:15454),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-SHOC2 (HGNC:15454),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-SHOC2 (HGNC:15454),BS2,Strong,-4 Points.,Strength
-SHOC2 (HGNC:15454),BS2,Supporting,-1 Point.,Strength
-SHOC2 (HGNC:15454),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-SHOC2 (HGNC:15454),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-SHOC2 (HGNC:15454),BS4,Strong,Requires only one informative meiosis.,General recommendation
-SHOC2 (HGNC:15454),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-SHOC2 (HGNC:15454),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-SHOC2 (HGNC:15454),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-SHOC2 (HGNC:15454),BP2,Strong,≥ (-4) Points.,Strength
-SHOC2 (HGNC:15454),BP2,Moderate,≥ (-2) Points.,Strength
-SHOC2 (HGNC:15454),BP2,Supporting,≥ (-1) Point.,None
-SHOC2 (HGNC:15454),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-SHOC2 (HGNC:15454),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SHOC2 (HGNC:15454),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-SHOC2 (HGNC:15454),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-SHOC2 (HGNC:15454),BP5,Strong,≥ (-4) Points.,Strength
-SHOC2 (HGNC:15454),BP5,Moderate,≥ (-2) Points.,Strength
-SHOC2 (HGNC:15454),BP5,Supporting,≥ (-1) Point.,None
-SHOC2 (HGNC:15454),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SHOC2 (HGNC:15454),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-SHOC2 (HGNC:15454),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSHOC2Version2.2.0_version=2.2.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSHOC2Version2.2.0_version=2.2.0.csv
deleted file mode 100644
index d40f27848fa1504fef59f302071112fd7dd63bd8..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSHOC2Version2.2.0_version=2.2.0.csv
+++ /dev/null
@@ -1,82 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-SHOC2 (HGNC:15454),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-SHOC2 (HGNC:15454),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SHOC2 (HGNC:15454),PS1,Strong,"Same amino acid change as a previously established pathogenic variant in 
-SHOC2
- regardless of nucleotide change.",Gene-specific
-SHOC2 (HGNC:15454),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-SHOC2 (HGNC:15454),PS2,Very Strong,4 Points.,Strength
-SHOC2 (HGNC:15454),PS2,Strong,2 Points.,None
-SHOC2 (HGNC:15454),PS2,Moderate,1 Point.,Strength
-SHOC2 (HGNC:15454),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",NA
-SHOC2 (HGNC:15454),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-SHOC2 (HGNC:15454),PS4,Strong,≥5 points.,Disease-specific
-SHOC2 (HGNC:15454),PS4,Moderate,≥3 points.,Strength
-SHOC2 (HGNC:15454),PS4,Supporting,≥1 points.,Strength
-SHOC2 (HGNC:15454),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-SHOC2 (HGNC:15454),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-SHOC2 (HGNC:15454),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-SHOC2 (HGNC:15454),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-SHOC2 (HGNC:15454),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-SHOC2 (HGNC:15454),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-SHOC2 (HGNC:15454),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SHOC2 (HGNC:15454),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,Strength
-SHOC2 (HGNC:15454),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,Disease-specific
-SHOC2 (HGNC:15454),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-SHOC2 (HGNC:15454),PM6,Strong,2 Points.,Strength
-SHOC2 (HGNC:15454),PM6,Moderate,1 Point.,None
-SHOC2 (HGNC:15454),PM6,Supporting,0.5 Points.,Strength
-SHOC2 (HGNC:15454),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-SHOC2 (HGNC:15454),PP1,Strong,≥7 informative meioses.,Strength
-SHOC2 (HGNC:15454),PP1,Moderate,≥5 informative meioses.,Strength
-SHOC2 (HGNC:15454),PP1,Supporting,≥3 informative meioses.,Disease-specific
-SHOC2 (HGNC:15454),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-SHOC2 (HGNC:15454),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-SHOC2 (HGNC:15454),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-SHOC2 (HGNC:15454),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-SHOC2 (HGNC:15454),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SHOC2 (HGNC:15454),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-SHOC2 (HGNC:15454),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-SHOC2 (HGNC:15454),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-SHOC2 (HGNC:15454),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-SHOC2 (HGNC:15454),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-SHOC2 (HGNC:15454),BS2,Strong,-4 Points.,Strength
-SHOC2 (HGNC:15454),BS2,Supporting,-1 Point.,Strength
-SHOC2 (HGNC:15454),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-SHOC2 (HGNC:15454),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-SHOC2 (HGNC:15454),BS4,Strong,Requires only one informative meiosis.,General recommendation
-SHOC2 (HGNC:15454),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-SHOC2 (HGNC:15454),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-SHOC2 (HGNC:15454),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-SHOC2 (HGNC:15454),BP2,Strong,≥ (-4) Points.,Strength
-SHOC2 (HGNC:15454),BP2,Moderate,≥ (-2) Points.,Strength
-SHOC2 (HGNC:15454),BP2,Supporting,≥ (-1) Point.,None
-SHOC2 (HGNC:15454),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-SHOC2 (HGNC:15454),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SHOC2 (HGNC:15454),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-SHOC2 (HGNC:15454),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-SHOC2 (HGNC:15454),BP5,Strong,≥ (-4) Points.,Strength
-SHOC2 (HGNC:15454),BP5,Moderate,≥ (-2) Points.,Strength
-SHOC2 (HGNC:15454),BP5,Supporting,≥ (-1) Point.,None
-SHOC2 (HGNC:15454),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SHOC2 (HGNC:15454),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-SHOC2 (HGNC:15454),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSHOC2Version2.3.0_version=2.3.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSHOC2Version2.3.0_version=2.3.0.csv
deleted file mode 100644
index 817561e53129856668e8033190112be5a252b1d4..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSHOC2Version2.3.0_version=2.3.0.csv
+++ /dev/null
@@ -1,82 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-SHOC2 (HGNC:15454),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-SHOC2 (HGNC:15454),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SHOC2 (HGNC:15454),PS1,Strong,"Same amino acid change as a previously established pathogenic variant in 
-SHOC2
- regardless of nucleotide change.",Gene-specific
-SHOC2 (HGNC:15454),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-SHOC2 (HGNC:15454),PS2,Very Strong,4 Points.,Strength
-SHOC2 (HGNC:15454),PS2,Strong,2 Points.,None
-SHOC2 (HGNC:15454),PS2,Moderate,1 Point.,Strength
-SHOC2 (HGNC:15454),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",NA
-SHOC2 (HGNC:15454),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-SHOC2 (HGNC:15454),PS4,Strong,≥5 points.,Disease-specific
-SHOC2 (HGNC:15454),PS4,Moderate,≥3 points.,Strength
-SHOC2 (HGNC:15454),PS4,Supporting,≥1 points.,Strength
-SHOC2 (HGNC:15454),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-SHOC2 (HGNC:15454),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-SHOC2 (HGNC:15454),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-SHOC2 (HGNC:15454),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-SHOC2 (HGNC:15454),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-SHOC2 (HGNC:15454),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-SHOC2 (HGNC:15454),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SHOC2 (HGNC:15454),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,Strength
-SHOC2 (HGNC:15454),PM5,Moderate,1 [likely] pathogenic residue change at the same codon.,Disease-specific
-SHOC2 (HGNC:15454),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-SHOC2 (HGNC:15454),PM6,Strong,2 Points.,Strength
-SHOC2 (HGNC:15454),PM6,Moderate,1 Point.,None
-SHOC2 (HGNC:15454),PM6,Supporting,0.5 Points.,Strength
-SHOC2 (HGNC:15454),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-SHOC2 (HGNC:15454),PP1,Strong,≥7 informative meioses.,Strength
-SHOC2 (HGNC:15454),PP1,Moderate,≥5 informative meioses.,Strength
-SHOC2 (HGNC:15454),PP1,Supporting,≥3 informative meioses.,Disease-specific
-SHOC2 (HGNC:15454),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-SHOC2 (HGNC:15454),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-SHOC2 (HGNC:15454),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-SHOC2 (HGNC:15454),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-SHOC2 (HGNC:15454),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SHOC2 (HGNC:15454),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-SHOC2 (HGNC:15454),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-SHOC2 (HGNC:15454),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-SHOC2 (HGNC:15454),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-SHOC2 (HGNC:15454),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-SHOC2 (HGNC:15454),BS2,Strong,-4 Points.,Strength
-SHOC2 (HGNC:15454),BS2,Supporting,-1 Point.,Strength
-SHOC2 (HGNC:15454),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-SHOC2 (HGNC:15454),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-SHOC2 (HGNC:15454),BS4,Strong,Requires only one informative meiosis.,General recommendation
-SHOC2 (HGNC:15454),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-SHOC2 (HGNC:15454),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-SHOC2 (HGNC:15454),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-SHOC2 (HGNC:15454),BP2,Strong,≥ (-4) Points.,Strength
-SHOC2 (HGNC:15454),BP2,Moderate,≥ (-2) Points.,Strength
-SHOC2 (HGNC:15454),BP2,Supporting,≥ (-1) Point.,None
-SHOC2 (HGNC:15454),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-SHOC2 (HGNC:15454),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SHOC2 (HGNC:15454),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-SHOC2 (HGNC:15454),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-SHOC2 (HGNC:15454),BP5,Strong,≥ (-4) Points.,Strength
-SHOC2 (HGNC:15454),BP5,Moderate,≥ (-2) Points.,Strength
-SHOC2 (HGNC:15454),BP5,Supporting,≥ (-1) Point.,None
-SHOC2 (HGNC:15454),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SHOC2 (HGNC:15454),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-SHOC2 (HGNC:15454),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS1Version2.0.0_version=2.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS1Version2.0.0_version=2.0.0.csv
deleted file mode 100644
index 586f1f0bcda416963e3dcde67b355d88e67114d7..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS1Version2.0.0_version=2.0.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-SOS1 (HGNC:11187),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-SOS1 (HGNC:11187),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SOS1 (HGNC:11187),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-SOS1
- and 
-SOS2.",Analogous Gene
-SOS1 (HGNC:11187),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-SOS1 (HGNC:11187),PS2,Very Strong,4 Points.,Strength
-SOS1 (HGNC:11187),PS2,Strong,2 Points.,None
-SOS1 (HGNC:11187),PS2,Moderate,1 Point.,Strength
-SOS1 (HGNC:11187),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-SOS1 (HGNC:11187),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-SOS1 (HGNC:11187),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-SOS1 (HGNC:11187),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-SOS1 (HGNC:11187),PS4,Strong,≥5 points.,Disease-specific
-SOS1 (HGNC:11187),PS4,Moderate,≥3 points.,Strength
-SOS1 (HGNC:11187),PS4,Supporting,≥1 points.,Strength
-SOS1 (HGNC:11187),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-SOS1 (HGNC:11187),PM1,Moderate,Applicable only to critical and well-established functional domains available in the supplementary table (PH domain [AA 420-500]). Not applicable to specific amino acid residues (see BP5).,Gene-specific
-SOS1 (HGNC:11187),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-SOS1 (HGNC:11187),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-SOS1 (HGNC:11187),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-SOS1 (HGNC:11187),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-SOS1 (HGNC:11187),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-SOS1 (HGNC:11187),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SOS1 (HGNC:11187),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-SOS1 (HGNC:11187),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,"Analogous Gene,Disease-specific"
-SOS1 (HGNC:11187),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-SOS1 (HGNC:11187),PM6,Strong,2 Points.,Strength
-SOS1 (HGNC:11187),PM6,Moderate,1 Point.,None
-SOS1 (HGNC:11187),PM6,Supporting,0.5 Points.,Strength
-SOS1 (HGNC:11187),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-SOS1 (HGNC:11187),PP1,Strong,≥7 informative meioses.,Strength
-SOS1 (HGNC:11187),PP1,Moderate,≥5 informative meioses.,Strength
-SOS1 (HGNC:11187),PP1,Supporting,≥3 informative meioses.,Disease-specific
-SOS1 (HGNC:11187),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-SOS1 (HGNC:11187),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-SOS1 (HGNC:11187),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-SOS1 (HGNC:11187),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-SOS1 (HGNC:11187),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SOS1 (HGNC:11187),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-SOS1 (HGNC:11187),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-SOS1 (HGNC:11187),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-SOS1 (HGNC:11187),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-SOS1 (HGNC:11187),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-SOS1 (HGNC:11187),BS2,Strong,-4 Points.,Strength
-SOS1 (HGNC:11187),BS2,Supporting,-1 Point.,Strength
-SOS1 (HGNC:11187),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-SOS1 (HGNC:11187),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-SOS1 (HGNC:11187),BS4,Strong,Requires only one informative meiosis.,General recommendation
-SOS1 (HGNC:11187),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-SOS1 (HGNC:11187),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-SOS1 (HGNC:11187),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-SOS1 (HGNC:11187),BP2,Strong,≥ (-4) Points.,Strength
-SOS1 (HGNC:11187),BP2,Moderate,≥ (-2) Points.,Strength
-SOS1 (HGNC:11187),BP2,Supporting,≥ (-1) Point.,None
-SOS1 (HGNC:11187),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-SOS1 (HGNC:11187),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SOS1 (HGNC:11187),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-SOS1 (HGNC:11187),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-SOS1 (HGNC:11187),BP5,Strong,≥ (-4) Points.,Strength
-SOS1 (HGNC:11187),BP5,Moderate,≥ (-2) Points.,Strength
-SOS1 (HGNC:11187),BP5,Supporting,≥ (-1) Point.,None
-SOS1 (HGNC:11187),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SOS1 (HGNC:11187),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-SOS1 (HGNC:11187),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS1Version2.1.0_version=2.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS1Version2.1.0_version=2.1.0.csv
deleted file mode 100644
index 72524767793587035a45c368819a38713ffa2730..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS1Version2.1.0_version=2.1.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-SOS1 (HGNC:11187),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-SOS1 (HGNC:11187),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SOS1 (HGNC:11187),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-SOS1
- and 
-SOS2.",Analogous Gene
-SOS1 (HGNC:11187),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-SOS1 (HGNC:11187),PS2,Very Strong,4 Points.,Strength
-SOS1 (HGNC:11187),PS2,Strong,2 Points.,None
-SOS1 (HGNC:11187),PS2,Moderate,1 Point.,Strength
-SOS1 (HGNC:11187),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-SOS1 (HGNC:11187),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-SOS1 (HGNC:11187),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-SOS1 (HGNC:11187),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-SOS1 (HGNC:11187),PS4,Strong,≥5 points.,Disease-specific
-SOS1 (HGNC:11187),PS4,Moderate,≥3 points.,Strength
-SOS1 (HGNC:11187),PS4,Supporting,≥1 points.,Strength
-SOS1 (HGNC:11187),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-SOS1 (HGNC:11187),PM1,Moderate,Applicable only to critical and well-established functional domains available in the supplementary table (PH domain [AA 420-500]). Not applicable to specific amino acid residues (see PM5).,Gene-specific
-SOS1 (HGNC:11187),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-SOS1 (HGNC:11187),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-SOS1 (HGNC:11187),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-SOS1 (HGNC:11187),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-SOS1 (HGNC:11187),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-SOS1 (HGNC:11187),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SOS1 (HGNC:11187),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-SOS1 (HGNC:11187),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,"Analogous Gene,Disease-specific"
-SOS1 (HGNC:11187),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-SOS1 (HGNC:11187),PM6,Strong,2 Points.,Strength
-SOS1 (HGNC:11187),PM6,Moderate,1 Point.,None
-SOS1 (HGNC:11187),PM6,Supporting,0.5 Points.,Strength
-SOS1 (HGNC:11187),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-SOS1 (HGNC:11187),PP1,Strong,≥7 informative meioses.,Strength
-SOS1 (HGNC:11187),PP1,Moderate,≥5 informative meioses.,Strength
-SOS1 (HGNC:11187),PP1,Supporting,≥3 informative meioses.,Disease-specific
-SOS1 (HGNC:11187),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-SOS1 (HGNC:11187),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-SOS1 (HGNC:11187),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-SOS1 (HGNC:11187),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-SOS1 (HGNC:11187),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SOS1 (HGNC:11187),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-SOS1 (HGNC:11187),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-SOS1 (HGNC:11187),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-SOS1 (HGNC:11187),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-SOS1 (HGNC:11187),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-SOS1 (HGNC:11187),BS2,Strong,-4 Points.,Strength
-SOS1 (HGNC:11187),BS2,Supporting,-1 Point.,Strength
-SOS1 (HGNC:11187),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-SOS1 (HGNC:11187),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-SOS1 (HGNC:11187),BS4,Strong,Requires only one informative meiosis.,General recommendation
-SOS1 (HGNC:11187),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-SOS1 (HGNC:11187),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-SOS1 (HGNC:11187),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-SOS1 (HGNC:11187),BP2,Strong,≥ (-4) Points.,Strength
-SOS1 (HGNC:11187),BP2,Moderate,≥ (-2) Points.,Strength
-SOS1 (HGNC:11187),BP2,Supporting,≥ (-1) Point.,None
-SOS1 (HGNC:11187),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-SOS1 (HGNC:11187),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SOS1 (HGNC:11187),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-SOS1 (HGNC:11187),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-SOS1 (HGNC:11187),BP5,Strong,≥ (-4) Points.,Strength
-SOS1 (HGNC:11187),BP5,Moderate,≥ (-2) Points.,Strength
-SOS1 (HGNC:11187),BP5,Supporting,≥ (-1) Point.,None
-SOS1 (HGNC:11187),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SOS1 (HGNC:11187),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-SOS1 (HGNC:11187),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS1Version2.2.0_version=2.2.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS1Version2.2.0_version=2.2.0.csv
deleted file mode 100644
index 72524767793587035a45c368819a38713ffa2730..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS1Version2.2.0_version=2.2.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-SOS1 (HGNC:11187),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-SOS1 (HGNC:11187),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SOS1 (HGNC:11187),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-SOS1
- and 
-SOS2.",Analogous Gene
-SOS1 (HGNC:11187),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-SOS1 (HGNC:11187),PS2,Very Strong,4 Points.,Strength
-SOS1 (HGNC:11187),PS2,Strong,2 Points.,None
-SOS1 (HGNC:11187),PS2,Moderate,1 Point.,Strength
-SOS1 (HGNC:11187),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-SOS1 (HGNC:11187),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-SOS1 (HGNC:11187),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-SOS1 (HGNC:11187),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-SOS1 (HGNC:11187),PS4,Strong,≥5 points.,Disease-specific
-SOS1 (HGNC:11187),PS4,Moderate,≥3 points.,Strength
-SOS1 (HGNC:11187),PS4,Supporting,≥1 points.,Strength
-SOS1 (HGNC:11187),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-SOS1 (HGNC:11187),PM1,Moderate,Applicable only to critical and well-established functional domains available in the supplementary table (PH domain [AA 420-500]). Not applicable to specific amino acid residues (see PM5).,Gene-specific
-SOS1 (HGNC:11187),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-SOS1 (HGNC:11187),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-SOS1 (HGNC:11187),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-SOS1 (HGNC:11187),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-SOS1 (HGNC:11187),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-SOS1 (HGNC:11187),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SOS1 (HGNC:11187),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-SOS1 (HGNC:11187),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,"Analogous Gene,Disease-specific"
-SOS1 (HGNC:11187),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-SOS1 (HGNC:11187),PM6,Strong,2 Points.,Strength
-SOS1 (HGNC:11187),PM6,Moderate,1 Point.,None
-SOS1 (HGNC:11187),PM6,Supporting,0.5 Points.,Strength
-SOS1 (HGNC:11187),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-SOS1 (HGNC:11187),PP1,Strong,≥7 informative meioses.,Strength
-SOS1 (HGNC:11187),PP1,Moderate,≥5 informative meioses.,Strength
-SOS1 (HGNC:11187),PP1,Supporting,≥3 informative meioses.,Disease-specific
-SOS1 (HGNC:11187),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-SOS1 (HGNC:11187),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-SOS1 (HGNC:11187),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-SOS1 (HGNC:11187),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-SOS1 (HGNC:11187),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SOS1 (HGNC:11187),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-SOS1 (HGNC:11187),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-SOS1 (HGNC:11187),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-SOS1 (HGNC:11187),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-SOS1 (HGNC:11187),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-SOS1 (HGNC:11187),BS2,Strong,-4 Points.,Strength
-SOS1 (HGNC:11187),BS2,Supporting,-1 Point.,Strength
-SOS1 (HGNC:11187),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-SOS1 (HGNC:11187),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-SOS1 (HGNC:11187),BS4,Strong,Requires only one informative meiosis.,General recommendation
-SOS1 (HGNC:11187),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-SOS1 (HGNC:11187),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-SOS1 (HGNC:11187),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-SOS1 (HGNC:11187),BP2,Strong,≥ (-4) Points.,Strength
-SOS1 (HGNC:11187),BP2,Moderate,≥ (-2) Points.,Strength
-SOS1 (HGNC:11187),BP2,Supporting,≥ (-1) Point.,None
-SOS1 (HGNC:11187),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-SOS1 (HGNC:11187),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SOS1 (HGNC:11187),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-SOS1 (HGNC:11187),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-SOS1 (HGNC:11187),BP5,Strong,≥ (-4) Points.,Strength
-SOS1 (HGNC:11187),BP5,Moderate,≥ (-2) Points.,Strength
-SOS1 (HGNC:11187),BP5,Supporting,≥ (-1) Point.,None
-SOS1 (HGNC:11187),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SOS1 (HGNC:11187),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-SOS1 (HGNC:11187),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS1Version2.3.0_version=2.3.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS1Version2.3.0_version=2.3.0.csv
deleted file mode 100644
index a120b95e8be9f789eb477b5a715375d257e990bc..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS1Version2.3.0_version=2.3.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-SOS1 (HGNC:11187),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-SOS1 (HGNC:11187),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SOS1 (HGNC:11187),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-SOS1
- and 
-SOS2.",Analogous Gene
-SOS1 (HGNC:11187),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-SOS1 (HGNC:11187),PS2,Very Strong,4 Points.,Strength
-SOS1 (HGNC:11187),PS2,Strong,2 Points.,None
-SOS1 (HGNC:11187),PS2,Moderate,1 Point.,Strength
-SOS1 (HGNC:11187),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-SOS1 (HGNC:11187),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-SOS1 (HGNC:11187),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-SOS1 (HGNC:11187),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-SOS1 (HGNC:11187),PS4,Strong,≥5 points.,Disease-specific
-SOS1 (HGNC:11187),PS4,Moderate,≥3 points.,Strength
-SOS1 (HGNC:11187),PS4,Supporting,≥1 points.,Strength
-SOS1 (HGNC:11187),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-SOS1 (HGNC:11187),PM1,Moderate,Applicable only to critical and well-established functional domains available in the supplementary table (PH domain [AA 420-500]). Not applicable to specific amino acid residues (see PM5).,Gene-specific
-SOS1 (HGNC:11187),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-SOS1 (HGNC:11187),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-SOS1 (HGNC:11187),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-SOS1 (HGNC:11187),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-SOS1 (HGNC:11187),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-SOS1 (HGNC:11187),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SOS1 (HGNC:11187),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-SOS1 (HGNC:11187),PM5,Moderate,1 [likely] pathogenic residue change at the same codon.,"Analogous Gene,Disease-specific"
-SOS1 (HGNC:11187),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-SOS1 (HGNC:11187),PM6,Strong,2 Points.,Strength
-SOS1 (HGNC:11187),PM6,Moderate,1 Point.,None
-SOS1 (HGNC:11187),PM6,Supporting,0.5 Points.,Strength
-SOS1 (HGNC:11187),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-SOS1 (HGNC:11187),PP1,Strong,≥7 informative meioses.,Strength
-SOS1 (HGNC:11187),PP1,Moderate,≥5 informative meioses.,Strength
-SOS1 (HGNC:11187),PP1,Supporting,≥3 informative meioses.,Disease-specific
-SOS1 (HGNC:11187),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-SOS1 (HGNC:11187),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-SOS1 (HGNC:11187),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-SOS1 (HGNC:11187),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-SOS1 (HGNC:11187),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SOS1 (HGNC:11187),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-SOS1 (HGNC:11187),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-SOS1 (HGNC:11187),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-SOS1 (HGNC:11187),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-SOS1 (HGNC:11187),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-SOS1 (HGNC:11187),BS2,Strong,-4 Points.,Strength
-SOS1 (HGNC:11187),BS2,Supporting,-1 Point.,Strength
-SOS1 (HGNC:11187),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-SOS1 (HGNC:11187),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-SOS1 (HGNC:11187),BS4,Strong,Requires only one informative meiosis.,General recommendation
-SOS1 (HGNC:11187),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-SOS1 (HGNC:11187),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-SOS1 (HGNC:11187),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-SOS1 (HGNC:11187),BP2,Strong,≥ (-4) Points.,Strength
-SOS1 (HGNC:11187),BP2,Moderate,≥ (-2) Points.,Strength
-SOS1 (HGNC:11187),BP2,Supporting,≥ (-1) Point.,None
-SOS1 (HGNC:11187),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-SOS1 (HGNC:11187),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SOS1 (HGNC:11187),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-SOS1 (HGNC:11187),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-SOS1 (HGNC:11187),BP5,Strong,≥ (-4) Points.,Strength
-SOS1 (HGNC:11187),BP5,Moderate,≥ (-2) Points.,Strength
-SOS1 (HGNC:11187),BP5,Supporting,≥ (-1) Point.,None
-SOS1 (HGNC:11187),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SOS1 (HGNC:11187),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-SOS1 (HGNC:11187),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS2Version2.0.0_version=2.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS2Version2.0.0_version=2.0.0.csv
deleted file mode 100644
index 3095f4cf92fbb55f2f9772c59c3c631629453f7e..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS2Version2.0.0_version=2.0.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-SOS2 (HGNC:11188),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-SOS2 (HGNC:11188),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SOS2 (HGNC:11188),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-SOS1
- and 
-SOS2.",Analogous Gene
-SOS2 (HGNC:11188),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-SOS2 (HGNC:11188),PS2,Very Strong,4 Points.,Strength
-SOS2 (HGNC:11188),PS2,Strong,2 Points.,None
-SOS2 (HGNC:11188),PS2,Moderate,1 Point.,Strength
-SOS2 (HGNC:11188),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-SOS2 (HGNC:11188),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-SOS2 (HGNC:11188),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-SOS2 (HGNC:11188),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-SOS2 (HGNC:11188),PS4,Strong,≥5 points.,Disease-specific
-SOS2 (HGNC:11188),PS4,Moderate,≥3 points.,Strength
-SOS2 (HGNC:11188),PS4,Supporting,≥1 points.,Strength
-SOS2 (HGNC:11188),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-SOS2 (HGNC:11188),PM1,Moderate,Applicable only to critical and well-established functional domains available in the supplementary table (PH domain [AA 418-498]). Not applicable to specific amino acid residues (see BP5).,Gene-specific
-SOS2 (HGNC:11188),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-SOS2 (HGNC:11188),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-SOS2 (HGNC:11188),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-SOS2 (HGNC:11188),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-SOS2 (HGNC:11188),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-SOS2 (HGNC:11188),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SOS2 (HGNC:11188),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-SOS2 (HGNC:11188),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,"Analogous Gene,Disease-specific"
-SOS2 (HGNC:11188),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-SOS2 (HGNC:11188),PM6,Strong,2 Points.,Strength
-SOS2 (HGNC:11188),PM6,Moderate,1 Point.,None
-SOS2 (HGNC:11188),PM6,Supporting,0.5 Points.,Strength
-SOS2 (HGNC:11188),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-SOS2 (HGNC:11188),PP1,Strong,≥7 informative meioses.,Strength
-SOS2 (HGNC:11188),PP1,Moderate,≥5 informative meioses.,Strength
-SOS2 (HGNC:11188),PP1,Supporting,≥3 informative meioses.,Disease-specific
-SOS2 (HGNC:11188),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-SOS2 (HGNC:11188),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-SOS2 (HGNC:11188),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-SOS2 (HGNC:11188),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-SOS2 (HGNC:11188),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SOS2 (HGNC:11188),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-SOS2 (HGNC:11188),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-SOS2 (HGNC:11188),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-SOS2 (HGNC:11188),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-SOS2 (HGNC:11188),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-SOS2 (HGNC:11188),BS2,Strong,-4 Points.,Strength
-SOS2 (HGNC:11188),BS2,Supporting,-1 Point.,Strength
-SOS2 (HGNC:11188),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-SOS2 (HGNC:11188),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-SOS2 (HGNC:11188),BS4,Strong,Requires only one informative meiosis.,General recommendation
-SOS2 (HGNC:11188),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-SOS2 (HGNC:11188),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-SOS2 (HGNC:11188),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-SOS2 (HGNC:11188),BP2,Strong,≥ (-4) Points.,Strength
-SOS2 (HGNC:11188),BP2,Moderate,≥ (-2) Points.,Strength
-SOS2 (HGNC:11188),BP2,Supporting,≥ (-1) Point.,None
-SOS2 (HGNC:11188),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-SOS2 (HGNC:11188),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SOS2 (HGNC:11188),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-SOS2 (HGNC:11188),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-SOS2 (HGNC:11188),BP5,Strong,≥ (-4) Points.,Strength
-SOS2 (HGNC:11188),BP5,Moderate,≥ (-2) Points.,Strength
-SOS2 (HGNC:11188),BP5,Supporting,≥ (-1) Point.,None
-SOS2 (HGNC:11188),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SOS2 (HGNC:11188),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-SOS2 (HGNC:11188),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS2Version2.1.0_version=2.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS2Version2.1.0_version=2.1.0.csv
deleted file mode 100644
index 17917f48c0a053209727c22e4ada72a71840b176..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS2Version2.1.0_version=2.1.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-SOS2 (HGNC:11188),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-SOS2 (HGNC:11188),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SOS2 (HGNC:11188),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-SOS1
- and 
-SOS2.",Analogous Gene
-SOS2 (HGNC:11188),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-SOS2 (HGNC:11188),PS2,Very Strong,4 Points.,Strength
-SOS2 (HGNC:11188),PS2,Strong,2 Points.,None
-SOS2 (HGNC:11188),PS2,Moderate,1 Point.,Strength
-SOS2 (HGNC:11188),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-SOS2 (HGNC:11188),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-SOS2 (HGNC:11188),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-SOS2 (HGNC:11188),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-SOS2 (HGNC:11188),PS4,Strong,≥5 points.,Disease-specific
-SOS2 (HGNC:11188),PS4,Moderate,≥3 points.,Strength
-SOS2 (HGNC:11188),PS4,Supporting,≥1 points.,Strength
-SOS2 (HGNC:11188),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-SOS2 (HGNC:11188),PM1,Moderate,Applicable only to critical and well-established functional domains available in the supplementary table (PH domain [AA 418-498]). Not applicable to specific amino acid residues (see PM5).,Gene-specific
-SOS2 (HGNC:11188),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-SOS2 (HGNC:11188),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-SOS2 (HGNC:11188),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-SOS2 (HGNC:11188),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-SOS2 (HGNC:11188),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-SOS2 (HGNC:11188),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SOS2 (HGNC:11188),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-SOS2 (HGNC:11188),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,"Analogous Gene,Disease-specific"
-SOS2 (HGNC:11188),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-SOS2 (HGNC:11188),PM6,Strong,2 Points.,Strength
-SOS2 (HGNC:11188),PM6,Moderate,1 Point.,None
-SOS2 (HGNC:11188),PM6,Supporting,0.5 Points.,Strength
-SOS2 (HGNC:11188),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-SOS2 (HGNC:11188),PP1,Strong,≥7 informative meioses.,Strength
-SOS2 (HGNC:11188),PP1,Moderate,≥5 informative meioses.,Strength
-SOS2 (HGNC:11188),PP1,Supporting,≥3 informative meioses.,Disease-specific
-SOS2 (HGNC:11188),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-SOS2 (HGNC:11188),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-SOS2 (HGNC:11188),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-SOS2 (HGNC:11188),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-SOS2 (HGNC:11188),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SOS2 (HGNC:11188),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-SOS2 (HGNC:11188),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-SOS2 (HGNC:11188),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-SOS2 (HGNC:11188),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-SOS2 (HGNC:11188),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-SOS2 (HGNC:11188),BS2,Strong,-4 Points.,Strength
-SOS2 (HGNC:11188),BS2,Supporting,-1 Point.,Strength
-SOS2 (HGNC:11188),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-SOS2 (HGNC:11188),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-SOS2 (HGNC:11188),BS4,Strong,Requires only one informative meiosis.,General recommendation
-SOS2 (HGNC:11188),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-SOS2 (HGNC:11188),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-SOS2 (HGNC:11188),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-SOS2 (HGNC:11188),BP2,Strong,≥ (-4) Points.,Strength
-SOS2 (HGNC:11188),BP2,Moderate,≥ (-2) Points.,Strength
-SOS2 (HGNC:11188),BP2,Supporting,≥ (-1) Point.,None
-SOS2 (HGNC:11188),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-SOS2 (HGNC:11188),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SOS2 (HGNC:11188),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-SOS2 (HGNC:11188),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-SOS2 (HGNC:11188),BP5,Strong,≥ (-4) Points.,Strength
-SOS2 (HGNC:11188),BP5,Moderate,≥ (-2) Points.,Strength
-SOS2 (HGNC:11188),BP5,Supporting,≥ (-1) Point.,None
-SOS2 (HGNC:11188),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SOS2 (HGNC:11188),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-SOS2 (HGNC:11188),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS2Version2.2.0_version=2.2.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS2Version2.2.0_version=2.2.0.csv
deleted file mode 100644
index 17917f48c0a053209727c22e4ada72a71840b176..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS2Version2.2.0_version=2.2.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-SOS2 (HGNC:11188),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-SOS2 (HGNC:11188),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SOS2 (HGNC:11188),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-SOS1
- and 
-SOS2.",Analogous Gene
-SOS2 (HGNC:11188),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-SOS2 (HGNC:11188),PS2,Very Strong,4 Points.,Strength
-SOS2 (HGNC:11188),PS2,Strong,2 Points.,None
-SOS2 (HGNC:11188),PS2,Moderate,1 Point.,Strength
-SOS2 (HGNC:11188),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-SOS2 (HGNC:11188),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-SOS2 (HGNC:11188),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-SOS2 (HGNC:11188),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-SOS2 (HGNC:11188),PS4,Strong,≥5 points.,Disease-specific
-SOS2 (HGNC:11188),PS4,Moderate,≥3 points.,Strength
-SOS2 (HGNC:11188),PS4,Supporting,≥1 points.,Strength
-SOS2 (HGNC:11188),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-SOS2 (HGNC:11188),PM1,Moderate,Applicable only to critical and well-established functional domains available in the supplementary table (PH domain [AA 418-498]). Not applicable to specific amino acid residues (see PM5).,Gene-specific
-SOS2 (HGNC:11188),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-SOS2 (HGNC:11188),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-SOS2 (HGNC:11188),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-SOS2 (HGNC:11188),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-SOS2 (HGNC:11188),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-SOS2 (HGNC:11188),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SOS2 (HGNC:11188),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-SOS2 (HGNC:11188),PM5,Moderate,1 [likely] pathogenic residue change at the same codon observed in ≥5 probands.,"Analogous Gene,Disease-specific"
-SOS2 (HGNC:11188),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-SOS2 (HGNC:11188),PM6,Strong,2 Points.,Strength
-SOS2 (HGNC:11188),PM6,Moderate,1 Point.,None
-SOS2 (HGNC:11188),PM6,Supporting,0.5 Points.,Strength
-SOS2 (HGNC:11188),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-SOS2 (HGNC:11188),PP1,Strong,≥7 informative meioses.,Strength
-SOS2 (HGNC:11188),PP1,Moderate,≥5 informative meioses.,Strength
-SOS2 (HGNC:11188),PP1,Supporting,≥3 informative meioses.,Disease-specific
-SOS2 (HGNC:11188),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-SOS2 (HGNC:11188),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-SOS2 (HGNC:11188),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-SOS2 (HGNC:11188),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-SOS2 (HGNC:11188),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SOS2 (HGNC:11188),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-SOS2 (HGNC:11188),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-SOS2 (HGNC:11188),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-SOS2 (HGNC:11188),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-SOS2 (HGNC:11188),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-SOS2 (HGNC:11188),BS2,Strong,-4 Points.,Strength
-SOS2 (HGNC:11188),BS2,Supporting,-1 Point.,Strength
-SOS2 (HGNC:11188),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-SOS2 (HGNC:11188),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-SOS2 (HGNC:11188),BS4,Strong,Requires only one informative meiosis.,General recommendation
-SOS2 (HGNC:11188),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-SOS2 (HGNC:11188),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-SOS2 (HGNC:11188),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-SOS2 (HGNC:11188),BP2,Strong,≥ (-4) Points.,Strength
-SOS2 (HGNC:11188),BP2,Moderate,≥ (-2) Points.,Strength
-SOS2 (HGNC:11188),BP2,Supporting,≥ (-1) Point.,None
-SOS2 (HGNC:11188),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-SOS2 (HGNC:11188),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SOS2 (HGNC:11188),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-SOS2 (HGNC:11188),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-SOS2 (HGNC:11188),BP5,Strong,≥ (-4) Points.,Strength
-SOS2 (HGNC:11188),BP5,Moderate,≥ (-2) Points.,Strength
-SOS2 (HGNC:11188),BP5,Supporting,≥ (-1) Point.,None
-SOS2 (HGNC:11188),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SOS2 (HGNC:11188),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-SOS2 (HGNC:11188),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS2Version2.3.0_version=2.3.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS2Version2.3.0_version=2.3.0.csv
deleted file mode 100644
index 037d51ccb540038f576f27e6f264743217cfa876..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSOS2Version2.3.0_version=2.3.0.csv
+++ /dev/null
@@ -1,86 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-SOS2 (HGNC:11188),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-SOS2 (HGNC:11188),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SOS2 (HGNC:11188),PS1,Strong,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in 
-SOS1
- and 
-SOS2.",Analogous Gene
-SOS2 (HGNC:11188),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-SOS2 (HGNC:11188),PS2,Very Strong,4 Points.,Strength
-SOS2 (HGNC:11188),PS2,Strong,2 Points.,None
-SOS2 (HGNC:11188),PS2,Moderate,1 Point.,Strength
-SOS2 (HGNC:11188),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-SOS2 (HGNC:11188),PS3,Moderate,Two or more different approved assays.,"Disease-specific,Gene-specific,Strength"
-SOS2 (HGNC:11188),PS3,Supporting,One approved assay.,"Disease-specific,Gene-specific,Strength"
-SOS2 (HGNC:11188),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-SOS2 (HGNC:11188),PS4,Strong,≥5 points.,Disease-specific
-SOS2 (HGNC:11188),PS4,Moderate,≥3 points.,Strength
-SOS2 (HGNC:11188),PS4,Supporting,≥1 points.,Strength
-SOS2 (HGNC:11188),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-SOS2 (HGNC:11188),PM1,Moderate,Applicable only to critical and well-established functional domains available in the supplementary table (PH domain [AA 418-498]). Not applicable to specific amino acid residues (see PM5).,Gene-specific
-SOS2 (HGNC:11188),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-SOS2 (HGNC:11188),PM2,Supporting,The variant must be absent from controls (gnomAD).,Strength
-SOS2 (HGNC:11188),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-SOS2 (HGNC:11188),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-SOS2 (HGNC:11188),PM4,Moderate,No known repetitive areas in gene. Use as described.,General recommendation
-SOS2 (HGNC:11188),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SOS2 (HGNC:11188),PM5,Strong,≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands.,"Analogous Gene,Strength"
-SOS2 (HGNC:11188),PM5,Moderate,1 [likely] pathogenic residue change at the same codon.,"Analogous Gene,Disease-specific"
-SOS2 (HGNC:11188),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-SOS2 (HGNC:11188),PM6,Strong,2 Points.,Strength
-SOS2 (HGNC:11188),PM6,Moderate,1 Point.,None
-SOS2 (HGNC:11188),PM6,Supporting,0.5 Points.,Strength
-SOS2 (HGNC:11188),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-SOS2 (HGNC:11188),PP1,Strong,≥7 informative meioses.,Strength
-SOS2 (HGNC:11188),PP1,Moderate,≥5 informative meioses.,Strength
-SOS2 (HGNC:11188),PP1,Supporting,≥3 informative meioses.,Disease-specific
-SOS2 (HGNC:11188),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-SOS2 (HGNC:11188),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-SOS2 (HGNC:11188),PP3,Supporting,"For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.",Disease-specific
-SOS2 (HGNC:11188),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-SOS2 (HGNC:11188),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SOS2 (HGNC:11188),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-SOS2 (HGNC:11188),BA1,Stand Alone,GnomAD filtering allele frequency ≥0.05%.,Disease-specific
-SOS2 (HGNC:11188),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-SOS2 (HGNC:11188),BS1,Strong,GnomAD filtering allele frequency ≥0.025%.,Disease-specific
-SOS2 (HGNC:11188),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-SOS2 (HGNC:11188),BS2,Strong,-4 Points.,Strength
-SOS2 (HGNC:11188),BS2,Supporting,-1 Point.,Strength
-SOS2 (HGNC:11188),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-SOS2 (HGNC:11188),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-SOS2 (HGNC:11188),BS4,Strong,Requires only one informative meiosis.,General recommendation
-SOS2 (HGNC:11188),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,
-SOS2 (HGNC:11188),BP1,Supporting,"This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.",Disease-specific
-SOS2 (HGNC:11188),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-SOS2 (HGNC:11188),BP2,Strong,≥ (-4) Points.,Strength
-SOS2 (HGNC:11188),BP2,Moderate,≥ (-2) Points.,Strength
-SOS2 (HGNC:11188),BP2,Supporting,≥ (-1) Point.,None
-SOS2 (HGNC:11188),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-SOS2 (HGNC:11188),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SOS2 (HGNC:11188),BP4,Supporting,For missense variants: REVEL ≤0.3.,Disease-specific
-SOS2 (HGNC:11188),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-SOS2 (HGNC:11188),BP5,Strong,≥ (-4) Points.,Strength
-SOS2 (HGNC:11188),BP5,Moderate,≥ (-2) Points.,Strength
-SOS2 (HGNC:11188),BP5,Supporting,≥ (-1) Point.,None
-SOS2 (HGNC:11188),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SOS2 (HGNC:11188),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-SOS2 (HGNC:11188),BP7,Supporting,A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.,General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
deleted file mode 100644
index f9b646c3cca5a540b7582afed784a2fc53f0863f..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
+++ /dev/null
@@ -1,1810 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-CDKL5 (HGNC:11411),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-CDKL5 (HGNC:11411),PVS1,Very Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-Use as defined by ClinGen SVI working group (PMID:30192042).
-
-
-Do not use PVS1 for truncating variants in CDKL5 Cterminus (exons 19-21, or after p.P904) when using the historically used transcript (NM_003159.2). PVS1 is applicable up to p.R948 when using the major brain isoform which has an alternative C-terminus (NM_001323289.2), for canonical splice site variants predicted to result in an out-of-frame product, for canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exons 7, 10, 13), and for the non-coding CDKL5 exon (exon 1).",Disease-specific
-CDKL5 (HGNC:11411),PVS1,Moderate,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Moderate is applicable for any truncating variant distal of p.R948 (when using the major brain isoform, NM_001323289.2) and for canonical splice site variants that flank exon 17 (in-frame exon).",Disease-specific
-CDKL5 (HGNC:11411),PVS1,Supporting,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Supporting is applicable for initiation codon variants in CDKL5, FOXG1, SLC9A6 and TCF4.",Disease-specific
-CDKL5 (HGNC:11411),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-CDKL5 (HGNC:11411),PS1,Strong,Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.,None
-CDKL5 (HGNC:11411),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-CDKL5 (HGNC:11411),PS2,Very Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-≥2 independent occurrences of PS2.
-
-
-≥2 independent occurrences of PM6 and one occurrence of PS2.",Strength
-CDKL5 (HGNC:11411),PS2,Strong,De novo (maternity and paternity confirmed) in a patient with the disease and no family history.,None
-CDKL5 (HGNC:11411),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-CDKL5 (HGNC:11411),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an out-offrame transcript.
-
-
-Do not use for canonical splice site variants and when PVS1 is used.",Disease-specific
-CDKL5 (HGNC:11411),PS3,Supporting,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).
-
-
-See tables for FOXG1, MECP2, CDKL5, TCF4, UBE3A.",Disease-specific
-CDKL5 (HGNC:11411),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-CDKL5 (HGNC:11411),PS4,Strong,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-5+ observations.",Strength
-CDKL5 (HGNC:11411),PS4,Moderate,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-3-4 observations.",Strength
-CDKL5 (HGNC:11411),PS4,Supporting,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-Use for 2nd independent occurrence.",Strength
-CDKL5 (HGNC:11411),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-CDKL5 (HGNC:11411),PM1,Moderate,"Located in a mutational hot spot and/or critical and well-established functional domain.
-
-
-
-
-(ATP binding region: aa 19-43; TEY phosphorylation site: aa 169-171).",Disease-specific
-CDKL5 (HGNC:11411),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-CDKL5 (HGNC:11411),PM2,Supporting,"Absent/rare from controls in an ethnically-matched cohort population sample.
-
-
-
-
-Use if absent, zero observations in control databases.",Strength
-CDKL5 (HGNC:11411),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-CDKL5 (HGNC:11411),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-CDKL5 (HGNC:11411),PM4,Moderate,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Do not use for in-frame deletions/insertions in CDKL5 C-terminus (exons 19-21, or after p.904) when using the NM_003159.2 transcript.",Disease-specific
-CDKL5 (HGNC:11411),PM4,Supporting,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",Strength
-CDKL5 (HGNC:11411),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-CDKL5 (HGNC:11411),PM5,Strong,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-≥2 different missense changes affecting the amino acid residue.
-
-
-Do not apply PM1 in these situations.",Strength
-CDKL5 (HGNC:11411),PM5,Moderate,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-Applicable to all genes as written.
-
-
-A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",None
-CDKL5 (HGNC:11411),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-CDKL5 (HGNC:11411),PM6,Very Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",Strength
-CDKL5 (HGNC:11411),PM6,Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥2 independent occurrences of PM6.
-
-
-Evidence from literature must be fully evaluated to support independent events.",Strength
-CDKL5 (HGNC:11411),PM6,Moderate,Confirmed de novo without confirmation of paternity and maternity.,None
-CDKL5 (HGNC:11411),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-CDKL5 (HGNC:11411),PP1,Strong,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-≥5 informative meiosis.
-
-
-Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",Strength
-CDKL5 (HGNC:11411),PP1,Moderate,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-3-4 informative meiosis.
-
-
-Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",Strength
-CDKL5 (HGNC:11411),PP1,Supporting,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-2 informative meiosis.
-
-
-Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",Strength
-CDKL5 (HGNC:11411),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-CDKL5 (HGNC:11411),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-CDKL5 (HGNC:11411),PP3,Supporting,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product.
-
-
-
-
-For missense variants use REVEL with a score ≥ 0.75.
-
-
-For splice site variants use MaxEntScan, NNSPLICE and HumanSplicingFinder when the majority of the predictions program support splicing alteration.",None
-CDKL5 (HGNC:11411),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-CDKL5 (HGNC:11411),PP4,Supporting,"Phenotype specific for disease with single genetic etiology.
-
-
-
-
-See gene specific clinical phenotype guidelines.",Disease-specific
-CDKL5 (HGNC:11411),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-CDKL5 (HGNC:11411),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-CDKL5 (HGNC:11411),BA1,Stand Alone,"Allele frequency above 0.05%.
-
-
-
-
-Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-CDKL5 (HGNC:11411),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-CDKL5 (HGNC:11411),BS1,Strong,"Allele frequency greater than expected for disease (0.025%).
-
-
-
-
-Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-CDKL5 (HGNC:11411),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-CDKL5 (HGNC:11411),BS2,Strong,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-2 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",Strength
-CDKL5 (HGNC:11411),BS2,Supporting,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-1 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",Strength
-CDKL5 (HGNC:11411),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-CDKL5 (HGNC:11411),BS3,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.
-
-
-
-
-RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.
-
-
-Not applicable for these genes for other functional studies (see tables for other accepted functional studies).",Disease-specific
-CDKL5 (HGNC:11411),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-CDKL5 (HGNC:11411),BS4,Strong,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member, when seen in two or more families.
-
-
-Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",Strength
-CDKL5 (HGNC:11411),BS4,Supporting,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member.
-
-
-Need to confirm that the family member is 'affected with a neurodevelopmental phenotype consistent with the gene' at a minimum.",Strength
-CDKL5 (HGNC:11411),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-CDKL5 (HGNC:11411),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-CDKL5 (HGNC:11411),BP2,Supporting,"Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.
-
-
-
-
-BP2 is not applicable for SLC9A6, UBE3A and CDKL5 for in trans state.",Disease-specific
-CDKL5 (HGNC:11411),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-CDKL5 (HGNC:11411),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-CDKL5 (HGNC:11411),BP4,Supporting,"Multiple lines of computational evidence suggest no impact on gene or gene product.
-
-
-
-
-For missense variants use REVEL with a score ≤ 0.15.
- For splice site variants use MaxEntScan, NNSPLICE and HumanSplicingFinder when the majority of the predictions program support no splicing alteration.",None
-CDKL5 (HGNC:11411),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-CDKL5 (HGNC:11411),BP5,Strong,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-≥3 cases with alternate molecular basis for disease.",Strength
-CDKL5 (HGNC:11411),BP5,Supporting,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-Do not apply for any gene if variant is de novo.",Disease-specific
-CDKL5 (HGNC:11411),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-CDKL5 (HGNC:11411),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-CDKL5 (HGNC:11411),BP7,Supporting,"A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
-
-
-
-
-Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",None
-FOXG1 (HGNC:3811),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-FOXG1 (HGNC:3811),PVS1,Very Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-Use as defined by ClinGen SVI working group (PMID:30192042).
-
-
-PVS1 is applicable up to p.S468.",Disease-specific
-FOXG1 (HGNC:3811),PVS1,Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Strong is applicable for any truncating variant from p.S469 to p.Q480.",
-FOXG1 (HGNC:3811),PVS1,Moderate,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Moderate is applicable for any truncating variant distal of p.Q480.",Disease-specific
-FOXG1 (HGNC:3811),PVS1,Supporting,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Supporting is applicable for initiation codon variants in CDKL5, FOXG1, SLC9A6 and TCF4.",Disease-specific
-FOXG1 (HGNC:3811),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-FOXG1 (HGNC:3811),PS1,Strong,Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.,None
-FOXG1 (HGNC:3811),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-FOXG1 (HGNC:3811),PS2,Very Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-≥2 independent occurrences of PS2.
-
-
-≥2 independent occurrences of PM6 and one occurrence of PS2.",Strength
-FOXG1 (HGNC:3811),PS2,Strong,De novo (maternity and paternity confirmed) in a patient with the disease and no family history.,None
-FOXG1 (HGNC:3811),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-FOXG1 (HGNC:3811),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an out-offrame transcript.
-
-
-Do not use for canonical splice site variants and when PVS1 is used.",Disease-specific
-FOXG1 (HGNC:3811),PS3,Supporting,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).
-
-
-See tables for FOXG1, MECP2, CDKL5, TCF4, UBE3A.",Disease-specific
-FOXG1 (HGNC:3811),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-FOXG1 (HGNC:3811),PS4,Strong,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-5+ observations.",Strength
-FOXG1 (HGNC:3811),PS4,Moderate,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-3-4 observations.",Strength
-FOXG1 (HGNC:3811),PS4,Supporting,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-Use for 2nd independent occurrence.",Strength
-FOXG1 (HGNC:3811),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-FOXG1 (HGNC:3811),PM1,Moderate,"Located in a mutational hot spot and/or critical and well-established functional domain.
-
-
-
-
-(Forkhead: aa 181-275).",Disease-specific
-FOXG1 (HGNC:3811),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-FOXG1 (HGNC:3811),PM2,Supporting,"Absent/rare from controls in an ethnically-matched cohort population sample.
-
-
-
-
-Use if absent, zero observations in control databases.",Strength
-FOXG1 (HGNC:3811),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-FOXG1 (HGNC:3811),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-FOXG1 (HGNC:3811),PM4,Moderate,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Do not use PM4 for in-frame deletions/insertions in the Histidine-rich region (p.37-p.57), Proline and Glutaminerich region (p.58-p.86) and Proline-rich region (p.105-p.112).",Disease-specific
-FOXG1 (HGNC:3811),PM4,Supporting,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",Strength
-FOXG1 (HGNC:3811),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-FOXG1 (HGNC:3811),PM5,Strong,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-≥2 different missense changes affecting the amino acid residue.
-
-
-Do not apply PM1 in these situations.",Strength
-FOXG1 (HGNC:3811),PM5,Moderate,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-Applicable to all genes as written.
-
-
-A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",None
-FOXG1 (HGNC:3811),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-FOXG1 (HGNC:3811),PM6,Very Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",Strength
-FOXG1 (HGNC:3811),PM6,Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥2 independent occurrences of PM6.
-
-
-Evidence from literature must be fully evaluated to support independent events.",Strength
-FOXG1 (HGNC:3811),PM6,Moderate,Confirmed de novo without confirmation of paternity and maternity.,None
-FOXG1 (HGNC:3811),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-FOXG1 (HGNC:3811),PP1,Strong,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-≥5 informative meiosis.
-
-
-Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",Strength
-FOXG1 (HGNC:3811),PP1,Moderate,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-3-4 informative meiosis.
-
-
-Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",Strength
-FOXG1 (HGNC:3811),PP1,Supporting,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-2 informative meiosis.
-
-
-Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",Strength
-FOXG1 (HGNC:3811),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-FOXG1 (HGNC:3811),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-FOXG1 (HGNC:3811),PP3,Supporting,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product.
-
-
-
-
-For missense variants use REVEL with a score ≥ 0.75.
-
-
-For splice site variants use MaxEntScan, NNSPLICE and HumanSplicingFinder when the majority of the predictions program support splicing alteration.",None
-FOXG1 (HGNC:3811),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-FOXG1 (HGNC:3811),PP4,Supporting,"Phenotype specific for disease with single genetic etiology.
-
-
-
-
-See gene specific clinical phenotype guidelines.",Disease-specific
-FOXG1 (HGNC:3811),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-FOXG1 (HGNC:3811),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-FOXG1 (HGNC:3811),BA1,Stand Alone,"Allele frequency above 0.05%.
-
-
-
-
-Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-FOXG1 (HGNC:3811),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-FOXG1 (HGNC:3811),BS1,Strong,"Allele frequency greater than expected for disease (0.025%).
-
-
-
-
-Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-FOXG1 (HGNC:3811),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-FOXG1 (HGNC:3811),BS2,Strong,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-2 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",Strength
-FOXG1 (HGNC:3811),BS2,Supporting,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-1 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",Strength
-FOXG1 (HGNC:3811),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-FOXG1 (HGNC:3811),BS3,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.
-
-
-
-
-RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.
-
-
-Not applicable for these genes for other functional studies (see tables for other accepted functional studies).",Disease-specific
-FOXG1 (HGNC:3811),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-FOXG1 (HGNC:3811),BS4,Strong,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member, when seen in two or more families.
-
-
-Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",Strength
-FOXG1 (HGNC:3811),BS4,Supporting,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member.
-
-
-Need to confirm that the family member is 'affected with a neurodevelopmental phenotype consistent with the gene' at a minimum.",Strength
-FOXG1 (HGNC:3811),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-FOXG1 (HGNC:3811),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-FOXG1 (HGNC:3811),BP2,Supporting,"Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.
-
-
-
-
-BP2 is applicable for MECP2, TCF4, FOXG1 for in trans state.",Disease-specific
-FOXG1 (HGNC:3811),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-FOXG1 (HGNC:3811),BP3,Supporting,"In-frame deletions/insertions in a repetitive region without a known function.
-
-
-
-
-Inframe expansions or deletions in FOXG1 repetitive regions: poly His (p.His47-p.His57), poly Gln (p.Gln70-p.Gln73) and poly Pro (p.Pro58-p.Pro61; p.Pro65-p.Pro69; p.Pro74-p.Pro80).",Disease-specific
-FOXG1 (HGNC:3811),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-FOXG1 (HGNC:3811),BP4,Supporting,"Multiple lines of computational evidence suggest no impact on gene or gene product.
-
-
-
-
-For missense variants use REVEL with a score ≤ 0.15.
- For splice site variants use MaxEntScan, NNSPLICE and HumanSplicingFinder when the majority of the predictions program support no splicing alteration.",None
-FOXG1 (HGNC:3811),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-FOXG1 (HGNC:3811),BP5,Strong,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-≥3 cases with alternate molecular basis for disease.",Strength
-FOXG1 (HGNC:3811),BP5,Supporting,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-Do not apply for any gene if variant is de novo.",Disease-specific
-FOXG1 (HGNC:3811),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-FOXG1 (HGNC:3811),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-FOXG1 (HGNC:3811),BP7,Supporting,"A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
-
-
-
-
-Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",None
-MECP2 (HGNC:6990),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-MECP2 (HGNC:6990),PVS1,Very Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-Use as defined by ClinGen SVI working group (PMID:30192042).
-
-
-PVS1 is applicable up to p.E472, for any frameshift variant that results in a read-through of the stop codon, for canonical splice site variants predicted to result in an out-offrame product, and for canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exon 3). PVS1 is not applicable for initiation codons.",Disease-specific
-MECP2 (HGNC:6990),PVS1,Moderate,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Moderate is applicable for any truncating variant distal of p.E472.",Disease-specific
-MECP2 (HGNC:6990),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MECP2 (HGNC:6990),PS1,Strong,Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.,None
-MECP2 (HGNC:6990),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-MECP2 (HGNC:6990),PS2,Very Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-≥2 independent occurrences of PS2.
-
-
-≥2 independent occurrences of PM6 and one occurrence of PS2.",Strength
-MECP2 (HGNC:6990),PS2,Strong,De novo (maternity and paternity confirmed) in a patient with the disease and no family history.,None
-MECP2 (HGNC:6990),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-MECP2 (HGNC:6990),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an out-offrame transcript.
-
-
-Do not use for canonical splice site variants and when PVS1 is used.",Disease-specific
-MECP2 (HGNC:6990),PS3,Supporting,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).
-
-
-See tables for FOXG1, MECP2, CDKL5, TCF4, UBE3A.",Disease-specific
-MECP2 (HGNC:6990),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-MECP2 (HGNC:6990),PS4,Strong,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-5+ observations.",Strength
-MECP2 (HGNC:6990),PS4,Moderate,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-3-4 observations.",Strength
-MECP2 (HGNC:6990),PS4,Supporting,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-Use for 2nd independent occurrence.",Strength
-MECP2 (HGNC:6990),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-MECP2 (HGNC:6990),PM1,Moderate,"Located in a mutational hot spot and/or critical and well-established functional domain.
-
-
-
-
-Methyl-DNA binding (MDB): aa 90-162; Transcriptional repression domain (TRD): aa 302-306.",Disease-specific
-MECP2 (HGNC:6990),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-MECP2 (HGNC:6990),PM2,Supporting,"Absent/rare from controls in an ethnically-matched cohort population sample.
-
-
-
-
-Use if absent, zero observations in control databases.",Strength
-MECP2 (HGNC:6990),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-MECP2 (HGNC:6990),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-MECP2 (HGNC:6990),PM4,Strong,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-PM4_Strong is applicable to stop-loss variants in MECP2 and UBE3A.",Disease-specific
-MECP2 (HGNC:6990),PM4,Moderate,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Do not use PM4 for in-frame deletions/insertions in the Proline-rich region of gene p.381-p.405).",Disease-specific
-MECP2 (HGNC:6990),PM4,Supporting,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",Strength
-MECP2 (HGNC:6990),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MECP2 (HGNC:6990),PM5,Strong,Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. ≥2 different missense changes affecting the amino acid residue. Do not apply PM1 in these situations.,Strength
-MECP2 (HGNC:6990),PM5,Moderate,Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. Applicable to all genes as written. A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.,None
-MECP2 (HGNC:6990),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-MECP2 (HGNC:6990),PM6,Very Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",Strength
-MECP2 (HGNC:6990),PM6,Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥2 independent occurrences of PM6.
-
-
-Evidence from literature must be fully evaluated to support independent events.",Strength
-MECP2 (HGNC:6990),PM6,Moderate,Confirmed de novo without confirmation of paternity and maternity.,None
-MECP2 (HGNC:6990),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-MECP2 (HGNC:6990),PP1,Strong,Co-segregation with disease in multiple affected family members. ≥5 informative meiosis .Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease),Strength
-MECP2 (HGNC:6990),PP1,Moderate,Co-segregation with disease in multiple affected family members. 3-4 informative meiosis. Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease),Strength
-MECP2 (HGNC:6990),PP1,Supporting,Co-segregation with disease in multiple affected family members. 2 informative meiosis. Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease,Strength
-MECP2 (HGNC:6990),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-MECP2 (HGNC:6990),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-MECP2 (HGNC:6990),PP3,Supporting,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product.
-
-
-
-
-For missense variants use REVEL with a score ≥ 0.75.
-
-
-For splice site variants use MaxEntScan, NNSPLICE and HumanSplicingFinder when the majority of the predictions program support splicing alteration.",None
-MECP2 (HGNC:6990),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-MECP2 (HGNC:6990),PP4,Supporting,"Phenotype specific for disease with single genetic etiology.
-
-
-
-
-See gene specific clinical phenotype guidelines.",Disease-specific
-MECP2 (HGNC:6990),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MECP2 (HGNC:6990),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-MECP2 (HGNC:6990),BA1,Stand Alone,"Allele frequency above 0.05%.
-
-
-
-
-Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-MECP2 (HGNC:6990),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-MECP2 (HGNC:6990),BS1,Strong,"Allele frequency greater than expected for disease (0.025%).
-
-
-
-
-Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-MECP2 (HGNC:6990),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-MECP2 (HGNC:6990),BS2,Strong,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-2 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",Strength
-MECP2 (HGNC:6990),BS2,Supporting,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-1 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",Strength
-MECP2 (HGNC:6990),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-MECP2 (HGNC:6990),BS3,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.
-
-
-
-
-RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.
-
-
-Not applicable for these genes for other functional studies (see tables for other accepted functional studies).",Disease-specific
-MECP2 (HGNC:6990),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-MECP2 (HGNC:6990),BS4,Strong,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member, when seen in two or more families.
-
-
-Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",Strength
-MECP2 (HGNC:6990),BS4,Supporting,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member.
-
-
-Need to confirm that the family member is 'affected with a neurodevelopmental phenotype consistent with the gene' at a minimum.",Strength
-MECP2 (HGNC:6990),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-MECP2 (HGNC:6990),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-MECP2 (HGNC:6990),BP2,Supporting,"Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.
-
-
-
-
-BP2 is applicable for MECP2, TCF4, FOXG1 for in trans state.",Disease-specific
-MECP2 (HGNC:6990),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-MECP2 (HGNC:6990),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-MECP2 (HGNC:6990),BP4,Supporting,"Multiple lines of computational evidence suggest no impact on gene or gene product.
-
-
-
-
-For missense variants use REVEL with a score ≤ 0.15.
- For splice site variants use MaxEntScan, NNSPLICE and HumanSplicingFinder when the majority of the predictions program support no splicing alteration.",None
-MECP2 (HGNC:6990),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-MECP2 (HGNC:6990),BP5,Strong,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-≥3 cases with alternate molecular basis for disease.",Strength
-MECP2 (HGNC:6990),BP5,Supporting,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-Do not apply for any gene if variant is de novo.",Disease-specific
-MECP2 (HGNC:6990),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MECP2 (HGNC:6990),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-MECP2 (HGNC:6990),BP7,Supporting,"A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
-
-
-
-
-Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",None
-SLC9A6 (HGNC:11079),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-SLC9A6 (HGNC:11079),PVS1,Very Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-Use as defined by ClinGen SVI working group (PMID:30192042).
-
-
-PVS1 is applicable up to p.A563, for canonical splice site variants predicted to result in an out-of-frame product, and for canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exon 10).",Disease-specific
-SLC9A6 (HGNC:11079),PVS1,Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Strong is applicable for any truncating variant from p.C564 to p.T601 and for canonical splice site variants that flank exon 3 (in-frame exon).",
-SLC9A6 (HGNC:11079),PVS1,Moderate,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Moderate is applicable for any truncating variant between p.Y602 to p.A669 and any frameshift variant that results in a read-through of the stop codon.",Disease-specific
-SLC9A6 (HGNC:11079),PVS1,Supporting,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Supporting is applicable for initiation codon variants in CDKL5, FOXG1, SLC9A6 and TCF4.",Disease-specific
-SLC9A6 (HGNC:11079),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SLC9A6 (HGNC:11079),PS1,Strong,Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.,None
-SLC9A6 (HGNC:11079),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-SLC9A6 (HGNC:11079),PS2,Very Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-≥2 independent occurrences of PS2.
-
-
-≥2 independent occurrences of PM6 and one occurrence of PS2.",Strength
-SLC9A6 (HGNC:11079),PS2,Strong,De novo (maternity and paternity confirmed) in a patient with the disease and no family history.,None
-SLC9A6 (HGNC:11079),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-SLC9A6 (HGNC:11079),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an out-offrame transcript.
-
-
-Do not use for canonical splice site variants and when PVS1 is used.",Disease-specific
-SLC9A6 (HGNC:11079),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-SLC9A6 (HGNC:11079),PS4,Strong,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-5+ observations.",Strength
-SLC9A6 (HGNC:11079),PS4,Moderate,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-3-4 observations.",Strength
-SLC9A6 (HGNC:11079),PS4,Supporting,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-Use for 2nd independent occurrence.",Strength
-SLC9A6 (HGNC:11079),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-SLC9A6 (HGNC:11079),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-SLC9A6 (HGNC:11079),PM2,Supporting,"Absent/rare from controls in an ethnically-matched cohort population sample.
-
-
-
-
-Use if absent, zero observations in control databases.",Strength
-SLC9A6 (HGNC:11079),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-SLC9A6 (HGNC:11079),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-SLC9A6 (HGNC:11079),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,Disease-specific
-SLC9A6 (HGNC:11079),PM4,Supporting,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",Strength
-SLC9A6 (HGNC:11079),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SLC9A6 (HGNC:11079),PM5,Strong,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-≥2 different missense changes affecting the amino acid residue.
-
-
-Do not apply PM1 in these situations.",Strength
-SLC9A6 (HGNC:11079),PM5,Moderate,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-Applicable to all genes as written.
-
-
-A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",None
-SLC9A6 (HGNC:11079),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-SLC9A6 (HGNC:11079),PM6,Very Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",Strength
-SLC9A6 (HGNC:11079),PM6,Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥2 independent occurrences of PM6.
-
-
-Evidence from literature must be fully evaluated to support independent events.",Strength
-SLC9A6 (HGNC:11079),PM6,Moderate,Confirmed de novo without confirmation of paternity and maternity.,None
-SLC9A6 (HGNC:11079),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-SLC9A6 (HGNC:11079),PP1,Strong,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-≥5 informative meiosis.
-
-
-Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",Strength
-SLC9A6 (HGNC:11079),PP1,Moderate,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-3-4 informative meiosis.
-
-
-Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",Strength
-SLC9A6 (HGNC:11079),PP1,Supporting,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-2 informative meiosis.
-
-
-Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",Strength
-SLC9A6 (HGNC:11079),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-SLC9A6 (HGNC:11079),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-SLC9A6 (HGNC:11079),PP3,Supporting,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product.
-
-
-
-
-For missense variants use REVEL with a score ≥ 0.75.
-
-
-For splice site variants use MaxEntScan, NNSPLICE and HumanSplicingFinder when the majority of the predictions program support splicing alteration.",None
-SLC9A6 (HGNC:11079),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-SLC9A6 (HGNC:11079),PP4,Supporting,"Phenotype specific for disease with single genetic etiology.
-
-
-
-
-See gene specific clinical phenotype guidelines.",Disease-specific
-SLC9A6 (HGNC:11079),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SLC9A6 (HGNC:11079),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-SLC9A6 (HGNC:11079),BA1,Stand Alone,"Allele frequency above 0.05%.
-
-
-
-
-Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-SLC9A6 (HGNC:11079),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-SLC9A6 (HGNC:11079),BS1,Strong,"Allele frequency greater than expected for disease (0.025%).
-
-
-
-
-Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-SLC9A6 (HGNC:11079),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-SLC9A6 (HGNC:11079),BS2,Strong,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-2 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",Strength
-SLC9A6 (HGNC:11079),BS2,Supporting,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-1 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",Strength
-SLC9A6 (HGNC:11079),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-SLC9A6 (HGNC:11079),BS3,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.
-
-
-
-
-RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.
-
-
-Not applicable for these genes for other functional studies (see tables for other accepted functional studies).",Disease-specific
-SLC9A6 (HGNC:11079),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-SLC9A6 (HGNC:11079),BS4,Strong,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member, when seen in two or more families.
-
-
-Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",Strength
-SLC9A6 (HGNC:11079),BS4,Supporting,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member.
-
-
-Need to confirm that the family member is 'affected with a neurodevelopmental phenotype consistent with the gene' at a minimum.",Strength
-SLC9A6 (HGNC:11079),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-SLC9A6 (HGNC:11079),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-SLC9A6 (HGNC:11079),BP2,Supporting,"Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.
-
-
-
-
-BP2 is not applicable for SLC9A6, UBE3A and CDKL5 for in trans state.",Disease-specific
-SLC9A6 (HGNC:11079),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-SLC9A6 (HGNC:11079),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SLC9A6 (HGNC:11079),BP4,Supporting,"Multiple lines of computational evidence suggest no impact on gene or gene product.
-
-
-
-
-For missense variants use REVEL with a score ≤ 0.15.
- For splice site variants use MaxEntScan, NNSPLICE and HumanSplicingFinder when the majority of the predictions program support no splicing alteration.",None
-SLC9A6 (HGNC:11079),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-SLC9A6 (HGNC:11079),BP5,Strong,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-≥3 cases with alternate molecular basis for disease.",Strength
-SLC9A6 (HGNC:11079),BP5,Supporting,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-The variant should be in the hemizygous state in the case with an alternate molecular basis for disease to be used.
-
-
-Do not apply for any gene if variant is de novo.",Disease-specific
-SLC9A6 (HGNC:11079),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SLC9A6 (HGNC:11079),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-SLC9A6 (HGNC:11079),BP7,Supporting,"A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
-
-
-
-
-Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",None
-TCF4 (HGNC:11634),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-TCF4 (HGNC:11634),PVS1,Very Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-Use as defined by ClinGen SVI working group (PMID:30192042).
-
-
-PVS1 is applicable up to p.E643, for any frameshift variant that results in a read-through of the stop codon, for canonical splice site variants predicted to result in an out-offrame product, and for canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exon 15).",Disease-specific
-TCF4 (HGNC:11634),PVS1,Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1 is applicable up to p.E643, for any frameshift variant that results in a read-through of the stop codon, for canonical splice site variants predicted to result in an out-of-frame product, and for canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exon 15).",
-TCF4 (HGNC:11634),PVS1,Moderate,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Moderate is applicable for any truncating variant distal of p.E643 and for single exon deletions that involve just non-coding exon 20.",Disease-specific
-TCF4 (HGNC:11634),PVS1,Supporting,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Supporting is applicable for initiation codon variants in CDKL5, FOXG1, SLC9A6 and TCF4.",Disease-specific
-TCF4 (HGNC:11634),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-TCF4 (HGNC:11634),PS1,Strong,Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.,None
-TCF4 (HGNC:11634),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-TCF4 (HGNC:11634),PS2,Very Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-≥2 independent occurrences of PS2.
-
-
-≥2 independent occurrences of PM6 and one occurrence of PS2.",Strength
-TCF4 (HGNC:11634),PS2,Strong,De novo (maternity and paternity confirmed) in a patient with the disease and no family history.,None
-TCF4 (HGNC:11634),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-TCF4 (HGNC:11634),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an out-offrame transcript.
-
-
-Do not use for canonical splice site variants and when PVS1 is used.",Disease-specific
-TCF4 (HGNC:11634),PS3,Supporting,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).
-
-
-See tables for FOXG1, MECP2, CDKL5, TCF4, UBE3A.",Disease-specific
-TCF4 (HGNC:11634),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-TCF4 (HGNC:11634),PS4,Strong,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-5+ observations.",Strength
-TCF4 (HGNC:11634),PS4,Moderate,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-3-4 observations.",Strength
-TCF4 (HGNC:11634),PS4,Supporting,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-Use for 2nd independent occurrence.",Strength
-TCF4 (HGNC:11634),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-TCF4 (HGNC:11634),PM1,Moderate,"Located in a mutational hot spot and/or critical and well-established functional domain.
-
-
-
-
-(basic Helix-Loop-Helix domain (bHLH): aa 564-617).",Disease-specific
-TCF4 (HGNC:11634),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-TCF4 (HGNC:11634),PM2,Supporting,"Absent/rare from controls in an ethnically-matched cohort population sample.
-
-
-
-
-Use if absent, zero observations in control databases.",Strength
-TCF4 (HGNC:11634),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-TCF4 (HGNC:11634),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-TCF4 (HGNC:11634),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,Disease-specific
-TCF4 (HGNC:11634),PM4,Supporting,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",Strength
-TCF4 (HGNC:11634),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-TCF4 (HGNC:11634),PM5,Strong,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-≥2 different missense changes affecting the amino acid residue.
-
-
-Do not apply PM1 in these situations.",Strength
-TCF4 (HGNC:11634),PM5,Moderate,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-Applicable to all genes as written.
-
-
-A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",None
-TCF4 (HGNC:11634),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-TCF4 (HGNC:11634),PM6,Very Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",Strength
-TCF4 (HGNC:11634),PM6,Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥2 independent occurrences of PM6.
-
-
-Evidence from literature must be fully evaluated to support independent events.",Strength
-TCF4 (HGNC:11634),PM6,Moderate,Confirmed de novo without confirmation of paternity and maternity.,None
-TCF4 (HGNC:11634),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-TCF4 (HGNC:11634),PP1,Strong,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-≥5 informative meiosis.
-
-
-Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",Strength
-TCF4 (HGNC:11634),PP1,Moderate,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-3-4 informative meiosis.
-
-
-Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",Strength
-TCF4 (HGNC:11634),PP1,Supporting,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-2 informative meiosis.
-
-
-Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",Strength
-TCF4 (HGNC:11634),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-TCF4 (HGNC:11634),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-TCF4 (HGNC:11634),PP3,Supporting,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product.
-
-
-
-
-For missense variants use REVEL with a score ≥ 0.75.
-
-
-For splice site variants use MaxEntScan, NNSPLICE and HumanSplicingFinder when the majority of the predictions program support splicing alteration.",None
-TCF4 (HGNC:11634),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-TCF4 (HGNC:11634),PP4,Supporting,"Phenotype specific for disease with single genetic etiology.
-
-
-
-
-See gene specific clinical phenotype guidelines.",Disease-specific
-TCF4 (HGNC:11634),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-TCF4 (HGNC:11634),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-TCF4 (HGNC:11634),BA1,Stand Alone,"Allele frequency above 0.05%.
-
-
-
-
-Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-TCF4 (HGNC:11634),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-TCF4 (HGNC:11634),BS1,Strong,"Allele frequency greater than expected for disease (0.025%).
-
-
-
-
-Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-TCF4 (HGNC:11634),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-TCF4 (HGNC:11634),BS2,Strong,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-2 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",Strength
-TCF4 (HGNC:11634),BS2,Supporting,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-1 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",Strength
-TCF4 (HGNC:11634),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-TCF4 (HGNC:11634),BS3,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.
-
-
-
-
-RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.
-
-
-Not applicable for these genes for other functional studies (see tables for other accepted functional studies).",Disease-specific
-TCF4 (HGNC:11634),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-TCF4 (HGNC:11634),BS4,Strong,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member, when seen in two or more families.
-
-
-Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",Strength
-TCF4 (HGNC:11634),BS4,Supporting,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member.
-
-
-Need to confirm that the family member is 'affected with a neurodevelopmental phenotype consistent with the gene' at a minimum.",Strength
-TCF4 (HGNC:11634),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-TCF4 (HGNC:11634),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-TCF4 (HGNC:11634),BP2,Supporting,"Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.
-
-
-
-
-BP2 is applicable for MECP2, TCF4, FOXG1 for in trans state.",Disease-specific
-TCF4 (HGNC:11634),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-TCF4 (HGNC:11634),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-TCF4 (HGNC:11634),BP4,Supporting,"For missense variants use REVEL with a score ≤ 0.15.
-
-
-For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site).",None
-TCF4 (HGNC:11634),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-TCF4 (HGNC:11634),BP5,Strong,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-≥3 cases with alternate molecular basis for disease.",Strength
-TCF4 (HGNC:11634),BP5,Supporting,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-Do not apply for any gene if variant is de novo.",Disease-specific
-TCF4 (HGNC:11634),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-TCF4 (HGNC:11634),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-TCF4 (HGNC:11634),BP7,Supporting,"A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
-
-
-
-
-Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",None
-UBE3A (HGNC:12496),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-UBE3A (HGNC:12496),PVS1,Very Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-Use as defined by ClinGen SVI working group (PMID:30192042).
-
-
-PVS1 is applicable up to p.K841, for any frameshift variant that results in a read-through of the stop codon, for initiation codon variants, and for canonical splice site variants predicted to result in an out-of-frame product.",Disease-specific
-UBE3A (HGNC:12496),PVS1,Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Strong is applicable for any truncating variant from p.K842 to p.G850 and for canonical splice site variants that flank exons 7, 8 (in-frame exons).",
-UBE3A (HGNC:12496),PVS1,Moderate,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Moderate is applicable for any truncating variant distal of p.G850.",Disease-specific
-UBE3A (HGNC:12496),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-UBE3A (HGNC:12496),PS1,Strong,Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.,None
-UBE3A (HGNC:12496),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-UBE3A (HGNC:12496),PS2,Very Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-≥2 independent occurrences of PS2.
-
-
-≥2 independent occurrences of PM6 and one occurrence of PS2.",
-UBE3A (HGNC:12496),PS2,Strong,De novo (maternity and paternity confirmed) in a patient with the disease and no family history.,None
-UBE3A (HGNC:12496),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-UBE3A (HGNC:12496),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an out-offrame transcript.
-
-
-Do not use for canonical splice site variants and when PVS1 is used.",Disease-specific
-UBE3A (HGNC:12496),PS3,Supporting,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).
-
-
-See tables for FOXG1, MECP2, CDKL5, TCF4, UBE3A.",Disease-specific
-UBE3A (HGNC:12496),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-UBE3A (HGNC:12496),PS4,Strong,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-5+ observations.",Strength
-UBE3A (HGNC:12496),PS4,Moderate,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-3-4 observations.",Strength
-UBE3A (HGNC:12496),PS4,Supporting,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-Use for 2nd independent occurrence.",Strength
-UBE3A (HGNC:12496),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-UBE3A (HGNC:12496),PM1,Moderate,"Located in a mutational hot spot and/or critical and well-established functional domain.
-
-
-
-
-3’ cysteine binding site: aa 820.",Disease-specific
-UBE3A (HGNC:12496),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-UBE3A (HGNC:12496),PM2,Supporting,"Absent/rare from controls in an ethnically-matched cohort population sample.
-
-
-
-
-Use if absent, zero observations in control databases.",Strength
-UBE3A (HGNC:12496),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-UBE3A (HGNC:12496),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-UBE3A (HGNC:12496),PM4,Strong,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-PM4_Strong is applicable to stop-loss variants in MECP2 and UBE3A.",Disease-specific
-UBE3A (HGNC:12496),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,Disease-specific
-UBE3A (HGNC:12496),PM4,Supporting,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",Strength
-UBE3A (HGNC:12496),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-UBE3A (HGNC:12496),PM5,Strong,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-≥2 different missense changes affecting the amino acid residue.
-
-
-Do not apply PM1 in these situations.",Strength
-UBE3A (HGNC:12496),PM5,Moderate,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-Applicable to all genes as written.
-
-
-A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",None
-UBE3A (HGNC:12496),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-UBE3A (HGNC:12496),PM6,Very Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",Strength
-UBE3A (HGNC:12496),PM6,Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥2 independent occurrences of PM6.
-
-
-Evidence from literature must be fully evaluated to support independent events.",Strength
-UBE3A (HGNC:12496),PM6,Moderate,Confirmed de novo without confirmation of paternity and maternity.,None
-UBE3A (HGNC:12496),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-UBE3A (HGNC:12496),PP1,Strong,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-≥5 informative meiosis.
-
-
-Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",Strength
-UBE3A (HGNC:12496),PP1,Moderate,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-3-4 informative meiosis.
-
-
-Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",Strength
-UBE3A (HGNC:12496),PP1,Supporting,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-2 informative meiosis.
-
-
-Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",Strength
-UBE3A (HGNC:12496),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-UBE3A (HGNC:12496),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-UBE3A (HGNC:12496),PP3,Supporting,"For missense variants use REVEL with a score ≥ 0.75.
-
-
-For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site).",None
-UBE3A (HGNC:12496),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-UBE3A (HGNC:12496),PP4,Supporting,"Phenotype specific for disease with single genetic etiology.
-
-
-
-
-See gene specific clinical phenotype guidelines.",Disease-specific
-UBE3A (HGNC:12496),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-UBE3A (HGNC:12496),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-UBE3A (HGNC:12496),BA1,Stand Alone,"Allele frequency above 0.05%.
-
-
-
-
-Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-UBE3A (HGNC:12496),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-UBE3A (HGNC:12496),BS1,Strong,"Allele frequency greater than expected for disease (0.025%).
-
-
-
-
-Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-UBE3A (HGNC:12496),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-UBE3A (HGNC:12496),BS2,Strong,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-4 unaffected (related and maternally inherited or unrelated) Het (UBE3A).",Strength
-UBE3A (HGNC:12496),BS2,Supporting,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-2 unaffected (related and maternally inherited or unrelated) Het (UBE3A),",Strength
-UBE3A (HGNC:12496),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-UBE3A (HGNC:12496),BS3,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.
-
-
-
-
-RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.
-
-
-Not applicable for these genes for other functional studies (see tables for other accepted functional studies).",Disease-specific
-UBE3A (HGNC:12496),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-UBE3A (HGNC:12496),BS4,Strong,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member, when seen in two or more families.
-
-
-Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",Strength
-UBE3A (HGNC:12496),BS4,Supporting,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member.
-
-
-Need to confirm that the family member is 'affected with a neurodevelopmental phenotype consistent with the gene' at a minimum.",Strength
-UBE3A (HGNC:12496),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-UBE3A (HGNC:12496),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-UBE3A (HGNC:12496),BP2,Supporting,"Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.
-
-
-
-
-BP2 is not applicable for SLC9A6, UBE3A and CDKL5 for in trans state.",Disease-specific
-UBE3A (HGNC:12496),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-UBE3A (HGNC:12496),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-UBE3A (HGNC:12496),BP4,Supporting,"For missense variants use REVEL with a score ≤ 0.15.
-
-
-For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site).",None
-UBE3A (HGNC:12496),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-UBE3A (HGNC:12496),BP5,Strong,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-≥3 cases with alternate molecular basis for disease.",Strength
-UBE3A (HGNC:12496),BP5,Supporting,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-Variant should also be maternally inherited in the case with an alternate molecular basis for disease for this criteria to be used.
-
-
-Do not apply for any gene if variant is de novo.",Disease-specific
-UBE3A (HGNC:12496),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-UBE3A (HGNC:12496),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-UBE3A (HGNC:12496),BP7,Supporting,"A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
-
-
-
-
-Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",None
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
deleted file mode 100644
index 171ccd7378c9af4ab5152a3d1f0a204a3da43823..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
+++ /dev/null
@@ -1,1773 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-CDKL5 (HGNC:11411),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-CDKL5 (HGNC:11411),PVS1,Very Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-Use as defined by ClinGen SVI working group (PMID:30192042).
-
-
-Do not use PVS1 for truncating variants in CDKL5 Cterminus (exons 19-21, or after p.P904) when using the historically used transcript (NM_003159.2). PVS1 is applicable up to p.R948 when using the major brain isoform which has an alternative C-terminus (NM_001323289.2), for canonical splice site variants predicted to result in an out-of-frame product, for canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exons 7, 10, 13), and for the non-coding CDKL5 exon (exon 1).",Disease-specific
-CDKL5 (HGNC:11411),PVS1,Moderate,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Moderate is applicable for any truncating variant distal of p.R948 (when using the major brain isoform, NM_001323289.2) and for canonical splice site variants that flank exon 17 (in-frame exon).",Disease-specific
-CDKL5 (HGNC:11411),PVS1,Supporting,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Supporting is applicable for initiation codon variants in CDKL5, FOXG1, SLC9A6 and TCF4.",Disease-specific
-CDKL5 (HGNC:11411),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-CDKL5 (HGNC:11411),PS1,Strong,Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.,None
-CDKL5 (HGNC:11411),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-CDKL5 (HGNC:11411),PS2,Very Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-≥2 independent occurrences of PS2.
-
-
-≥2 independent occurrences of PM6 and one occurrence of PS2.",Strength
-CDKL5 (HGNC:11411),PS2,Strong,De novo (maternity and paternity confirmed) in a patient with the disease and no family history.,None
-CDKL5 (HGNC:11411),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-CDKL5 (HGNC:11411),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an out-offrame transcript.
-
-
-Do not use for canonical splice site variants and when PVS1 is used.",Disease-specific
-CDKL5 (HGNC:11411),PS3,Supporting,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).
-
-
-See tables for FOXG1, MECP2, CDKL5, TCF4, UBE3A.",Disease-specific
-CDKL5 (HGNC:11411),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-CDKL5 (HGNC:11411),PS4,Strong,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-5+ observations.",Strength
-CDKL5 (HGNC:11411),PS4,Moderate,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-3-4 observations.",Strength
-CDKL5 (HGNC:11411),PS4,Supporting,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-Use for 2nd independent occurrence.",Strength
-CDKL5 (HGNC:11411),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-CDKL5 (HGNC:11411),PM1,Moderate,"Located in a mutational hot spot and/or critical and well-established functional domain.
-
-
-
-
-(ATP binding region: aa 19-43; TEY phosphorylation site: aa 169-171).",Disease-specific
-CDKL5 (HGNC:11411),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-CDKL5 (HGNC:11411),PM2,Supporting,"Absent/rare from controls in an ethnically-matched cohort population sample.
-
-
-
-
-Use if absent, zero observations in control databases.",Strength
-CDKL5 (HGNC:11411),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-CDKL5 (HGNC:11411),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-CDKL5 (HGNC:11411),PM4,Moderate,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Do not use for in-frame deletions/insertions in CDKL5 C-terminus (exons 19-21, or after p.904) when using the NM_003159.2 transcript.",Disease-specific
-CDKL5 (HGNC:11411),PM4,Supporting,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",Strength
-CDKL5 (HGNC:11411),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-CDKL5 (HGNC:11411),PM5,Strong,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-≥2 different missense changes affecting the amino acid residue.
-
-
-Do not apply PM1 in these situations.",Strength
-CDKL5 (HGNC:11411),PM5,Moderate,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-Applicable to all genes as written.
-
-
-A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",None
-CDKL5 (HGNC:11411),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-CDKL5 (HGNC:11411),PM6,Very Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",Strength
-CDKL5 (HGNC:11411),PM6,Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥2 independent occurrences of PM6.
-
-
-Evidence from literature must be fully evaluated to support independent events.",Strength
-CDKL5 (HGNC:11411),PM6,Moderate,Confirmed de novo without confirmation of paternity and maternity.,None
-CDKL5 (HGNC:11411),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-CDKL5 (HGNC:11411),PP1,Strong,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-≥5 informative meiosis.
-
-
-Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",Strength
-CDKL5 (HGNC:11411),PP1,Moderate,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-3-4 informative meiosis.
-
-
-Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",Strength
-CDKL5 (HGNC:11411),PP1,Supporting,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-2 informative meiosis.
-
-
-Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",Strength
-CDKL5 (HGNC:11411),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-CDKL5 (HGNC:11411),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-CDKL5 (HGNC:11411),PP3,Supporting,"For missense variants use REVEL with a score ≥ 0.75.
-
-
-For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site).",None
-CDKL5 (HGNC:11411),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-CDKL5 (HGNC:11411),PP4,Supporting,"Phenotype specific for disease with single genetic etiology.
-
-
-
-
-See gene specific clinical phenotype guidelines.",Disease-specific
-CDKL5 (HGNC:11411),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-CDKL5 (HGNC:11411),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-CDKL5 (HGNC:11411),BA1,Stand Alone,"Allele frequency above 0.05%.
-
-
-
-
-Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-CDKL5 (HGNC:11411),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-CDKL5 (HGNC:11411),BS1,Strong,"Allele frequency greater than expected for disease (0.025%).
-
-
-
-
-Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-CDKL5 (HGNC:11411),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-CDKL5 (HGNC:11411),BS2,Strong,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-2 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",Strength
-CDKL5 (HGNC:11411),BS2,Supporting,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-1 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",Strength
-CDKL5 (HGNC:11411),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-CDKL5 (HGNC:11411),BS3,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.
-
-
-
-
-RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.
-
-
-Not applicable for these genes for other functional studies (see tables for other accepted functional studies).",Disease-specific
-CDKL5 (HGNC:11411),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-CDKL5 (HGNC:11411),BS4,Strong,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member, when seen in two or more families.
-
-
-Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",Strength
-CDKL5 (HGNC:11411),BS4,Supporting,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member.
-
-
-Need to confirm that the family member is 'affected with a neurodevelopmental phenotype consistent with the gene' at a minimum.",Strength
-CDKL5 (HGNC:11411),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-CDKL5 (HGNC:11411),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-CDKL5 (HGNC:11411),BP2,Supporting,"Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.
-
-
-
-
-BP2 is not applicable for SLC9A6, UBE3A and CDKL5 for in trans state.",Disease-specific
-CDKL5 (HGNC:11411),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-CDKL5 (HGNC:11411),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-CDKL5 (HGNC:11411),BP4,Supporting,"For missense variants use REVEL with a score ≤ 0.15.
-
-
-For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site).",None
-CDKL5 (HGNC:11411),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-CDKL5 (HGNC:11411),BP5,Strong,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-≥3 cases with alternate molecular basis for disease.",Strength
-CDKL5 (HGNC:11411),BP5,Supporting,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-Do not apply for any gene if variant is de novo.",Disease-specific
-CDKL5 (HGNC:11411),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-CDKL5 (HGNC:11411),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-CDKL5 (HGNC:11411),BP7,Supporting,"A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
-
-
-
-
-Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",None
-FOXG1 (HGNC:3811),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-FOXG1 (HGNC:3811),PVS1,Very Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-Use as defined by ClinGen SVI working group (PMID:30192042).
-
-
-PVS1 is applicable up to p.S468.",Disease-specific
-FOXG1 (HGNC:3811),PVS1,Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Strong is applicable for any truncating variant from p.S469 to p.Q480.",
-FOXG1 (HGNC:3811),PVS1,Moderate,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Moderate is applicable for any truncating variant distal of p.Q480.",Disease-specific
-FOXG1 (HGNC:3811),PVS1,Supporting,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Supporting is applicable for initiation codon variants in CDKL5, FOXG1, SLC9A6 and TCF4.",Disease-specific
-FOXG1 (HGNC:3811),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-FOXG1 (HGNC:3811),PS1,Strong,Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.,None
-FOXG1 (HGNC:3811),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-FOXG1 (HGNC:3811),PS2,Very Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-≥2 independent occurrences of PS2.
-
-
-≥2 independent occurrences of PM6 and one occurrence of PS2.",Strength
-FOXG1 (HGNC:3811),PS2,Strong,De novo (maternity and paternity confirmed) in a patient with the disease and no family history.,None
-FOXG1 (HGNC:3811),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-FOXG1 (HGNC:3811),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an out-offrame transcript.
-
-
-Do not use for canonical splice site variants and when PVS1 is used.",Disease-specific
-FOXG1 (HGNC:3811),PS3,Supporting,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).
-
-
-See tables for FOXG1, MECP2, CDKL5, TCF4, UBE3A.",Disease-specific
-FOXG1 (HGNC:3811),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-FOXG1 (HGNC:3811),PS4,Strong,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-5+ observations.",Strength
-FOXG1 (HGNC:3811),PS4,Moderate,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-3-4 observations.",Strength
-FOXG1 (HGNC:3811),PS4,Supporting,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-Use for 2nd independent occurrence.",Strength
-FOXG1 (HGNC:3811),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-FOXG1 (HGNC:3811),PM1,Moderate,"Located in a mutational hot spot and/or critical and well-established functional domain.
-
-
-
-
-(Forkhead: aa 181-275).",Disease-specific
-FOXG1 (HGNC:3811),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-FOXG1 (HGNC:3811),PM2,Supporting,"Absent/rare from controls in an ethnically-matched cohort population sample.
-
-
-
-
-Use if absent, zero observations in control databases.",Strength
-FOXG1 (HGNC:3811),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-FOXG1 (HGNC:3811),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-FOXG1 (HGNC:3811),PM4,Moderate,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Do not use PM4 for in-frame deletions/insertions in the Histidine-rich region (p.37-p.57), Proline and Glutaminerich region (p.58-p.86) and Proline-rich region (p.105-p.112).",Disease-specific
-FOXG1 (HGNC:3811),PM4,Supporting,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",Strength
-FOXG1 (HGNC:3811),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-FOXG1 (HGNC:3811),PM5,Strong,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-≥2 different missense changes affecting the amino acid residue.
-
-
-Do not apply PM1 in these situations.",Strength
-FOXG1 (HGNC:3811),PM5,Moderate,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-Applicable to all genes as written.
-
-
-A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",None
-FOXG1 (HGNC:3811),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-FOXG1 (HGNC:3811),PM6,Very Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",Strength
-FOXG1 (HGNC:3811),PM6,Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥2 independent occurrences of PM6.
-
-
-Evidence from literature must be fully evaluated to support independent events.",Strength
-FOXG1 (HGNC:3811),PM6,Moderate,Confirmed de novo without confirmation of paternity and maternity.,None
-FOXG1 (HGNC:3811),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-FOXG1 (HGNC:3811),PP1,Strong,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-≥5 informative meiosis.
-
-
-Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",Strength
-FOXG1 (HGNC:3811),PP1,Moderate,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-3-4 informative meiosis.
-
-
-Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",Strength
-FOXG1 (HGNC:3811),PP1,Supporting,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-2 informative meiosis.
-
-
-Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",Strength
-FOXG1 (HGNC:3811),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-FOXG1 (HGNC:3811),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-FOXG1 (HGNC:3811),PP3,Supporting,"For missense variants use REVEL with a score ≥ 0.75.
-
-
-For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site).",None
-FOXG1 (HGNC:3811),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-FOXG1 (HGNC:3811),PP4,Supporting,"Phenotype specific for disease with single genetic etiology.
-
-
-
-
-See gene specific clinical phenotype guidelines.",Disease-specific
-FOXG1 (HGNC:3811),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-FOXG1 (HGNC:3811),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-FOXG1 (HGNC:3811),BA1,Stand Alone,"Allele frequency above 0.05%.
-
-
-
-
-Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-FOXG1 (HGNC:3811),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-FOXG1 (HGNC:3811),BS1,Strong,"Allele frequency greater than expected for disease (0.025%).
-
-
-
-
-Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-FOXG1 (HGNC:3811),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-FOXG1 (HGNC:3811),BS2,Strong,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-2 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",Strength
-FOXG1 (HGNC:3811),BS2,Supporting,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-1 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",Strength
-FOXG1 (HGNC:3811),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-FOXG1 (HGNC:3811),BS3,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.
-
-
-
-
-RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.
-
-
-Not applicable for these genes for other functional studies (see tables for other accepted functional studies).",Disease-specific
-FOXG1 (HGNC:3811),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-FOXG1 (HGNC:3811),BS4,Strong,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member, when seen in two or more families.
-
-
-Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",Strength
-FOXG1 (HGNC:3811),BS4,Supporting,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member.
-
-
-Need to confirm that the family member is 'affected with a neurodevelopmental phenotype consistent with the gene' at a minimum.",Strength
-FOXG1 (HGNC:3811),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-FOXG1 (HGNC:3811),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-FOXG1 (HGNC:3811),BP2,Supporting,"Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.
-
-
-
-
-BP2 is applicable for MECP2, TCF4, FOXG1 for in trans state.",Disease-specific
-FOXG1 (HGNC:3811),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-FOXG1 (HGNC:3811),BP3,Supporting,"In-frame deletions/insertions in a repetitive region without a known function.
-
-
-
-
-Inframe expansions or deletions in FOXG1 repetitive regions: poly His (p.His47-p.His57), poly Gln (p.Gln70-p.Gln73) and poly Pro (p.Pro58-p.Pro61; p.Pro65-p.Pro69; p.Pro74-p.Pro80).",Disease-specific
-FOXG1 (HGNC:3811),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-FOXG1 (HGNC:3811),BP4,Supporting,"For missense variants use REVEL with a score ≤ 0.15.
-
-
-For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site).",None
-FOXG1 (HGNC:3811),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-FOXG1 (HGNC:3811),BP5,Strong,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-≥3 cases with alternate molecular basis for disease.",Strength
-FOXG1 (HGNC:3811),BP5,Supporting,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-Do not apply for any gene if variant is de novo.",Disease-specific
-FOXG1 (HGNC:3811),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-FOXG1 (HGNC:3811),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-FOXG1 (HGNC:3811),BP7,Supporting,"A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
-
-
-
-
-Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",None
-MECP2 (HGNC:6990),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-MECP2 (HGNC:6990),PVS1,Very Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-Use as defined by ClinGen SVI working group (PMID:30192042).
-
-
-PVS1 is applicable up to p.E472, for any frameshift variant that results in a read-through of the stop codon, for canonical splice site variants predicted to result in an out-offrame product, and for canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exon 3). PVS1 is not applicable for initiation codons.",Disease-specific
-MECP2 (HGNC:6990),PVS1,Moderate,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Moderate is applicable for any truncating variant distal of p.E472.",Disease-specific
-MECP2 (HGNC:6990),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MECP2 (HGNC:6990),PS1,Strong,Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.,None
-MECP2 (HGNC:6990),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-MECP2 (HGNC:6990),PS2,Very Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-≥2 independent occurrences of PS2.
-
-
-≥2 independent occurrences of PM6 and one occurrence of PS2.",Strength
-MECP2 (HGNC:6990),PS2,Strong,De novo (maternity and paternity confirmed) in a patient with the disease and no family history.,None
-MECP2 (HGNC:6990),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-MECP2 (HGNC:6990),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an out-offrame transcript.
-
-
-Do not use for canonical splice site variants and when PVS1 is used.",Disease-specific
-MECP2 (HGNC:6990),PS3,Supporting,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).
-
-
-See tables for FOXG1, MECP2, CDKL5, TCF4, UBE3A.",Disease-specific
-MECP2 (HGNC:6990),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-MECP2 (HGNC:6990),PS4,Strong,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-5+ observations.",Strength
-MECP2 (HGNC:6990),PS4,Moderate,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-3-4 observations.",Strength
-MECP2 (HGNC:6990),PS4,Supporting,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-Use for 2nd independent occurrence.",Strength
-MECP2 (HGNC:6990),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-MECP2 (HGNC:6990),PM1,Moderate,"Located in a mutational hot spot and/or critical and well-established functional domain.
-
-
-
-
-Methyl-DNA binding (MDB): aa 90-162; Transcriptional repression domain (TRD): aa 302-306.",Disease-specific
-MECP2 (HGNC:6990),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-MECP2 (HGNC:6990),PM2,Supporting,"Absent/rare from controls in an ethnically-matched cohort population sample.
-
-
-
-
-Use if absent, zero observations in control databases.",Strength
-MECP2 (HGNC:6990),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-MECP2 (HGNC:6990),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-MECP2 (HGNC:6990),PM4,Strong,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-PM4_Strong is applicable to stop-loss variants in MECP2 and UBE3A.",Disease-specific
-MECP2 (HGNC:6990),PM4,Moderate,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Do not use PM4 for in-frame deletions/insertions in the Proline-rich region of gene p.381-p.405).",Disease-specific
-MECP2 (HGNC:6990),PM4,Supporting,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",Strength
-MECP2 (HGNC:6990),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MECP2 (HGNC:6990),PM5,Strong,Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. ≥2 different missense changes affecting the amino acid residue. Do not apply PM1 in these situations.,Strength
-MECP2 (HGNC:6990),PM5,Moderate,Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. Applicable to all genes as written. A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.,None
-MECP2 (HGNC:6990),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-MECP2 (HGNC:6990),PM6,Very Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",Strength
-MECP2 (HGNC:6990),PM6,Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥2 independent occurrences of PM6.
-
-
-Evidence from literature must be fully evaluated to support independent events.",Strength
-MECP2 (HGNC:6990),PM6,Moderate,Confirmed de novo without confirmation of paternity and maternity.,None
-MECP2 (HGNC:6990),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-MECP2 (HGNC:6990),PP1,Strong,Co-segregation with disease in multiple affected family members. ≥5 informative meiosis .Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease),Strength
-MECP2 (HGNC:6990),PP1,Moderate,Co-segregation with disease in multiple affected family members. 3-4 informative meiosis. Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease),Strength
-MECP2 (HGNC:6990),PP1,Supporting,Co-segregation with disease in multiple affected family members. 2 informative meiosis. Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease,Strength
-MECP2 (HGNC:6990),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-MECP2 (HGNC:6990),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-MECP2 (HGNC:6990),PP3,Supporting,"For missense variants use REVEL with a score ≥ 0.75.
-
-
-For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site).",None
-MECP2 (HGNC:6990),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-MECP2 (HGNC:6990),PP4,Supporting,"Phenotype specific for disease with single genetic etiology.
-
-
-
-
-See gene specific clinical phenotype guidelines.",Disease-specific
-MECP2 (HGNC:6990),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MECP2 (HGNC:6990),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-MECP2 (HGNC:6990),BA1,Stand Alone,"Allele frequency above 0.05%.
-
-
-
-
-Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-MECP2 (HGNC:6990),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-MECP2 (HGNC:6990),BS1,Strong,"Allele frequency greater than expected for disease (0.025%).
-
-
-
-
-Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-MECP2 (HGNC:6990),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-MECP2 (HGNC:6990),BS2,Strong,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-2 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",Strength
-MECP2 (HGNC:6990),BS2,Supporting,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-1 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",Strength
-MECP2 (HGNC:6990),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-MECP2 (HGNC:6990),BS3,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.
-
-
-
-
-RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.
-
-
-Not applicable for these genes for other functional studies (see tables for other accepted functional studies).",Disease-specific
-MECP2 (HGNC:6990),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-MECP2 (HGNC:6990),BS4,Strong,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member, when seen in two or more families.
-
-
-Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",Strength
-MECP2 (HGNC:6990),BS4,Supporting,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member.
-
-
-Need to confirm that the family member is 'affected with a neurodevelopmental phenotype consistent with the gene' at a minimum.",Strength
-MECP2 (HGNC:6990),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-MECP2 (HGNC:6990),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-MECP2 (HGNC:6990),BP2,Supporting,"Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.
-
-
-
-
-BP2 is applicable for MECP2, TCF4, FOXG1 for in trans state.",Disease-specific
-MECP2 (HGNC:6990),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-MECP2 (HGNC:6990),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-MECP2 (HGNC:6990),BP4,Supporting,"For missense variants use REVEL with a score ≤ 0.15.
-
-
-For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site).",None
-MECP2 (HGNC:6990),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-MECP2 (HGNC:6990),BP5,Strong,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-≥3 cases with alternate molecular basis for disease.",Strength
-MECP2 (HGNC:6990),BP5,Supporting,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-Do not apply for any gene if variant is de novo.",Disease-specific
-MECP2 (HGNC:6990),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MECP2 (HGNC:6990),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-MECP2 (HGNC:6990),BP7,Supporting,"A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
-
-
-
-
-Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",None
-SLC9A6 (HGNC:11079),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-SLC9A6 (HGNC:11079),PVS1,Very Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-Use as defined by ClinGen SVI working group (PMID:30192042).
-
-
-PVS1 is applicable up to p.A563, for canonical splice site variants predicted to result in an out-of-frame product, and for canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exon 10).",Disease-specific
-SLC9A6 (HGNC:11079),PVS1,Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Strong is applicable for any truncating variant from p.C564 to p.T601 and for canonical splice site variants that flank exon 3 (in-frame exon).",
-SLC9A6 (HGNC:11079),PVS1,Moderate,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Moderate is applicable for any truncating variant between p.Y602 to p.A669 and any frameshift variant that results in a read-through of the stop codon.",Disease-specific
-SLC9A6 (HGNC:11079),PVS1,Supporting,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Supporting is applicable for initiation codon variants in CDKL5, FOXG1, SLC9A6 and TCF4.",Disease-specific
-SLC9A6 (HGNC:11079),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SLC9A6 (HGNC:11079),PS1,Strong,Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.,None
-SLC9A6 (HGNC:11079),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-SLC9A6 (HGNC:11079),PS2,Very Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-≥2 independent occurrences of PS2.
-
-
-≥2 independent occurrences of PM6 and one occurrence of PS2.",Strength
-SLC9A6 (HGNC:11079),PS2,Strong,De novo (maternity and paternity confirmed) in a patient with the disease and no family history.,None
-SLC9A6 (HGNC:11079),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-SLC9A6 (HGNC:11079),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an out-offrame transcript.
-
-
-Do not use for canonical splice site variants and when PVS1 is used.",Disease-specific
-SLC9A6 (HGNC:11079),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-SLC9A6 (HGNC:11079),PS4,Strong,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-5+ observations.",Strength
-SLC9A6 (HGNC:11079),PS4,Moderate,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-3-4 observations.",Strength
-SLC9A6 (HGNC:11079),PS4,Supporting,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-Use for 2nd independent occurrence.",Strength
-SLC9A6 (HGNC:11079),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-SLC9A6 (HGNC:11079),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-SLC9A6 (HGNC:11079),PM2,Supporting,"Absent/rare from controls in an ethnically-matched cohort population sample.
-
-
-
-
-Use if absent, zero observations in control databases.",Strength
-SLC9A6 (HGNC:11079),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-SLC9A6 (HGNC:11079),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-SLC9A6 (HGNC:11079),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,Disease-specific
-SLC9A6 (HGNC:11079),PM4,Supporting,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",Strength
-SLC9A6 (HGNC:11079),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SLC9A6 (HGNC:11079),PM5,Strong,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-≥2 different missense changes affecting the amino acid residue.
-
-
-Do not apply PM1 in these situations.",Strength
-SLC9A6 (HGNC:11079),PM5,Moderate,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-Applicable to all genes as written.
-
-
-A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",None
-SLC9A6 (HGNC:11079),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-SLC9A6 (HGNC:11079),PM6,Very Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",Strength
-SLC9A6 (HGNC:11079),PM6,Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥2 independent occurrences of PM6.
-
-
-Evidence from literature must be fully evaluated to support independent events.",Strength
-SLC9A6 (HGNC:11079),PM6,Moderate,Confirmed de novo without confirmation of paternity and maternity.,None
-SLC9A6 (HGNC:11079),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-SLC9A6 (HGNC:11079),PP1,Strong,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-≥5 informative meiosis.
-
-
-Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",Strength
-SLC9A6 (HGNC:11079),PP1,Moderate,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-3-4 informative meiosis.
-
-
-Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",Strength
-SLC9A6 (HGNC:11079),PP1,Supporting,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-2 informative meiosis.
-
-
-Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",Strength
-SLC9A6 (HGNC:11079),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-SLC9A6 (HGNC:11079),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-SLC9A6 (HGNC:11079),PP3,Supporting,"For missense variants use REVEL with a score ≥ 0.75.
-
-
-For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site).",None
-SLC9A6 (HGNC:11079),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-SLC9A6 (HGNC:11079),PP4,Supporting,"Phenotype specific for disease with single genetic etiology.
-
-
-
-
-See gene specific clinical phenotype guidelines.",Disease-specific
-SLC9A6 (HGNC:11079),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SLC9A6 (HGNC:11079),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-SLC9A6 (HGNC:11079),BA1,Stand Alone,"Allele frequency above 0.05%.
-
-
-
-
-Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-SLC9A6 (HGNC:11079),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-SLC9A6 (HGNC:11079),BS1,Strong,"Allele frequency greater than expected for disease (0.025%).
-
-
-
-
-Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-SLC9A6 (HGNC:11079),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-SLC9A6 (HGNC:11079),BS2,Strong,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-2 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",Strength
-SLC9A6 (HGNC:11079),BS2,Supporting,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-1 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",Strength
-SLC9A6 (HGNC:11079),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-SLC9A6 (HGNC:11079),BS3,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.
-
-
-
-
-RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.
-
-
-Not applicable for these genes for other functional studies (see tables for other accepted functional studies).",Disease-specific
-SLC9A6 (HGNC:11079),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-SLC9A6 (HGNC:11079),BS4,Strong,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member, when seen in two or more families.
-
-
-Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",Strength
-SLC9A6 (HGNC:11079),BS4,Supporting,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member.
-
-
-Need to confirm that the family member is 'affected with a neurodevelopmental phenotype consistent with the gene' at a minimum.",Strength
-SLC9A6 (HGNC:11079),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-SLC9A6 (HGNC:11079),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-SLC9A6 (HGNC:11079),BP2,Supporting,"Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.
-
-
-
-
-BP2 is not applicable for SLC9A6, UBE3A and CDKL5 for in trans state.",Disease-specific
-SLC9A6 (HGNC:11079),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-SLC9A6 (HGNC:11079),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SLC9A6 (HGNC:11079),BP4,Supporting,"For missense variants use REVEL with a score ≤ 0.15.
-
-
-For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site).",None
-SLC9A6 (HGNC:11079),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-SLC9A6 (HGNC:11079),BP5,Strong,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-≥3 cases with alternate molecular basis for disease.",Strength
-SLC9A6 (HGNC:11079),BP5,Supporting,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-The variant should be in the hemizygous state in the case with an alternate molecular basis for disease to be used.
-
-
-Do not apply for any gene if variant is de novo.",Disease-specific
-SLC9A6 (HGNC:11079),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SLC9A6 (HGNC:11079),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-SLC9A6 (HGNC:11079),BP7,Supporting,"A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
-
-
-
-
-Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",None
-TCF4 (HGNC:11634),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-TCF4 (HGNC:11634),PVS1,Very Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-Use as defined by ClinGen SVI working group (PMID:30192042).
-
-
-PVS1 is applicable up to p.E643, for any frameshift variant that results in a read-through of the stop codon, for canonical splice site variants predicted to result in an out-offrame product, and for canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exon 15).",Disease-specific
-TCF4 (HGNC:11634),PVS1,Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1 is applicable up to p.E643, for any frameshift variant that results in a read-through of the stop codon, for canonical splice site variants predicted to result in an out-of-frame product, and for canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exon 15).",
-TCF4 (HGNC:11634),PVS1,Moderate,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Moderate is applicable for any truncating variant distal of p.E643 and for single exon deletions that involve just non-coding exon 20.",Disease-specific
-TCF4 (HGNC:11634),PVS1,Supporting,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Supporting is applicable for initiation codon variants in CDKL5, FOXG1, SLC9A6 and TCF4.",Disease-specific
-TCF4 (HGNC:11634),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-TCF4 (HGNC:11634),PS1,Strong,Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.,None
-TCF4 (HGNC:11634),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-TCF4 (HGNC:11634),PS2,Very Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-≥2 independent occurrences of PS2.
-
-
-≥2 independent occurrences of PM6 and one occurrence of PS2.",Strength
-TCF4 (HGNC:11634),PS2,Strong,De novo (maternity and paternity confirmed) in a patient with the disease and no family history.,None
-TCF4 (HGNC:11634),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-TCF4 (HGNC:11634),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an out-offrame transcript.
-
-
-Do not use for canonical splice site variants and when PVS1 is used.",Disease-specific
-TCF4 (HGNC:11634),PS3,Supporting,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).
-
-
-See tables for FOXG1, MECP2, CDKL5, TCF4, UBE3A.",Disease-specific
-TCF4 (HGNC:11634),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-TCF4 (HGNC:11634),PS4,Strong,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-5+ observations.",Strength
-TCF4 (HGNC:11634),PS4,Moderate,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-3-4 observations.",Strength
-TCF4 (HGNC:11634),PS4,Supporting,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-Use for 2nd independent occurrence.",Strength
-TCF4 (HGNC:11634),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-TCF4 (HGNC:11634),PM1,Moderate,"Located in a mutational hot spot and/or critical and well-established functional domain.
-
-
-
-
-(basic Helix-Loop-Helix domain (bHLH): aa 564-617).",Disease-specific
-TCF4 (HGNC:11634),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-TCF4 (HGNC:11634),PM2,Supporting,"Absent/rare from controls in an ethnically-matched cohort population sample.
-
-
-
-
-Use if absent, zero observations in control databases.",Strength
-TCF4 (HGNC:11634),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-TCF4 (HGNC:11634),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-TCF4 (HGNC:11634),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,Disease-specific
-TCF4 (HGNC:11634),PM4,Supporting,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",Strength
-TCF4 (HGNC:11634),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-TCF4 (HGNC:11634),PM5,Strong,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-≥2 different missense changes affecting the amino acid residue.
-
-
-Do not apply PM1 in these situations.",Strength
-TCF4 (HGNC:11634),PM5,Moderate,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-Applicable to all genes as written.
-
-
-A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",None
-TCF4 (HGNC:11634),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-TCF4 (HGNC:11634),PM6,Very Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",Strength
-TCF4 (HGNC:11634),PM6,Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥2 independent occurrences of PM6.
-
-
-Evidence from literature must be fully evaluated to support independent events.",Strength
-TCF4 (HGNC:11634),PM6,Moderate,Confirmed de novo without confirmation of paternity and maternity.,None
-TCF4 (HGNC:11634),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-TCF4 (HGNC:11634),PP1,Strong,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-≥5 informative meiosis.
-
-
-Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",Strength
-TCF4 (HGNC:11634),PP1,Moderate,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-3-4 informative meiosis.
-
-
-Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",Strength
-TCF4 (HGNC:11634),PP1,Supporting,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-2 informative meiosis.
-
-
-Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",Strength
-TCF4 (HGNC:11634),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-TCF4 (HGNC:11634),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-TCF4 (HGNC:11634),PP3,Supporting,"For missense variants use REVEL with a score ≥ 0.75.
-
-
-For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site).",None
-TCF4 (HGNC:11634),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-TCF4 (HGNC:11634),PP4,Supporting,"Phenotype specific for disease with single genetic etiology.
-
-
-
-
-See gene specific clinical phenotype guidelines.",Disease-specific
-TCF4 (HGNC:11634),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-TCF4 (HGNC:11634),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-TCF4 (HGNC:11634),BA1,Stand Alone,"Allele frequency above 0.05%.
-
-
-
-
-Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-TCF4 (HGNC:11634),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-TCF4 (HGNC:11634),BS1,Strong,"Allele frequency greater than expected for disease (0.025%).
-
-
-
-
-Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-TCF4 (HGNC:11634),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-TCF4 (HGNC:11634),BS2,Strong,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-2 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",Strength
-TCF4 (HGNC:11634),BS2,Supporting,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-1 unaffected (related or unrelated) Het (FOXG1, TCF4), Hemi (SLC9A6), Het or Hemi (CDKL5, MECP2).",Strength
-TCF4 (HGNC:11634),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-TCF4 (HGNC:11634),BS3,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.
-
-
-
-
-RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.
-
-
-Not applicable for these genes for other functional studies (see tables for other accepted functional studies).",Disease-specific
-TCF4 (HGNC:11634),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-TCF4 (HGNC:11634),BS4,Strong,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member, when seen in two or more families.
-
-
-Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",Strength
-TCF4 (HGNC:11634),BS4,Supporting,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member.
-
-
-Need to confirm that the family member is 'affected with a neurodevelopmental phenotype consistent with the gene' at a minimum.",Strength
-TCF4 (HGNC:11634),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-TCF4 (HGNC:11634),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-TCF4 (HGNC:11634),BP2,Supporting,"Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.
-
-
-
-
-BP2 is applicable for MECP2, TCF4, FOXG1 for in trans state.",Disease-specific
-TCF4 (HGNC:11634),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-TCF4 (HGNC:11634),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-TCF4 (HGNC:11634),BP4,Supporting,"For missense variants use REVEL with a score ≤ 0.15.
-
-
-For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site).",None
-TCF4 (HGNC:11634),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-TCF4 (HGNC:11634),BP5,Strong,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-≥3 cases with alternate molecular basis for disease.",Strength
-TCF4 (HGNC:11634),BP5,Supporting,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-Do not apply for any gene if variant is de novo.",Disease-specific
-TCF4 (HGNC:11634),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-TCF4 (HGNC:11634),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-TCF4 (HGNC:11634),BP7,Supporting,"A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
-
-
-
-
-Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",None
-UBE3A (HGNC:12496),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-UBE3A (HGNC:12496),PVS1,Very Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-Use as defined by ClinGen SVI working group (PMID:30192042).
-
-
-PVS1 is applicable up to p.K841, for any frameshift variant that results in a read-through of the stop codon, for initiation codon variants, and for canonical splice site variants predicted to result in an out-of-frame product.",Disease-specific
-UBE3A (HGNC:12496),PVS1,Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Strong is applicable for any truncating variant from p.K842 to p.G850 and for canonical splice site variants that flank exons 7, 8 (in-frame exons).",
-UBE3A (HGNC:12496),PVS1,Moderate,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Moderate is applicable for any truncating variant distal of p.G850.",Disease-specific
-UBE3A (HGNC:12496),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-UBE3A (HGNC:12496),PS1,Strong,Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.,None
-UBE3A (HGNC:12496),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-UBE3A (HGNC:12496),PS2,Very Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-≥2 independent occurrences of PS2.
-
-
-≥2 independent occurrences of PM6 and one occurrence of PS2.",
-UBE3A (HGNC:12496),PS2,Strong,De novo (maternity and paternity confirmed) in a patient with the disease and no family history.,None
-UBE3A (HGNC:12496),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-UBE3A (HGNC:12496),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an out-offrame transcript.
-
-
-Do not use for canonical splice site variants and when PVS1 is used.",Disease-specific
-UBE3A (HGNC:12496),PS3,Supporting,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).
-
-
-See tables for FOXG1, MECP2, CDKL5, TCF4, UBE3A.",Disease-specific
-UBE3A (HGNC:12496),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-UBE3A (HGNC:12496),PS4,Strong,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-5+ observations.",Strength
-UBE3A (HGNC:12496),PS4,Moderate,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-3-4 observations.",Strength
-UBE3A (HGNC:12496),PS4,Supporting,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-Use for 2nd independent occurrence.",Strength
-UBE3A (HGNC:12496),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-UBE3A (HGNC:12496),PM1,Moderate,"Located in a mutational hot spot and/or critical and well-established functional domain.
-
-
-
-
-3’ cysteine binding site: aa 820.",Disease-specific
-UBE3A (HGNC:12496),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-UBE3A (HGNC:12496),PM2,Supporting,"Absent/rare from controls in an ethnically-matched cohort population sample.
-
-
-
-
-Use if absent, zero observations in control databases.",Strength
-UBE3A (HGNC:12496),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-UBE3A (HGNC:12496),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-UBE3A (HGNC:12496),PM4,Strong,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-PM4_Strong is applicable to stop-loss variants in MECP2 and UBE3A.",Disease-specific
-UBE3A (HGNC:12496),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,Disease-specific
-UBE3A (HGNC:12496),PM4,Supporting,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",Strength
-UBE3A (HGNC:12496),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-UBE3A (HGNC:12496),PM5,Strong,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-≥2 different missense changes affecting the amino acid residue.
-
-
-Do not apply PM1 in these situations.",Strength
-UBE3A (HGNC:12496),PM5,Moderate,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-Applicable to all genes as written.
-
-
-A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",None
-UBE3A (HGNC:12496),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-UBE3A (HGNC:12496),PM6,Very Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",Strength
-UBE3A (HGNC:12496),PM6,Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥2 independent occurrences of PM6.
-
-
-Evidence from literature must be fully evaluated to support independent events.",Strength
-UBE3A (HGNC:12496),PM6,Moderate,Confirmed de novo without confirmation of paternity and maternity.,None
-UBE3A (HGNC:12496),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-UBE3A (HGNC:12496),PP1,Strong,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-≥5 informative meiosis.
-
-
-Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",Strength
-UBE3A (HGNC:12496),PP1,Moderate,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-3-4 informative meiosis.
-
-
-Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",Strength
-UBE3A (HGNC:12496),PP1,Supporting,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-2 informative meiosis.
-
-
-Note: individuals must have disease consistent with reported phenotype (even if on the mild end of spectrum of the disease).",Strength
-UBE3A (HGNC:12496),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-UBE3A (HGNC:12496),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-UBE3A (HGNC:12496),PP3,Supporting,"For missense variants use REVEL with a score ≥ 0.75.
-
-
-For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site).",None
-UBE3A (HGNC:12496),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-UBE3A (HGNC:12496),PP4,Supporting,"Phenotype specific for disease with single genetic etiology.
-
-
-
-
-See gene specific clinical phenotype guidelines.",Disease-specific
-UBE3A (HGNC:12496),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-UBE3A (HGNC:12496),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-UBE3A (HGNC:12496),BA1,Stand Alone,"Allele frequency above 0.05%.
-
-
-
-
-Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-UBE3A (HGNC:12496),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-UBE3A (HGNC:12496),BS1,Strong,"Allele frequency greater than expected for disease (0.025%).
-
-
-
-
-Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-UBE3A (HGNC:12496),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-UBE3A (HGNC:12496),BS2,Strong,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-4 unaffected (related and maternally inherited or unrelated) Het (UBE3A).",Strength
-UBE3A (HGNC:12496),BS2,Supporting,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-2 unaffected (related and maternally inherited or unrelated) Het (UBE3A),",Strength
-UBE3A (HGNC:12496),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-UBE3A (HGNC:12496),BS3,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.
-
-
-
-
-RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.
-
-
-Not applicable for these genes for other functional studies (see tables for other accepted functional studies).",Disease-specific
-UBE3A (HGNC:12496),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-UBE3A (HGNC:12496),BS4,Strong,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member, when seen in two or more families.
-
-
-Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",Strength
-UBE3A (HGNC:12496),BS4,Supporting,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member.
-
-
-Need to confirm that the family member is 'affected with a neurodevelopmental phenotype consistent with the gene' at a minimum.",Strength
-UBE3A (HGNC:12496),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-UBE3A (HGNC:12496),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-UBE3A (HGNC:12496),BP2,Supporting,"Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.
-
-
-
-
-BP2 is not applicable for SLC9A6, UBE3A and CDKL5 for in trans state.",Disease-specific
-UBE3A (HGNC:12496),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-UBE3A (HGNC:12496),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-UBE3A (HGNC:12496),BP4,Supporting,"For missense variants use REVEL with a score ≤ 0.15.
-
-
-For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site).",None
-UBE3A (HGNC:12496),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-UBE3A (HGNC:12496),BP5,Strong,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-≥3 cases with alternate molecular basis for disease.",Strength
-UBE3A (HGNC:12496),BP5,Supporting,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-Variant should also be maternally inherited in the case with an alternate molecular basis for disease for this criteria to be used.
-
-
-Do not apply for any gene if variant is de novo.",Disease-specific
-UBE3A (HGNC:12496),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-UBE3A (HGNC:12496),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-UBE3A (HGNC:12496),BP7,Supporting,"A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
-
-
-
-
-Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",None
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDKL5Version3.0.0_version=3.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDKL5Version3.0.0_version=3.0.0.csv
deleted file mode 100644
index 08827f84a4d48e3be3a2fd6deb42d66cec1364f4..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDKL5Version3.0.0_version=3.0.0.csv
+++ /dev/null
@@ -1,306 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-CDKL5 (HGNC:11411),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-CDKL5 (HGNC:11411),PVS1,Very Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-Use as defined by ClinGen SVI working group (PMID:30192042).
-
-
-PVS1 is applicable up to p.R948 
-when using the major brain isoform which has an alternative C-terminus (NM_001323289.2)
-, for canonical splice site variants predicted to result in an out-of-frame product, for canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exons 7, 10, 13), and for the non-coding CDKL5 exon (exon 1).",Disease-specific
-CDKL5 (HGNC:11411),PVS1,Moderate,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Moderate is applicable for any truncating variant distal of p.R948.(
-when using the major brain isoform, NM_001323289.2
-) and for canonical splice site variants that flank exon 17 (in-frame exon).",Disease-specific
-CDKL5 (HGNC:11411),PVS1,Supporting,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Supporting is applicable for initiation codon variants in 
-CDKL5.",Disease-specific
-CDKL5 (HGNC:11411),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-CDKL5 (HGNC:11411),PS1,Strong,Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.,None
-CDKL5 (HGNC:11411),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-CDKL5 (HGNC:11411),PS2,Very Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-≥2 independent occurrences of PS2.
-
-
-≥2 independent occurrences of PM6 and one occurrence of PS2.",No change
-CDKL5 (HGNC:11411),PS2,Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\
-
-
-
-
-1 occurrence of PS2.",None
-CDKL5 (HGNC:11411),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-CDKL5 (HGNC:11411),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an out-offrame transcript.
-
-
-Do not use for canonical splice site variants and when PVS1 is used.",Disease-specific
-CDKL5 (HGNC:11411),PS3,Supporting,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).
-
-
-See included table for acceptable functional studies.",Disease-specific
-CDKL5 (HGNC:11411),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-CDKL5 (HGNC:11411),PS4,Strong,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-5+ observations.",Strength
-CDKL5 (HGNC:11411),PS4,Moderate,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-3-4 observations.",Strength
-CDKL5 (HGNC:11411),PS4,Supporting,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-Use for 2nd independent occurrence.",Strength
-CDKL5 (HGNC:11411),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-CDKL5 (HGNC:11411),PM1,Moderate,"Located in a mutational hot spot and/or critical and well-established functional domain.
-
-
-
-
-ATP binding region: aa 19-43; TEY phosphorylation site: aa 169-171
-1
-,
-4
-,
-2
-,
-3",Disease-specific
-CDKL5 (HGNC:11411),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-CDKL5 (HGNC:11411),PM2,Supporting,"Absent/rare from controls in an ethnically-matched cohort population sample.
-
-
-
-
-Use if absent, zero observations in control databases.",Strength
-CDKL5 (HGNC:11411),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-CDKL5 (HGNC:11411),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-CDKL5 (HGNC:11411),PM4,Moderate,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Do not use for in-frame deletions/insertions in CDKL5 C-terminus (exons 19-21, or after p.904) (when using the NM_003159.2 transcript).",Disease-specific
-CDKL5 (HGNC:11411),PM4,Supporting,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",Strength
-CDKL5 (HGNC:11411),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-CDKL5 (HGNC:11411),PM5,Strong,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-≥2 different missense changes affecting the amino acid residue.
-
-
-Do not apply PM1 in these situations.",Strength
-CDKL5 (HGNC:11411),PM5,Moderate,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-Applicable to all genes as written.
-
-
-A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",None
-CDKL5 (HGNC:11411),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-CDKL5 (HGNC:11411),PM6,Very Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",Strength
-CDKL5 (HGNC:11411),PM6,Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥2 independent occurrences of PM6.
-
-
-Evidence from literature must be fully evaluated to support independent events.",Strength
-CDKL5 (HGNC:11411),PM6,Moderate,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-1 occurrence of PM6.",None
-CDKL5 (HGNC:11411),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-CDKL5 (HGNC:11411),PP1,Strong,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-≥5 informative meiosis",Strength
-CDKL5 (HGNC:11411),PP1,Moderate,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-3-4 informative meiosis",Strength
-CDKL5 (HGNC:11411),PP1,Supporting,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-2 informative meiosis",Strength
-CDKL5 (HGNC:11411),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-CDKL5 (HGNC:11411),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-CDKL5 (HGNC:11411),PP3,Supporting,"For missense variants use REVEL with a score ≥ 0.75.
-
-
-For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site).",None
-CDKL5 (HGNC:11411),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-CDKL5 (HGNC:11411),PP4,Supporting,"Phenotype specific for disease with single genetic etiology.
-
-
-
-
-See gene specific clinical phenotype guidelines.",Disease-specific
-CDKL5 (HGNC:11411),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-CDKL5 (HGNC:11411),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-CDKL5 (HGNC:11411),BA1,Stand Alone,"Allele frequency above 0.05%.
-
-
-
-
-Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-CDKL5 (HGNC:11411),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-CDKL5 (HGNC:11411),BS1,Strong,"Allele frequency greater than expected for disease (0.025%).
-
-
-
-
-Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-CDKL5 (HGNC:11411),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-CDKL5 (HGNC:11411),BS2,Strong,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-2 unaffected (related or unrelated) heterozygotes or hemizygotes",Strength
-CDKL5 (HGNC:11411),BS2,Supporting,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-1 unaffected (related or unrelated) heterozygote or hemizygote",Strength
-CDKL5 (HGNC:11411),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-CDKL5 (HGNC:11411),BS3,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.
-
-
-
-
-RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.
-
-
-Not applicable for these genes for other functional studies (see tables for other accepted functional studies).",Disease-specific
-CDKL5 (HGNC:11411),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-CDKL5 (HGNC:11411),BS4,Strong,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member, when seen in two or more families",Strength
-CDKL5 (HGNC:11411),BS4,Supporting,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member",Strength
-CDKL5 (HGNC:11411),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-CDKL5 (HGNC:11411),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-CDKL5 (HGNC:11411),BP2,Supporting,"Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.
-
-
-
-
-BP2 is not applicable for 
-in trans
- state.",Disease-specific
-CDKL5 (HGNC:11411),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-CDKL5 (HGNC:11411),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-CDKL5 (HGNC:11411),BP4,Supporting,"For missense variants use REVEL with a score ≤ 0.15.
-
-
-For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site).",None
-CDKL5 (HGNC:11411),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-CDKL5 (HGNC:11411),BP5,Strong,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-≥3 cases with alternate molecular basis for disease.",Strength
-CDKL5 (HGNC:11411),BP5,Supporting,Variant found in a case with an alternate molecular basis for disease.,Disease-specific
-CDKL5 (HGNC:11411),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-CDKL5 (HGNC:11411),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-CDKL5 (HGNC:11411),BP7,Supporting,"A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
-
-
-
-
-Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",None
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDKL5Version4.0.0_version=4.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDKL5Version4.0.0_version=4.0.0.csv
deleted file mode 100644
index 21724ecf841aa6c62c7d521ffbd9a1d0492d66ab..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDKL5Version4.0.0_version=4.0.0.csv
+++ /dev/null
@@ -1,369 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-CDKL5 (HGNC:11411),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-CDKL5 (HGNC:11411),PVS1,Very Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-Use as defined by ClinGen SVI working group (PMID:30192042).
-
-
-PVS1 is applicable for:
-
-
-Null variants up to p.R948 
-when using the major brain isoform which has an alternative C-terminus (NM_001323289.2)
-
-
-Frameshift variants that result in a read-through of the stop codon
-
-
-Canonical splice site variants predicted to result in an out-of-frame product
-
-
-Canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exons 7, 10, 13) and for the non-coding CDKL5 exon (exon 1) 
-(NM_001323289.2).
-
-
-In-frame deletions including the PM1 functional domains (p.V19_K43 ATP binding domain or p.T169_Y171 TEY phosphorylation domain)
-
-
-Deletions and duplications ≥1 exon in size (that are completely contained within the CDKL5 gene) where the reading frame is disrupted and NMD is predicted to occur
-
-
-A full gene deletion",Disease-specific
-CDKL5 (HGNC:11411),PVS1,Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Strong is applicable for:
-
-
-Cannonical splice site variants that flank exon 18 
-(the final exon of NM_001323289.2)
-
-
-Single to multi exon deletions that disrupt the reading frame such that exon 18 
-(the final exon of NM_001323289.2)
- is truncated/altered
-
-
-Duplications ≥1 exon in size (that are completely contained within the CDKL5 gene) where the reading frame is presumed to be disrupted and NMD is predicted to occur",Disease-specific
-CDKL5 (HGNC:11411),PVS1,Moderate,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Moderate is applicable for:
-
-
-Any truncating variant distal of p.R948 (
-when using the major brain isoform, NM_001323289.2
-)
-
-
-Canonical splice site variants that flank exon 17 (in-frame exon) (
-NM_001323289.2
-)","Disease-specific,Strength"
-CDKL5 (HGNC:11411),PVS1,Supporting,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Supporting is applicable for initiation codon variants in 
-CDKL5.","Disease-specific,Strength"
-CDKL5 (HGNC:11411),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-CDKL5 (HGNC:11411),PS1,Strong,Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.,None
-CDKL5 (HGNC:11411),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-CDKL5 (HGNC:11411),PS2,Very Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-≥2 independent occurrences of PS2.
-
-
-≥2 independent occurrences of PM6 and one occurrence of PS2.",No change
-CDKL5 (HGNC:11411),PS2,Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-1 occurrence of PS2.",None
-CDKL5 (HGNC:11411),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-CDKL5 (HGNC:11411),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an out-offrame transcript.
-
-
-Do not use for canonical splice site variants and when PVS1 is used.",Disease-specific
-CDKL5 (HGNC:11411),PS3,Supporting,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).
-
-
-See included table for acceptable functional studies.",Disease-specific
-CDKL5 (HGNC:11411),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-CDKL5 (HGNC:11411),PS4,Strong,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-5+ observations.",Strength
-CDKL5 (HGNC:11411),PS4,Moderate,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-3-4 observations.",Strength
-CDKL5 (HGNC:11411),PS4,Supporting,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-Use for 2nd independent occurrence.",Strength
-CDKL5 (HGNC:11411),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-CDKL5 (HGNC:11411),PM1,Moderate,"Located in a mutational hot spot and/or critical and well-established functional domain.
-
-
-
-
-ATP binding region: aa 19-43; TEY phosphorylation site: aa 169-171
-1
-,
-4
-,
-2
-,
-3",Disease-specific
-CDKL5 (HGNC:11411),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-CDKL5 (HGNC:11411),PM2,Supporting,"Absent/rare from controls in an ethnically-matched cohort population sample.
-
-
-
-
-Use if absent, zero observations in control databases.",Strength
-CDKL5 (HGNC:11411),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-CDKL5 (HGNC:11411),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-CDKL5 (HGNC:11411),PM4,Moderate,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Do not use for in-frame deletions/insertions in CDKL5 C-terminus (exons 19-21, or after p.P904) 
-(when using the NM_003159.2 transcript)
-.",Disease-specific
-CDKL5 (HGNC:11411),PM4,Supporting,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",Strength
-CDKL5 (HGNC:11411),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-CDKL5 (HGNC:11411),PM5,Strong,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-≥2 different missense changes affecting the amino acid residue.
-
-
-Do not apply PM1 in these situations.",Strength
-CDKL5 (HGNC:11411),PM5,Moderate,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-Applicable to all genes as written.
-
-
-A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",None
-CDKL5 (HGNC:11411),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-CDKL5 (HGNC:11411),PM6,Very Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",Strength
-CDKL5 (HGNC:11411),PM6,Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥2 independent occurrences of PM6.
-
-
-Evidence from literature must be fully evaluated to support independent events.",Strength
-CDKL5 (HGNC:11411),PM6,Moderate,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-1 occurrence of PM6.",None
-CDKL5 (HGNC:11411),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-CDKL5 (HGNC:11411),PP1,Strong,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-≥5 informative meiosis",Strength
-CDKL5 (HGNC:11411),PP1,Moderate,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-3-4 informative meiosis",Strength
-CDKL5 (HGNC:11411),PP1,Supporting,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-2 informative meiosis",Strength
-CDKL5 (HGNC:11411),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-CDKL5 (HGNC:11411),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-CDKL5 (HGNC:11411),PP3,Supporting,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-
-
-
-
-For missense variants use REVEL with a score ≥ 0.644.
-
-
-For splice site variants use SpliceAI with a score ≥ 0.2.",General recommendation
-CDKL5 (HGNC:11411),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-CDKL5 (HGNC:11411),PP4,Supporting,"Phenotype specific for disease with single genetic etiology.
-
-
-
-
-See gene specific clinical phenotype guidelines.",Disease-specific
-CDKL5 (HGNC:11411),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-CDKL5 (HGNC:11411),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-CDKL5 (HGNC:11411),BA1,Stand Alone,"Allele frequency above 0.05%.
-
-
-
-
-Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-CDKL5 (HGNC:11411),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-CDKL5 (HGNC:11411),BS1,Strong,"Allele frequency greater than expected for disease (0.025%).
-
-
-
-
-Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-CDKL5 (HGNC:11411),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-CDKL5 (HGNC:11411),BS2,Strong,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-2 unaffected (related or unrelated) heterozygotes or hemizygotes",Strength
-CDKL5 (HGNC:11411),BS2,Supporting,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-1 unaffected (related or unrelated) heterozygote or hemizygote",Strength
-CDKL5 (HGNC:11411),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-CDKL5 (HGNC:11411),BS3,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.
-
-
-
-
-RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.
-
-
-Not applicable for other functional studies.",Disease-specific
-CDKL5 (HGNC:11411),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-CDKL5 (HGNC:11411),BS4,Strong,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member, when seen in two or more families",Strength
-CDKL5 (HGNC:11411),BS4,Supporting,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member",Strength
-CDKL5 (HGNC:11411),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-CDKL5 (HGNC:11411),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-CDKL5 (HGNC:11411),BP2,Supporting,"Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.
-
-
-
-
-BP2 is not applicable for 
-in trans
- state.",Disease-specific
-CDKL5 (HGNC:11411),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-CDKL5 (HGNC:11411),BP3,Supporting,"In-frame deletions/insertions in a repetitive region without a known function. 
-
-
-
-
-BP3 is applicable if there are in-frame deletions/duplications in a repetitive region where other in-frame deletions/duplications have been observed with an overall frequency commensurate with the BA1 threshold for this gene.",None
-CDKL5 (HGNC:11411),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-CDKL5 (HGNC:11411),BP4,Supporting,"For missense variants use REVEL with a score ≤ 0.290.
-
-
-For splice site variants use SpliceAI with a score ≤ 0.1.",General recommendation
-CDKL5 (HGNC:11411),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-CDKL5 (HGNC:11411),BP5,Strong,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-≥3 cases with alternate molecular basis for disease.",Strength
-CDKL5 (HGNC:11411),BP5,Supporting,Variant found in a case with an alternate molecular basis for disease.,Disease-specific
-CDKL5 (HGNC:11411),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-CDKL5 (HGNC:11411),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-CDKL5 (HGNC:11411),BP7,Supporting,"A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
-
-
-
-
-Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.
-
-
-For splice site variants use SpliceAI with a score ≤ 0.1.",None
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDKL5Version4.1.0_version=4.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDKL5Version4.1.0_version=4.1.0.csv
deleted file mode 100644
index e0b5e3feda22c2553b49120b825d8f61b77c462c..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDKL5Version4.1.0_version=4.1.0.csv
+++ /dev/null
@@ -1,380 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-CDKL5 (HGNC:11411),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-CDKL5 (HGNC:11411),PVS1,Very Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-Use as defined by ClinGen SVI working group (PMID:30192042).
-
-
-PVS1 is applicable for:
-
-
-Null variants up to p.R948 
-when using the major brain isoform which has an alternative C-terminus (NM_001323289.2)
-
-
-Frameshift variants that result in a read-through of the stop codon
-
-
-Canonical splice site variants predicted to result in an out-of-frame product
-
-
-Canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exons 7, 10, 13) and for the non-coding CDKL5 exon (exon 1) 
-(NM_001323289.2).
-
-
-In-frame deletions including the PM1 functional domains (p.V19_K43 ATP binding domain or p.T169_Y171 TEY phosphorylation domain)
-
-
-Deletions and duplications ≥1 exon in size (that are completely contained within the CDKL5 gene) where the reading frame is disrupted and NMD is predicted to occur
-
-
-A full gene deletion",Disease-specific
-CDKL5 (HGNC:11411),PVS1,Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Strong is applicable for:
-
-
-Cannonical splice site variants that flank exon 18 
-(the final exon of NM_001323289.2)
-
-
-Single to multi exon deletions that disrupt the reading frame such that exon 18 
-(the final exon of NM_001323289.2)
- is truncated/altered
-
-
-Duplications ≥1 exon in size (that are completely contained within the CDKL5 gene) where the reading frame is presumed to be disrupted and NMD is predicted to occur",Disease-specific
-CDKL5 (HGNC:11411),PVS1,Moderate,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Moderate is applicable for:
-
-
-Any truncating variant distal of p.R948 (
-when using the major brain isoform, NM_001323289.2
-)
-
-
-Canonical splice site variants that flank exon 17 (in-frame exon) (
-NM_001323289.2
-)","Disease-specific,Strength"
-CDKL5 (HGNC:11411),PVS1,Supporting,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Supporting is applicable for initiation codon variants in 
-CDKL5.","Disease-specific,Strength"
-CDKL5 (HGNC:11411),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-CDKL5 (HGNC:11411),PS1,Strong,Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.,None
-CDKL5 (HGNC:11411),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-CDKL5 (HGNC:11411),PS2,Very Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-≥2 independent occurrences of PS2.
-
-
-≥2 independent occurrences of PM6 and one occurrence of PS2.",No change
-CDKL5 (HGNC:11411),PS2,Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-1 occurrence of PS2.",None
-CDKL5 (HGNC:11411),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-CDKL5 (HGNC:11411),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an out-offrame transcript.
-
-
-Do not use for canonical splice site variants and when PVS1 is used.",Disease-specific
-CDKL5 (HGNC:11411),PS3,Supporting,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).
-
-
-See included table for acceptable functional studies.",Disease-specific
-CDKL5 (HGNC:11411),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-CDKL5 (HGNC:11411),PS4,Strong,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-5+ observations.",Strength
-CDKL5 (HGNC:11411),PS4,Moderate,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-3-4 observations.",Strength
-CDKL5 (HGNC:11411),PS4,Supporting,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-Use for 2nd independent occurrence.",Strength
-CDKL5 (HGNC:11411),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-CDKL5 (HGNC:11411),PM1,Moderate,"Located in a mutational hot spot and/or critical and well-established functional domain.
-
-
-
-
-ATP binding region: aa 19-43; TEY phosphorylation site: aa 169-171
-1
-,
-4
-,
-2
-,
-3",Disease-specific
-CDKL5 (HGNC:11411),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-CDKL5 (HGNC:11411),PM2,Supporting,"Absent/rare from controls in an ethnically-matched cohort population sample.
-
-
-
-
-Use if absent, zero observations in control databases.",Strength
-CDKL5 (HGNC:11411),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-CDKL5 (HGNC:11411),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-CDKL5 (HGNC:11411),PM4,Moderate,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Do not use for in-frame deletions/insertions in CDKL5 C-terminus (exons 19-21, or after p.P904) 
-(when using the NM_003159.2 transcript)
-.",Disease-specific
-CDKL5 (HGNC:11411),PM4,Supporting,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",Strength
-CDKL5 (HGNC:11411),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-CDKL5 (HGNC:11411),PM5,Strong,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-≥2 different missense changes affecting the amino acid residue.
-
-
-Do not apply PM1 in these situations.",Strength
-CDKL5 (HGNC:11411),PM5,Moderate,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-Applicable to all genes as written.
-
-
-A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",None
-CDKL5 (HGNC:11411),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-CDKL5 (HGNC:11411),PM6,Very Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",Strength
-CDKL5 (HGNC:11411),PM6,Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥2 independent occurrences of PM6.
-
-
-Evidence from literature must be fully evaluated to support independent events.",Strength
-CDKL5 (HGNC:11411),PM6,Moderate,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-1 occurrence of PM6.",None
-CDKL5 (HGNC:11411),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-CDKL5 (HGNC:11411),PP1,Strong,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-≥5 informative meiosis",Strength
-CDKL5 (HGNC:11411),PP1,Moderate,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-3-4 informative meiosis",Strength
-CDKL5 (HGNC:11411),PP1,Supporting,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-2 informative meiosis",Strength
-CDKL5 (HGNC:11411),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-CDKL5 (HGNC:11411),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-CDKL5 (HGNC:11411),PP3,Supporting,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-
-
-
-
-For missense variants use REVEL with a score ≥ 0.644.
-
-
-For splice site variants use SpliceAI with a score ≥ 0.2.",General recommendation
-CDKL5 (HGNC:11411),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-CDKL5 (HGNC:11411),PP4,Supporting,"Phenotype specific for disease with single genetic etiology.
-
-
-
-
-See gene specific clinical phenotype guidelines.",Disease-specific
-CDKL5 (HGNC:11411),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-CDKL5 (HGNC:11411),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-CDKL5 (HGNC:11411),BA1,Stand Alone,"Allele frequency above 0.05%.
-
-
-
-
-Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-CDKL5 (HGNC:11411),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-CDKL5 (HGNC:11411),BS1,Strong,"Allele frequency greater than expected for disease (0.025%).
-
-
-
-
-Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-CDKL5 (HGNC:11411),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-CDKL5 (HGNC:11411),BS2,Strong,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-2 unaffected (related or unrelated) heterozygotes or hemizygotes",Strength
-CDKL5 (HGNC:11411),BS2,Supporting,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-1 unaffected (related or unrelated) heterozygote or hemizygote",Strength
-CDKL5 (HGNC:11411),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-CDKL5 (HGNC:11411),BS3,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.
-
-
-
-
-RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.
-
-
-Not applicable for other functional studies.",Disease-specific
-CDKL5 (HGNC:11411),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-CDKL5 (HGNC:11411),BS4,Strong,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member, when seen in two or more families",Strength
-CDKL5 (HGNC:11411),BS4,Supporting,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member",Strength
-CDKL5 (HGNC:11411),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-CDKL5 (HGNC:11411),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-CDKL5 (HGNC:11411),BP2,Supporting,"Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.
-
-
-
-
-BP2 is not applicable for 
-in trans
- state.",Disease-specific
-CDKL5 (HGNC:11411),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-CDKL5 (HGNC:11411),BP3,Supporting,"In-frame deletions/insertions in a repetitive region without a known function. 
-
-
-
-
-BP3 is applicable if there are in-frame deletions/duplications in a repetitive region where other in-frame deletions/duplications have been observed with an overall frequency commensurate with the BA1 threshold for this gene.",None
-CDKL5 (HGNC:11411),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-CDKL5 (HGNC:11411),BP4,Supporting,"For missense variants use REVEL with a score ≤ 0.290.
-
-
-For splice site variants use SpliceAI with a score ≤ 0.1.",General recommendation
-CDKL5 (HGNC:11411),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-CDKL5 (HGNC:11411),BP5,Strong,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-≥3 cases with alternate molecular basis for disease.",Strength
-CDKL5 (HGNC:11411),BP5,Moderate,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-2 cases with alternate molecular basis for disease.",Strength
-CDKL5 (HGNC:11411),BP5,Supporting,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-1 case with alternate molecular basis for disease.",Disease-specific
-CDKL5 (HGNC:11411),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-CDKL5 (HGNC:11411),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-CDKL5 (HGNC:11411),BP7,Supporting,"A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
-
-
-
-
-Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.
-
-
-For splice site variants use SpliceAI with a score ≤ 0.1.",None
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforFOXG1Version3.0.0_version=3.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforFOXG1Version3.0.0_version=3.0.0.csv
deleted file mode 100644
index a2ab3d0a44caee76abcc630363138c1fe41ddfcc..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforFOXG1Version3.0.0_version=3.0.0.csv
+++ /dev/null
@@ -1,315 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-FOXG1 (HGNC:3811),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-FOXG1 (HGNC:3811),PVS1,Very Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-Use as defined by ClinGen SVI working group (PMID:30192042).
-
-
-PVS1 is applicable up to p.S468
-1",Disease-specific
-FOXG1 (HGNC:3811),PVS1,Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Strong is applicable for any truncating variant from p.G469 to p.Q480
-6
-.",Disease-specific
-FOXG1 (HGNC:3811),PVS1,Moderate,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Moderate is applicable for any truncating variant distal of p.Q480.",Disease-specific
-FOXG1 (HGNC:3811),PVS1,Supporting,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Supporting is applicable for initiation codon variants in 
-FOXG1.",Disease-specific
-FOXG1 (HGNC:3811),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-FOXG1 (HGNC:3811),PS1,Strong,Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.,None
-FOXG1 (HGNC:3811),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-FOXG1 (HGNC:3811),PS2,Very Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-≥2 independent occurrences of PS2.
-
-
-≥2 independent occurrences of PM6 and one occurrence of PS2.
-
-
-Evidence from literature must be fully evaluated to support independent events.",None
-FOXG1 (HGNC:3811),PS2,Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-1 occurrence of PS2.",None
-FOXG1 (HGNC:3811),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-FOXG1 (HGNC:3811),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an out-of-frame transcript.
-
-
-Do not use for canonical splice site variants and when PVS1 is used.",Disease-specific
-FOXG1 (HGNC:3811),PS3,Supporting,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).
-
-
-See included table for acceptable functional studies.",Disease-specific
-FOXG1 (HGNC:3811),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-FOXG1 (HGNC:3811),PS4,Strong,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-5+ observations.",Strength
-FOXG1 (HGNC:3811),PS4,Moderate,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-3-4 observations.",Strength
-FOXG1 (HGNC:3811),PS4,Supporting,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-Use for 2nd independent occurrence.",Strength
-FOXG1 (HGNC:3811),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-FOXG1 (HGNC:3811),PM1,Moderate,"Located in a mutational hot spot and/or critical and well-established functional domain.
-
-
-
-
-Forkhead: aa 181-275
-7
-,
-8",Disease-specific
-FOXG1 (HGNC:3811),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-FOXG1 (HGNC:3811),PM2,Supporting,"Absent/rare from controls in an ethnically-matched cohort population sample.
-
-
-
-
-Use if absent, zero observations in control databases.",Strength
-FOXG1 (HGNC:3811),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-FOXG1 (HGNC:3811),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-FOXG1 (HGNC:3811),PM4,Moderate,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Do not use PM4 for in-frame deletions/insertions in the Histidine-rich region (p.37-p.57), Proline- and Glutamine-rich region (p.58-p.86) and Proline-rich region (p.105-p.112).",Disease-specific
-FOXG1 (HGNC:3811),PM4,Supporting,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",Strength
-FOXG1 (HGNC:3811),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-FOXG1 (HGNC:3811),PM5,Strong,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-≥2 different missense changes affecting the amino acid residue.
-
-
-Do not apply PM1 in these situations.",Strength
-FOXG1 (HGNC:3811),PM5,Moderate,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",None
-FOXG1 (HGNC:3811),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-FOXG1 (HGNC:3811),PM6,Very Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",Strength
-FOXG1 (HGNC:3811),PM6,Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥2 independent occurrences of PM6.
-
-
-Evidence from literature must be fully evaluated to support independent events.",Strength
-FOXG1 (HGNC:3811),PM6,Moderate,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-1 occurrence of PM6.",None
-FOXG1 (HGNC:3811),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-FOXG1 (HGNC:3811),PP1,Strong,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-≥5 informative meiosis",Strength
-FOXG1 (HGNC:3811),PP1,Moderate,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-3-4 informative meiosis",Strength
-FOXG1 (HGNC:3811),PP1,Supporting,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-2 informative meiosis",Strength
-FOXG1 (HGNC:3811),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-FOXG1 (HGNC:3811),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-FOXG1 (HGNC:3811),PP3,Supporting,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product.
-
-
-
-
-For missense variants use REVEL with a score ≥ 0.75.
-
-
-For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site).",General recommendation
-FOXG1 (HGNC:3811),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-FOXG1 (HGNC:3811),PP4,Supporting,"Phenotype specific for disease with single genetic etiology.
-
-
-
-
-See gene specific clinical phenotype guidelines.",Disease-specific
-FOXG1 (HGNC:3811),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-FOXG1 (HGNC:3811),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-FOXG1 (HGNC:3811),BA1,Stand Alone,"Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-FOXG1 (HGNC:3811),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-FOXG1 (HGNC:3811),BS1,Strong,"Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-FOXG1 (HGNC:3811),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-FOXG1 (HGNC:3811),BS2,Strong,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-2 unaffected (related or unrelated) heterozygotes.",Strength
-FOXG1 (HGNC:3811),BS2,Supporting,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-1 unaffected (related or unrelated) heterozygote",Strength
-FOXG1 (HGNC:3811),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-FOXG1 (HGNC:3811),BS3,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.
-
-
-
-
-RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.
-
-
-Not applicable for these genes for other functional studies (see tables for other accepted functional studies).",Disease-specific
-FOXG1 (HGNC:3811),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-FOXG1 (HGNC:3811),BS4,Strong,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member, when seen in two or more families",Strength
-FOXG1 (HGNC:3811),BS4,Supporting,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member",Strength
-FOXG1 (HGNC:3811),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-FOXG1 (HGNC:3811),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-FOXG1 (HGNC:3811),BP2,Supporting,"Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.
-
-
-
-
-Applicable for 
-in trans
- state",Disease-specific
-FOXG1 (HGNC:3811),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-FOXG1 (HGNC:3811),BP3,Supporting,"In-frame deletions/insertions in a repetitive region without a known function
-
-
-
-
-Inframe expansions or deletions in 
-FOXG1
- repetitive regions: poly His (p.His47-p.His57), poly Gln (p.Gln70-p.Gln73) and poly Pro (p.Pro58-p.Pro61; p.Pro65-p.Pro69; p.Pro74-p.Pro80)",Disease-specific
-FOXG1 (HGNC:3811),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-FOXG1 (HGNC:3811),BP4,Supporting,"For missense variants use REVEL with a score ≤ 0.15.
-
-
-For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site).",None
-FOXG1 (HGNC:3811),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-FOXG1 (HGNC:3811),BP5,Strong,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-≥3 cases with alternate molecular basis for disease.",Strength
-FOXG1 (HGNC:3811),BP5,Supporting,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-1-2 cases with alternate molecular basis for disease.",Disease-specific
-FOXG1 (HGNC:3811),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-FOXG1 (HGNC:3811),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-FOXG1 (HGNC:3811),BP7,Supporting,"A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
-
-
-
-
-Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",None
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforFOXG1Version4.0.0_version=4.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforFOXG1Version4.0.0_version=4.0.0.csv
deleted file mode 100644
index 9b608c1570f048d7f977e3c2b0d324ce392c6d4e..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforFOXG1Version4.0.0_version=4.0.0.csv
+++ /dev/null
@@ -1,327 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-FOXG1 (HGNC:3811),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-FOXG1 (HGNC:3811),PVS1,Very Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-Use as defined by ClinGen SVI working group (PMID:30192042).
-
-
-PVS1 is applicable up to p.S468
-1",Disease-specific
-FOXG1 (HGNC:3811),PVS1,Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Strong is applicable for any truncating variant from p.G469 to p.Q480
-6
-.",Disease-specific
-FOXG1 (HGNC:3811),PVS1,Moderate,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Moderate is applicable for any truncating variant distal of p.Q480.",Disease-specific
-FOXG1 (HGNC:3811),PVS1,Supporting,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Supporting is applicable for initiation codon variants in 
-FOXG1.",Disease-specific
-FOXG1 (HGNC:3811),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-FOXG1 (HGNC:3811),PS1,Strong,Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.,None
-FOXG1 (HGNC:3811),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-FOXG1 (HGNC:3811),PS2,Very Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-≥2 independent occurrences of PS2.
-
-
-≥2 independent occurrences of PM6 and one occurrence of PS2.
-
-
-Evidence from literature must be fully evaluated to support independent events.",None
-FOXG1 (HGNC:3811),PS2,Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-1 occurrence of PS2.",None
-FOXG1 (HGNC:3811),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-FOXG1 (HGNC:3811),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an out-of-frame transcript.
-
-
-Do not use for canonical splice site variants and when PVS1 is used.",Disease-specific
-FOXG1 (HGNC:3811),PS3,Supporting,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).
-
-
-See included table for acceptable functional studies.",Disease-specific
-FOXG1 (HGNC:3811),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-FOXG1 (HGNC:3811),PS4,Strong,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-5+ observations.",Strength
-FOXG1 (HGNC:3811),PS4,Moderate,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-3-4 observations.",Strength
-FOXG1 (HGNC:3811),PS4,Supporting,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-Use for 2nd independent occurrence.",Strength
-FOXG1 (HGNC:3811),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-FOXG1 (HGNC:3811),PM1,Moderate,"Located in a mutational hot spot and/or critical and well-established functional domain.
-
-
-
-
-Forkhead: aa 181-275
-3
-,
-4",Disease-specific
-FOXG1 (HGNC:3811),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-FOXG1 (HGNC:3811),PM2,Supporting,"Absent/rare from controls in an ethnically-matched cohort population sample.
-
-
-
-
-Use if absent, zero observations in control databases.",Strength
-FOXG1 (HGNC:3811),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-FOXG1 (HGNC:3811),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-FOXG1 (HGNC:3811),PM4,Moderate,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Do not use PM4 for in-frame deletions/insertions in the Histidine-rich region (p.37-p.57), Proline- and Glutamine-rich region (p.58-p.86) and Proline-rich region (p.105-p.112).",Disease-specific
-FOXG1 (HGNC:3811),PM4,Supporting,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",Strength
-FOXG1 (HGNC:3811),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-FOXG1 (HGNC:3811),PM5,Strong,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-≥2 different missense changes affecting the amino acid residue.
-
-
-Do not apply PM1 in these situations.",Strength
-FOXG1 (HGNC:3811),PM5,Moderate,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",None
-FOXG1 (HGNC:3811),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-FOXG1 (HGNC:3811),PM6,Very Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",Strength
-FOXG1 (HGNC:3811),PM6,Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥2 independent occurrences of PM6.
-
-
-Evidence from literature must be fully evaluated to support independent events.",Strength
-FOXG1 (HGNC:3811),PM6,Moderate,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-1 occurrence of PM6.",None
-FOXG1 (HGNC:3811),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-FOXG1 (HGNC:3811),PP1,Strong,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-≥5 informative meiosis",Strength
-FOXG1 (HGNC:3811),PP1,Moderate,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-3-4 informative meiosis",Strength
-FOXG1 (HGNC:3811),PP1,Supporting,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-2 informative meiosis",Strength
-FOXG1 (HGNC:3811),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-FOXG1 (HGNC:3811),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-FOXG1 (HGNC:3811),PP3,Supporting,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product.
-
-
-
-
-For missense variants use REVEL with a score ≥ 0.644.
-
-
-For splice site variants use SpliceAI with a score ≥ 0.2.",General recommendation
-FOXG1 (HGNC:3811),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-FOXG1 (HGNC:3811),PP4,Supporting,"Phenotype specific for disease with single genetic etiology.
-
-
-
-
-See gene specific clinical phenotype guidelines.",Disease-specific
-FOXG1 (HGNC:3811),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-FOXG1 (HGNC:3811),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-FOXG1 (HGNC:3811),BA1,Stand Alone,"Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-FOXG1 (HGNC:3811),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-FOXG1 (HGNC:3811),BS1,Strong,"Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-FOXG1 (HGNC:3811),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-FOXG1 (HGNC:3811),BS2,Strong,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-2 unaffected (related or unrelated) heterozygotes.",Strength
-FOXG1 (HGNC:3811),BS2,Supporting,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-1 unaffected (related or unrelated) heterozygote",Strength
-FOXG1 (HGNC:3811),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-FOXG1 (HGNC:3811),BS3,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.
-
-
-
-
-RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.
-
-
-Not applicable for other functional studies.",Disease-specific
-FOXG1 (HGNC:3811),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-FOXG1 (HGNC:3811),BS4,Strong,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member, when seen in two or more families",Strength
-FOXG1 (HGNC:3811),BS4,Supporting,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member",Strength
-FOXG1 (HGNC:3811),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-FOXG1 (HGNC:3811),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-FOXG1 (HGNC:3811),BP2,Supporting,"Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.
-
-
-
-
-Applicable for 
-in trans
- state",Disease-specific
-FOXG1 (HGNC:3811),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-FOXG1 (HGNC:3811),BP3,Supporting,"In-frame deletions/insertions in a repetitive region without a known function
-
-
-
-
-Inframe expansions or deletions in 
-FOXG1
- repetitive regions: poly His (p.His47-p.His57), poly Gln (p.Gln70-p.Gln73) and poly Pro (p.Pro58-p.Pro61; p.Pro65-p.Pro69; p.Pro74-p.Pro80)
-
-
-BP3 is applicable if there are in-frame deletions/duplications in a repetitive region where other in-frame deletions/duplications have been observed with an overall frequency commensurate with the BA1 threshold for this gene.",Disease-specific
-FOXG1 (HGNC:3811),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-FOXG1 (HGNC:3811),BP4,Supporting,"For missense variants use REVEL with a score ≤ 0.290.
-
-
-For splice site variants use SpliceAI with a score ≤ 0.1.",General recommendation
-FOXG1 (HGNC:3811),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-FOXG1 (HGNC:3811),BP5,Strong,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-≥3 cases with alternate molecular basis for disease.",Strength
-FOXG1 (HGNC:3811),BP5,Moderate,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-2 cases with alternate molecular basis for disease.",Strength
-FOXG1 (HGNC:3811),BP5,Supporting,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-1 case with alternate molecular basis for disease.",Disease-specific
-FOXG1 (HGNC:3811),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-FOXG1 (HGNC:3811),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-FOXG1 (HGNC:3811),BP7,Supporting,"A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
-
-
-
-
-Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.
-
-
-For splice site variants use SpliceAI with a score ≤ 0.1.",None
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforFOXG1Version4.1.0_version=4.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforFOXG1Version4.1.0_version=4.1.0.csv
deleted file mode 100644
index 11f3b55c7679db80a99caade0b84cad25ed16671..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforFOXG1Version4.1.0_version=4.1.0.csv
+++ /dev/null
@@ -1,333 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-FOXG1 (HGNC:3811),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-FOXG1 (HGNC:3811),PVS1,Very Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-Use as defined by ClinGen SVI working group (PMID:30192042).
-
-
-PVS1 is applicable for
-
-
-Null variants up to p.S468 
-1
-
-
-A full gene deletion",Disease-specific
-FOXG1 (HGNC:3811),PVS1,Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Strong is applicable for any truncating variant from p.G469 to p.Q480 
-2
-.",Disease-specific
-FOXG1 (HGNC:3811),PVS1,Moderate,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Moderate is applicable for any truncating variant distal of p.Q480.",Disease-specific
-FOXG1 (HGNC:3811),PVS1,Supporting,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Supporting is applicable for initiation codon variants in 
-FOXG1.",Disease-specific
-FOXG1 (HGNC:3811),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-FOXG1 (HGNC:3811),PS1,Strong,Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.,None
-FOXG1 (HGNC:3811),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-FOXG1 (HGNC:3811),PS2,Very Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-≥2 independent occurrences of PS2.
-
-
-≥2 independent occurrences of PM6 and one occurrence of PS2.
-
-
-Evidence from literature must be fully evaluated to support independent events.",None
-FOXG1 (HGNC:3811),PS2,Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-1 occurrence of PS2.",None
-FOXG1 (HGNC:3811),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-FOXG1 (HGNC:3811),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an out-of-frame transcript.
-
-
-Do not use for canonical splice site variants and when PVS1 is used.",Disease-specific
-FOXG1 (HGNC:3811),PS3,Supporting,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).
-
-
-See included table for acceptable functional studies.",Disease-specific
-FOXG1 (HGNC:3811),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-FOXG1 (HGNC:3811),PS4,Strong,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-5+ observations.",Strength
-FOXG1 (HGNC:3811),PS4,Moderate,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-3-4 observations.",Strength
-FOXG1 (HGNC:3811),PS4,Supporting,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-Use for 2nd independent occurrence.",Strength
-FOXG1 (HGNC:3811),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-FOXG1 (HGNC:3811),PM1,Moderate,"Located in a mutational hot spot and/or critical and well-established functional domain.
-
-
-
-
-Forkhead: aa 181-275
-3
-,
-4",Disease-specific
-FOXG1 (HGNC:3811),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-FOXG1 (HGNC:3811),PM2,Supporting,"Absent/rare from controls in an ethnically-matched cohort population sample.
-
-
-
-
-Use if absent, zero observations in control databases.",Strength
-FOXG1 (HGNC:3811),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-FOXG1 (HGNC:3811),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-FOXG1 (HGNC:3811),PM4,Moderate,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Do not use PM4 for in-frame deletions/insertions in the Histidine-rich region (p.37-p.57), Proline- and Glutamine-rich region (p.58-p.86) and Proline-rich region (p.105-p.112).",Disease-specific
-FOXG1 (HGNC:3811),PM4,Supporting,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",Strength
-FOXG1 (HGNC:3811),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-FOXG1 (HGNC:3811),PM5,Strong,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-≥2 different missense changes affecting the amino acid residue.
-
-
-Do not apply PM1 in these situations.",Strength
-FOXG1 (HGNC:3811),PM5,Moderate,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",None
-FOXG1 (HGNC:3811),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-FOXG1 (HGNC:3811),PM6,Very Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",Strength
-FOXG1 (HGNC:3811),PM6,Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥2 independent occurrences of PM6.
-
-
-Evidence from literature must be fully evaluated to support independent events.",Strength
-FOXG1 (HGNC:3811),PM6,Moderate,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-1 occurrence of PM6.",None
-FOXG1 (HGNC:3811),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-FOXG1 (HGNC:3811),PP1,Strong,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-≥5 informative meiosis",Strength
-FOXG1 (HGNC:3811),PP1,Moderate,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-3-4 informative meiosis",Strength
-FOXG1 (HGNC:3811),PP1,Supporting,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-2 informative meiosis",Strength
-FOXG1 (HGNC:3811),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-FOXG1 (HGNC:3811),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-FOXG1 (HGNC:3811),PP3,Supporting,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product.
-
-
-
-
-For missense variants use REVEL with a score ≥ 0.644.
-
-
-For splice site variants use SpliceAI with a score ≥ 0.2.",General recommendation
-FOXG1 (HGNC:3811),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-FOXG1 (HGNC:3811),PP4,Supporting,"Phenotype specific for disease with single genetic etiology.
-
-
-
-
-See gene specific clinical phenotype guidelines.",Disease-specific
-FOXG1 (HGNC:3811),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-FOXG1 (HGNC:3811),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-FOXG1 (HGNC:3811),BA1,Stand Alone,"Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-FOXG1 (HGNC:3811),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-FOXG1 (HGNC:3811),BS1,Strong,"Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-FOXG1 (HGNC:3811),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-FOXG1 (HGNC:3811),BS2,Strong,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-2 unaffected (related or unrelated) heterozygotes.",Strength
-FOXG1 (HGNC:3811),BS2,Supporting,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-1 unaffected (related or unrelated) heterozygote",Strength
-FOXG1 (HGNC:3811),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-FOXG1 (HGNC:3811),BS3,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.
-
-
-
-
-RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.
-
-
-Not applicable for other functional studies.",Disease-specific
-FOXG1 (HGNC:3811),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-FOXG1 (HGNC:3811),BS4,Strong,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member, when seen in two or more families",Strength
-FOXG1 (HGNC:3811),BS4,Supporting,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member",Strength
-FOXG1 (HGNC:3811),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-FOXG1 (HGNC:3811),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-FOXG1 (HGNC:3811),BP2,Supporting,"Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.
-
-
-
-
-Applicable for 
-in trans
- state",Disease-specific
-FOXG1 (HGNC:3811),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-FOXG1 (HGNC:3811),BP3,Supporting,"In-frame deletions/insertions in a repetitive region without a known function
-
-
-
-
-Inframe expansions or deletions in 
-FOXG1
- repetitive regions: poly His (p.His47-p.His57), poly Gln (p.Gln70-p.Gln73) and poly Pro (p.Pro58-p.Pro61; p.Pro65-p.Pro69; p.Pro74-p.Pro80)
-
-
-BP3 is applicable if there are in-frame deletions/duplications in a repetitive region where other in-frame deletions/duplications have been observed with an overall frequency commensurate with the BA1 threshold for this gene.",Disease-specific
-FOXG1 (HGNC:3811),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-FOXG1 (HGNC:3811),BP4,Supporting,"For missense variants use REVEL with a score ≤ 0.290.
-
-
-For splice site variants use SpliceAI with a score ≤ 0.1.",General recommendation
-FOXG1 (HGNC:3811),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-FOXG1 (HGNC:3811),BP5,Strong,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-≥3 cases with alternate molecular basis for disease.",Strength
-FOXG1 (HGNC:3811),BP5,Moderate,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-2 cases with alternate molecular basis for disease.",Strength
-FOXG1 (HGNC:3811),BP5,Supporting,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-1 case with alternate molecular basis for disease.",Disease-specific
-FOXG1 (HGNC:3811),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-FOXG1 (HGNC:3811),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-FOXG1 (HGNC:3811),BP7,Supporting,"A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
-
-
-
-
-Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.
-
-
-For splice site variants use SpliceAI with a score ≤ 0.1.",None
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMECP2Version3.0.0_version=3.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMECP2Version3.0.0_version=3.0.0.csv
deleted file mode 100644
index 99ac90a16c8fc76fb82a8b75caea3e9a6babda9c..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMECP2Version3.0.0_version=3.0.0.csv
+++ /dev/null
@@ -1,283 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-MECP2 (HGNC:6990),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-MECP2 (HGNC:6990),PVS1,Very Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-Use as defined by ClinGen SVI working group (PMID:30192042).
-
-
-PVS1 is applicable up to p.E472, for any frameshift variant that results in a read-through of the stop codon, for canonical splice site variants predicted to result in an out-offrame product, and for canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exon 3). PVS1 is not applicable for initiation codons",Disease-specific
-MECP2 (HGNC:6990),PVS1,Moderate,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Moderate is applicable for any truncating variant distal of p.E472.",Disease-specific
-MECP2 (HGNC:6990),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MECP2 (HGNC:6990),PS1,Strong,Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.,None
-MECP2 (HGNC:6990),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-MECP2 (HGNC:6990),PS2,Very Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-≥2 independent occurrences of PS2.
-
-
-≥2 independent occurrences of PM6 and one occurrence of PS2.",None
-MECP2 (HGNC:6990),PS2,Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-1 occurrence of PS2.",None
-MECP2 (HGNC:6990),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-MECP2 (HGNC:6990),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an out-offrame transcript.
-
-
-Do not use for canonical splice site variants and when PVS1 is used.",Disease-specific
-MECP2 (HGNC:6990),PS3,Supporting,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).
-
-
-See included table for approved functional studies.",Disease-specific
-MECP2 (HGNC:6990),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-MECP2 (HGNC:6990),PS4,Strong,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-5+ observations.",Strength
-MECP2 (HGNC:6990),PS4,Moderate,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-3-4 observations.",Strength
-MECP2 (HGNC:6990),PS4,Supporting,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-Use for 2nd independent occurrence.",Strength
-MECP2 (HGNC:6990),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-MECP2 (HGNC:6990),PM1,Moderate,"Located in a mutational hot spot and/or critical and well-established functional domain.
-
-
-
-
-Methyl-DNA binding (MBD): aa 90-162
-
-
-Transcirptional repression domain (TRD): aa 302-306",Disease-specific
-MECP2 (HGNC:6990),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-MECP2 (HGNC:6990),PM2,Supporting,"Absent/rare from controls in an ethnically-matched cohort population sample.
-
-
-
-
-Use if absent, zero observations in control databases.",Strength
-MECP2 (HGNC:6990),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-MECP2 (HGNC:6990),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-MECP2 (HGNC:6990),PM4,Strong,"Protein length changes due to stop-loss variants.
-
-
-
-
-PM4_Strong is applicable to stop-loss variants in 
-MECP2
-, as several stop loss variants in this gene has been described in affected individuals.
-2",Disease-specific
-MECP2 (HGNC:6990),PM4,Moderate,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Do not use PM4 for in-frame deletions/insertions in the Proline-rich region of gene (p.381-p.405)",Disease-specific
-MECP2 (HGNC:6990),PM4,Supporting,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",Strength
-MECP2 (HGNC:6990),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MECP2 (HGNC:6990),PM5,Strong,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-≥2 different missense changes affecting the amino acid residue.
-
-
-Do not apply PM1 in these situations.",Strength
-MECP2 (HGNC:6990),PM5,Moderate,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",None
-MECP2 (HGNC:6990),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-MECP2 (HGNC:6990),PM6,Very Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥4 independent occurrences of PM6. 
-
-
-Evidence from literature must be fully evaluated to support independent events.",Strength
-MECP2 (HGNC:6990),PM6,Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥2 independent occurrences of PM6.
-
-
-Evidence from literature must be fully evaluated to support independent events.",Strength
-MECP2 (HGNC:6990),PM6,Moderate,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-1 occurrence of PM6.",None
-MECP2 (HGNC:6990),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-MECP2 (HGNC:6990),PP1,Strong,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-≥5 informative meiosis",Strength
-MECP2 (HGNC:6990),PP1,Moderate,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-3-4 informative meiosis",Strength
-MECP2 (HGNC:6990),PP1,Supporting,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-2 informative meiosis",Strength
-MECP2 (HGNC:6990),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-MECP2 (HGNC:6990),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-MECP2 (HGNC:6990),PP3,Supporting,"For missense variants use REVEL with a score ≥ 0.75.
-
-
-For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site).",None
-MECP2 (HGNC:6990),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-MECP2 (HGNC:6990),PP4,Supporting,"Phenotype specific for disease with single genetic etiology.
-
-
-
-
-See gene specific clinical phenotype guidelines.",Disease-specific
-MECP2 (HGNC:6990),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MECP2 (HGNC:6990),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-MECP2 (HGNC:6990),BA1,Stand Alone,"Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-MECP2 (HGNC:6990),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-MECP2 (HGNC:6990),BS1,Strong,"Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-MECP2 (HGNC:6990),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-MECP2 (HGNC:6990),BS2,Strong,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-2 unaffected (related or unrelated) heterozygotes or hemizygotes.",Strength
-MECP2 (HGNC:6990),BS2,Supporting,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-1 unaffected (related or unrelated) heterozygote or hemizygote",Strength
-MECP2 (HGNC:6990),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-MECP2 (HGNC:6990),BS3,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.
-
-
-
-
-RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.
-
-
-Not applicable for these genes for other functional studies (see tables for other accepted functional studies).",Disease-specific
-MECP2 (HGNC:6990),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-MECP2 (HGNC:6990),BS4,Strong,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member, when seen in two or more families",Strength
-MECP2 (HGNC:6990),BS4,Supporting,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member",Strength
-MECP2 (HGNC:6990),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-MECP2 (HGNC:6990),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-MECP2 (HGNC:6990),BP2,Supporting,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder.,Disease-specific
-MECP2 (HGNC:6990),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-MECP2 (HGNC:6990),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-MECP2 (HGNC:6990),BP4,Supporting,"For missense variants use REVEL with a score ≤ 0.15.
-
-
-For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site).",None
-MECP2 (HGNC:6990),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-MECP2 (HGNC:6990),BP5,Strong,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-≥3 cases with alternate molecular basis for disease.",Strength
-MECP2 (HGNC:6990),BP5,Supporting,Variant found in a case with an alternate molecular basis for disease.,Disease-specific
-MECP2 (HGNC:6990),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MECP2 (HGNC:6990),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-MECP2 (HGNC:6990),BP7,Supporting,"A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
-
-
-
-
-Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",None
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMECP2Version4.1.0_version=4.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMECP2Version4.1.0_version=4.1.0.csv
deleted file mode 100644
index 67182a92e967d99245daefa1d1b6efc61c2d4bf5..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMECP2Version4.1.0_version=4.1.0.csv
+++ /dev/null
@@ -1,338 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-MECP2 (HGNC:6990),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-MECP2 (HGNC:6990),PVS1,Very Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-Use as defined by ClinGen SVI working group (PMID:30192042).
-
-
-PVS1 is applicable for:
-
-
-Null variants up to p.E472
-
-
-Any frameshift variant that results in a read-through of the stop codon
-
-
-Canonical splice site variants predicted to result in an out-of-frame product
-
-
-Canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exon 3)
-
-
-A full gene deletion
-
-
-
-
-
-
-PVS1 is 
-not
- applicable for initiation codons.",Disease-specific
-MECP2 (HGNC:6990),PVS1,Strong,"PVS1_Strong is applicable for:
-
-
-Canonical splice site variants or deletions (single exon to full gene deletion) resulting in exon skipping or use of a cryptic splice site that disrupts reading frame and is 
-NOT
- predicted to undergo NMD, but the truncated/altered region is critical to protein function (exon 4).","Disease-specific,Strength"
-MECP2 (HGNC:6990),PVS1,Moderate,PVS1_Moderate is applicable for any truncating variant distal of p.E472.,"Disease-specific,Strength"
-MECP2 (HGNC:6990),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MECP2 (HGNC:6990),PS1,Strong,Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.,None
-MECP2 (HGNC:6990),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-MECP2 (HGNC:6990),PS2,Very Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-≥2 independent occurrences of PS2.
-
-
-≥2 independent occurrences of PM6 and one occurrence of PS2.",None
-MECP2 (HGNC:6990),PS2,Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-1 occurrence of PS2.",None
-MECP2 (HGNC:6990),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-MECP2 (HGNC:6990),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an out-offrame transcript.
-
-
-Do not use for canonical splice site variants and when PVS1 is used.",Disease-specific
-MECP2 (HGNC:6990),PS3,Supporting,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).
-
-
-See included table for approved functional studies.",Disease-specific
-MECP2 (HGNC:6990),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-MECP2 (HGNC:6990),PS4,Strong,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-5+ observations.",Strength
-MECP2 (HGNC:6990),PS4,Moderate,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-3-4 observations.",Strength
-MECP2 (HGNC:6990),PS4,Supporting,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-Use for 2nd independent occurrence.",Strength
-MECP2 (HGNC:6990),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-MECP2 (HGNC:6990),PM1,Moderate,"Located in a mutational hot spot and/or critical and well-established functional domain.
-
-
-
-
-Methyl-DNA binding (MBD): aa 90-162
-
-
-Transcirptional repression domain (TRD): aa 302-306",Disease-specific
-MECP2 (HGNC:6990),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-MECP2 (HGNC:6990),PM2,Supporting,"Absent/rare from controls in an ethnically-matched cohort population sample.
-
-
-
-
-Use if absent, zero observations in control databases.",Strength
-MECP2 (HGNC:6990),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-MECP2 (HGNC:6990),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-MECP2 (HGNC:6990),PM4,Strong,"Protein length changes due to stop-loss variants.
-
-
-
-
-PM4_Strong is applicable to stop-loss variants in 
-MECP2
-, as several stop loss variants in this gene has been described in affected individuals.
-2",Disease-specific
-MECP2 (HGNC:6990),PM4,Moderate,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Do not use PM4 for in-frame deletions/insertions in the Proline-rich region of gene (p.381-p.405)",Disease-specific
-MECP2 (HGNC:6990),PM4,Supporting,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",Strength
-MECP2 (HGNC:6990),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-MECP2 (HGNC:6990),PM5,Strong,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-≥2 different missense changes affecting the amino acid residue.
-
-
-Do not apply PM1 in these situations.",Strength
-MECP2 (HGNC:6990),PM5,Moderate,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",None
-MECP2 (HGNC:6990),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-MECP2 (HGNC:6990),PM6,Very Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥4 independent occurrences of PM6. 
-
-
-Evidence from literature must be fully evaluated to support independent events.",Strength
-MECP2 (HGNC:6990),PM6,Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥2 independent occurrences of PM6.
-
-
-Evidence from literature must be fully evaluated to support independent events.",Strength
-MECP2 (HGNC:6990),PM6,Moderate,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-1 occurrence of PM6.",None
-MECP2 (HGNC:6990),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-MECP2 (HGNC:6990),PP1,Strong,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-≥5 informative meiosis",Strength
-MECP2 (HGNC:6990),PP1,Moderate,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-3-4 informative meiosis",Strength
-MECP2 (HGNC:6990),PP1,Supporting,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-2 informative meiosis",Strength
-MECP2 (HGNC:6990),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-MECP2 (HGNC:6990),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-MECP2 (HGNC:6990),PP3,Supporting,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-
-
-
-
-For missense variants use REVEL with a score ≥ 0.644.
-
-
-For splice site variants use SpliceAI with a score ≥ 0.2.",General recommendation
-MECP2 (HGNC:6990),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-MECP2 (HGNC:6990),PP4,Supporting,"Phenotype specific for disease with single genetic etiology.
-
-
-
-
-See gene specific clinical phenotype guidelines.",Disease-specific
-MECP2 (HGNC:6990),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MECP2 (HGNC:6990),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-MECP2 (HGNC:6990),BA1,Stand Alone,"Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-MECP2 (HGNC:6990),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-MECP2 (HGNC:6990),BS1,Strong,"Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-MECP2 (HGNC:6990),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-MECP2 (HGNC:6990),BS2,Strong,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-2 unaffected (related or unrelated) heterozygotes or hemizygotes.",Strength
-MECP2 (HGNC:6990),BS2,Supporting,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-1 unaffected (related or unrelated) heterozygote or hemizygote",Strength
-MECP2 (HGNC:6990),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-MECP2 (HGNC:6990),BS3,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.
-
-
-
-
-RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.
-
-
-Not applicable for other functional studies.",Disease-specific
-MECP2 (HGNC:6990),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-MECP2 (HGNC:6990),BS4,Strong,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member, when seen in two or more families",Strength
-MECP2 (HGNC:6990),BS4,Supporting,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member",Strength
-MECP2 (HGNC:6990),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-MECP2 (HGNC:6990),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-MECP2 (HGNC:6990),BP2,Supporting,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder.,Disease-specific
-MECP2 (HGNC:6990),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-MECP2 (HGNC:6990),BP3,Supporting,"In-frame deletions/insertions in a repetitive region without a known function. 
-
-
-
-
-BP3 is applicable if there are in-frame deletions/duplications in a repetitive region where other in-frame deletions/duplications have been observed with an overall frequency commensurate with the BA1 threshold for this gene.",None
-MECP2 (HGNC:6990),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-MECP2 (HGNC:6990),BP4,Supporting,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-
-
-
-
-For missense variants use REVEL with a score ≤ 0.290.
-
-
-For splice site variants use SpliceAI with a score ≤ 0.1.",None
-MECP2 (HGNC:6990),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-MECP2 (HGNC:6990),BP5,Strong,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-≥3 cases with alternate molecular basis for disease.",Strength
-MECP2 (HGNC:6990),BP5,Moderate,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-2 cases with alternate molecular basis for disease.",Strength
-MECP2 (HGNC:6990),BP5,Supporting,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-1 case with alternate molecular basis for disease.",Disease-specific
-MECP2 (HGNC:6990),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-MECP2 (HGNC:6990),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-MECP2 (HGNC:6990),BP7,Supporting,"A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
-
-
-
-
-Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.
-
-
-For splice site variants use SpliceAI with a score ≤ 0.1.",None
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSLC9A6Version3.0.0_version=3.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSLC9A6Version3.0.0_version=3.0.0.csv
deleted file mode 100644
index 45e59005a4356bcdcc131d8018248c941e02f493..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSLC9A6Version3.0.0_version=3.0.0.csv
+++ /dev/null
@@ -1,289 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-SLC9A6 (HGNC:11079),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-SLC9A6 (HGNC:11079),PVS1,Very Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-Use as defined by ClinGen SVI working group (PMID:30192042).
-
-
-PVS1 is applicable up to p.A563, for canonical splice site variants predicted to result in an out-of-frame product, for canonical splice site variants or single exon in-frame deletion predicted to preserve the reading frame (exon 10), and multiple in-frame exon deletions that include exon 10.",Disease-specific
-SLC9A6 (HGNC:11079),PVS1,Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Strong is applicable for any truncating variant from p.C564 to p.T601 and for canonical splice site variants that flank exon 3 (in-frame exon).
-2
-,
-3
-,
-1",Disease-specific
-SLC9A6 (HGNC:11079),PVS1,Moderate,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Moderate is applicable for any truncating variant between p.Y602 to p.A669 and any frameshift variant that results in a read-through of the stop codon.",Disease-specific
-SLC9A6 (HGNC:11079),PVS1,Supporting,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Supporting is applicable for initiation codon variants in 
-SLC9A6",Disease-specific
-SLC9A6 (HGNC:11079),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SLC9A6 (HGNC:11079),PS1,Strong,Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.,None
-SLC9A6 (HGNC:11079),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-SLC9A6 (HGNC:11079),PS2,Very Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-≥2 independent occurrences of PS2.
-
-
-≥2 independent occurrences of PM6 and one occurrence of PS2.
-
-
-Evidence from literature must be fully evaluated to support independent events.",General recommendation
-SLC9A6 (HGNC:11079),PS2,Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-1 occurrence of PS2",None
-SLC9A6 (HGNC:11079),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-SLC9A6 (HGNC:11079),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an out-of-frame transcript.
-
-
-Do not use for canonical splice site variants and when PVS1 is used.",Disease-specific
-SLC9A6 (HGNC:11079),PS3,Supporting,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).",Disease-specific
-SLC9A6 (HGNC:11079),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-SLC9A6 (HGNC:11079),PS4,Strong,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-5+ observations.",Strength
-SLC9A6 (HGNC:11079),PS4,Moderate,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-3-4 observations.",Strength
-SLC9A6 (HGNC:11079),PS4,Supporting,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-Use for 2nd independent occurrence.",Strength
-SLC9A6 (HGNC:11079),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-SLC9A6 (HGNC:11079),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-SLC9A6 (HGNC:11079),PM2,Supporting,"Absent/rare from controls in an ethnically-matched cohort population sample.
-
-
-
-
-Use if absent, zero observations in control databases.",Strength
-SLC9A6 (HGNC:11079),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-SLC9A6 (HGNC:11079),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-SLC9A6 (HGNC:11079),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,No change
-SLC9A6 (HGNC:11079),PM4,Supporting,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Smaller in-frame events (< 3 amino acid residues).",Strength
-SLC9A6 (HGNC:11079),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SLC9A6 (HGNC:11079),PM5,Strong,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-≥2 different missense changes affecting the amino acid residue.
-
-
-Do not apply PM1 in these situations.",Strength
-SLC9A6 (HGNC:11079),PM5,Moderate,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",None
-SLC9A6 (HGNC:11079),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-SLC9A6 (HGNC:11079),PM6,Very Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",Strength
-SLC9A6 (HGNC:11079),PM6,Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥2 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",Strength
-SLC9A6 (HGNC:11079),PM6,Moderate,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-1 occurrence of PM6",None
-SLC9A6 (HGNC:11079),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-SLC9A6 (HGNC:11079),PP1,Strong,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-≥5 informative meiosis",Strength
-SLC9A6 (HGNC:11079),PP1,Moderate,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-3-4 informative meiosis",Strength
-SLC9A6 (HGNC:11079),PP1,Supporting,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-2 informative meiosis",Strength
-SLC9A6 (HGNC:11079),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-SLC9A6 (HGNC:11079),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-SLC9A6 (HGNC:11079),PP3,Supporting,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product.
-
-
-
-
-For missense variants use REVEL with a score ≥ 0.75.
-
-
-For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site).",General recommendation
-SLC9A6 (HGNC:11079),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-SLC9A6 (HGNC:11079),PP4,Supporting,"Phenotype specific for disease with single genetic etiology.
-
-
-
-
-See gene specific clinical phenotype guidelines.",Disease-specific
-SLC9A6 (HGNC:11079),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SLC9A6 (HGNC:11079),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-SLC9A6 (HGNC:11079),BA1,Stand Alone,"Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-SLC9A6 (HGNC:11079),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-SLC9A6 (HGNC:11079),BS1,Strong,"Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-SLC9A6 (HGNC:11079),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-SLC9A6 (HGNC:11079),BS2,Strong,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-2 unaffected (related or unrelated) hemizygotes",Strength
-SLC9A6 (HGNC:11079),BS2,Supporting,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-1 unaffected (related or unrelated) hemizygote",Strength
-SLC9A6 (HGNC:11079),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-SLC9A6 (HGNC:11079),BS3,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.
-
-
-
-
-RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.
-
-
-Not applicable for these genes for other functional studies (see tables for other accepted functional studies).",Disease-specific
-SLC9A6 (HGNC:11079),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-SLC9A6 (HGNC:11079),BS4,Strong,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member, when seen in two or more families",Strength
-SLC9A6 (HGNC:11079),BS4,Supporting,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member",Strength
-SLC9A6 (HGNC:11079),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-SLC9A6 (HGNC:11079),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-SLC9A6 (HGNC:11079),BP2,Supporting,"Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.
-
-
-
-
-BP2 is not applicable for SLC9A6 for 
-in trans
- state.",Disease-specific
-SLC9A6 (HGNC:11079),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-SLC9A6 (HGNC:11079),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SLC9A6 (HGNC:11079),BP4,Supporting,"For missense variants use REVEL with a score ≤ 0.15.
-
-
-For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site).",None
-SLC9A6 (HGNC:11079),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-SLC9A6 (HGNC:11079),BP5,Strong,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-≥3 cases with alternate molecular basis for disease.",Strength
-SLC9A6 (HGNC:11079),BP5,Supporting,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-1-2 cases with alternate molecular basis for disease",Disease-specific
-SLC9A6 (HGNC:11079),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SLC9A6 (HGNC:11079),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-SLC9A6 (HGNC:11079),BP7,Supporting,"A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
-
-
-
-
-Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",None
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTCF4Version3.0.0_version=3.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTCF4Version3.0.0_version=3.0.0.csv
deleted file mode 100644
index 938fa7070d496e7becbaeb6b03263228149f6167..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTCF4Version3.0.0_version=3.0.0.csv
+++ /dev/null
@@ -1,294 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-TCF4 (HGNC:11634),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-TCF4 (HGNC:11634),PVS1,Very Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-Use as defined by ClinGen SVI working group (PMID:30192042).
-
-
-PVS1 is applicable up to p.E643 which corresponds to the distal most de novo truncating variant in an affected patient reported to date.
-1
-
-
-PVS1 can be applied for any frameshift variant that results in a read-through of the stop codon, for canonical splice site variants predicted to result in an out-of-frame product, and for canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exon 15).",Disease-specific
-TCF4 (HGNC:11634),PVS1,Moderate,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Moderate is applicable for any truncating variant distal of p.E643 and for single exon deletions that involve just non-coding exon 20.",Disease-specific
-TCF4 (HGNC:11634),PVS1,Supporting,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Supporting is applicable for initiation codon variants in 
-TCF4.",Disease-specific
-TCF4 (HGNC:11634),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-TCF4 (HGNC:11634),PS1,Strong,Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.,None
-TCF4 (HGNC:11634),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-TCF4 (HGNC:11634),PS2,Very Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-≥2 independent occurrences of PS2.
-
-
-≥2 independent occurrences of PM6 and one occurrence of PS2.
-
-
-Evidence from literature must be fully evaluated to support independent events.",Strength
-TCF4 (HGNC:11634),PS2,Strong,De novo (maternity and paternity confirmed) in a patient with the disease and no family history.,None
-TCF4 (HGNC:11634),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-TCF4 (HGNC:11634),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an out-offrame transcript.
-
-
-Do not use for canonical splice site variants and when PVS1 is used.",Disease-specific
-TCF4 (HGNC:11634),PS3,Supporting,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).
-
-
-See included table for acceptable functional studies.",Disease-specific
-TCF4 (HGNC:11634),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-TCF4 (HGNC:11634),PS4,Strong,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-5+ observations.",Strength
-TCF4 (HGNC:11634),PS4,Moderate,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-3-4 observations.",Strength
-TCF4 (HGNC:11634),PS4,Supporting,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-Use for 2nd independent occurrence.",Strength
-TCF4 (HGNC:11634),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-TCF4 (HGNC:11634),PM1,Moderate,"Located in a mutational hot spot and/or critical and well-established functional domain.
-
-
-
-
-Basic Helix-Loop-Helix domain (bHLH): aa 564-617
-3
-,
-2",Disease-specific
-TCF4 (HGNC:11634),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-TCF4 (HGNC:11634),PM2,Supporting,"Absent/rare from controls in an ethnically-matched cohort population sample.
-
-
-
-
-Use if absent, zero observations in control databases.",Strength
-TCF4 (HGNC:11634),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-TCF4 (HGNC:11634),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-TCF4 (HGNC:11634),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,None
-TCF4 (HGNC:11634),PM4,Supporting,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",Strength
-TCF4 (HGNC:11634),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-TCF4 (HGNC:11634),PM5,Strong,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-≥2 different missense changes affecting the amino acid residue.
-
-
-Do not apply PM1 in these situations.",Strength
-TCF4 (HGNC:11634),PM5,Moderate,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",None
-TCF4 (HGNC:11634),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-TCF4 (HGNC:11634),PM6,Very Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥4 independent occurrences of PM6.",Strength
-TCF4 (HGNC:11634),PM6,Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥2 independent occurrences of PM6.",Strength
-TCF4 (HGNC:11634),PM6,Moderate,Confirmed de novo without confirmation of paternity and maternity.,No change
-TCF4 (HGNC:11634),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-TCF4 (HGNC:11634),PP1,Strong,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-≥5 informative meiosis",Strength
-TCF4 (HGNC:11634),PP1,Moderate,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-3-4 informative meiosis",Strength
-TCF4 (HGNC:11634),PP1,Supporting,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-2 informative meiosis",Strength
-TCF4 (HGNC:11634),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-TCF4 (HGNC:11634),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-TCF4 (HGNC:11634),PP3,Supporting,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product.
-
-
-
-
-For missense variants use REVEL with a score ≥ 0.75.
-
-
-For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site).",Clarification
-TCF4 (HGNC:11634),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-TCF4 (HGNC:11634),PP4,Supporting,"Phenotype specific for disease with single genetic etiology.
-
-
-
-
-See gene specific clinical phenotype guidelines.",Disease-specific
-TCF4 (HGNC:11634),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-TCF4 (HGNC:11634),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-TCF4 (HGNC:11634),BA1,Stand Alone,"Allele frequency above 0.05%.
-
-
-
-
-Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-TCF4 (HGNC:11634),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-TCF4 (HGNC:11634),BS1,Strong,"Allele frequency greater than expected for disease.
-
-
-
-
-Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-TCF4 (HGNC:11634),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-TCF4 (HGNC:11634),BS2,Strong,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-2 unaffected (related or unrelated) heterozygotes",Strength
-TCF4 (HGNC:11634),BS2,Supporting,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-1 unaffected (related or unrelated) heterozygote",Strength
-TCF4 (HGNC:11634),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-TCF4 (HGNC:11634),BS3,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.
-
-
-
-
-RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.
-
-
-Not applicable for these genes for other functional studies (see tables for other accepted functional studies).",Disease-specific
-TCF4 (HGNC:11634),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-TCF4 (HGNC:11634),BS4,Strong,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member, when seen in two or more families
-
-
-Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",Strength
-TCF4 (HGNC:11634),BS4,Supporting,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member",Strength
-TCF4 (HGNC:11634),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-TCF4 (HGNC:11634),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-TCF4 (HGNC:11634),BP2,Supporting,"Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.
-
-
-
-
-Applicable for 
-TCF4
- for 
-in trans
- state",Disease-specific
-TCF4 (HGNC:11634),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-TCF4 (HGNC:11634),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-TCF4 (HGNC:11634),BP4,Supporting,"For missense variants use REVEL with a score ≤ 0.15.
-
-
-For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site).",None
-TCF4 (HGNC:11634),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-TCF4 (HGNC:11634),BP5,Strong,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-≥3 cases with alternate molecular basis for disease.",Strength
-TCF4 (HGNC:11634),BP5,Supporting,Variant found in a case with an alternate molecular basis for disease.,Disease-specific
-TCF4 (HGNC:11634),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-TCF4 (HGNC:11634),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-TCF4 (HGNC:11634),BP7,Supporting,"A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
-
-
-
-
-Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",None
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTCF4Version4.0.0_version=4.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTCF4Version4.0.0_version=4.0.0.csv
deleted file mode 100644
index e899d4daebae7724c2fc467b8dd987fd6645e9b4..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTCF4Version4.0.0_version=4.0.0.csv
+++ /dev/null
@@ -1,348 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-TCF4 (HGNC:11634),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-TCF4 (HGNC:11634),PVS1,Very Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-Use as defined by ClinGen SVI working group (PMID:30192042).
-
-
-PVS1 can be applied for:
-
-
-Null variants up to p.E643, which corresponds to the distal most de novo truncating variant in an affected patient reported to date.
-4
-
-
-Any frameshift variant that results in a read-through of the stop codon
-
-
-Canonical splice site variants predicted to result in an out-of-frame product
-
-
-Canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exon 15)
-
-
-In-frame deletions including the PM1 functional domains (p.E564_V617 (bHLH))
-
-
-Deletions and duplications ≥1 exon in size (that are completely contained within the 
-TCF4
- gene) where the reading frame is disrupted and NMD is predicted to occur
-
-
-Exon skipping or single exon deletion of exon 19 predicted to disrupt the reading frame but is not predicted to undergo NMD
-
-
-A full gene deletion",Disease-specific
-TCF4 (HGNC:11634),PVS1,Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Strong is applicable for single to multi exon deletions that preserve the reading frame and the variant removes <10% of the protein.",Disease-specific
-TCF4 (HGNC:11634),PVS1,Moderate,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Moderate is applicable for any truncating variant distal of p.E643 and for single exon deletions that involve just non-coding exon 20.",Disease-specific
-TCF4 (HGNC:11634),PVS1,Supporting,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Supporting is applicable for initiation codon variants in 
-TCF4.",Disease-specific
-TCF4 (HGNC:11634),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-TCF4 (HGNC:11634),PS1,Strong,Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.,None
-TCF4 (HGNC:11634),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-TCF4 (HGNC:11634),PS2,Very Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-≥2 independent occurrences of PS2.
-
-
-≥2 independent occurrences of PM6 and one occurrence of PS2.
-
-
-Evidence from literature must be fully evaluated to support independent events.",Strength
-TCF4 (HGNC:11634),PS2,Strong,De novo (maternity and paternity confirmed) in a patient with the disease and no family history.,None
-TCF4 (HGNC:11634),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-TCF4 (HGNC:11634),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an out-offrame transcript.
-
-
-Do not use for canonical splice site variants and when PVS1 is used.",Disease-specific
-TCF4 (HGNC:11634),PS3,Supporting,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).
-
-
-See included table for acceptable functional studies.",Disease-specific
-TCF4 (HGNC:11634),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-TCF4 (HGNC:11634),PS4,Strong,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-5+ observations.",Strength
-TCF4 (HGNC:11634),PS4,Moderate,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-3-4 observations.",Strength
-TCF4 (HGNC:11634),PS4,Supporting,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-Use for 2nd independent occurrence.",Strength
-TCF4 (HGNC:11634),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-TCF4 (HGNC:11634),PM1,Moderate,"Located in a mutational hot spot and/or critical and well-established functional domain.
-
-
-
-
-Basic Helix-Loop-Helix domain (bHLH): aa 564-617
-3
-,
-2",Disease-specific
-TCF4 (HGNC:11634),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-TCF4 (HGNC:11634),PM2,Supporting,"Absent/rare from controls in an ethnically-matched cohort population sample.
-
-
-
-
-Use if absent, zero observations in control databases.",Strength
-TCF4 (HGNC:11634),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-TCF4 (HGNC:11634),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-TCF4 (HGNC:11634),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,None
-TCF4 (HGNC:11634),PM4,Supporting,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domains for each gene).",Strength
-TCF4 (HGNC:11634),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-TCF4 (HGNC:11634),PM5,Strong,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-≥2 different missense changes affecting the amino acid residue.
-
-
-Do not apply PM1 in these situations.",Strength
-TCF4 (HGNC:11634),PM5,Moderate,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",None
-TCF4 (HGNC:11634),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-TCF4 (HGNC:11634),PM6,Very Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥4 independent occurrences of PM6.",Strength
-TCF4 (HGNC:11634),PM6,Strong,"Confirmed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥2 independent occurrences of PM6.",Strength
-TCF4 (HGNC:11634),PM6,Moderate,Confirmed de novo without confirmation of paternity and maternity.,No change
-TCF4 (HGNC:11634),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-TCF4 (HGNC:11634),PP1,Strong,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-≥5 informative meiosis",Strength
-TCF4 (HGNC:11634),PP1,Moderate,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-3-4 informative meiosis",Strength
-TCF4 (HGNC:11634),PP1,Supporting,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-2 informative meiosis",Strength
-TCF4 (HGNC:11634),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-TCF4 (HGNC:11634),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-TCF4 (HGNC:11634),PP3,Supporting,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product.
-
-
-
-
-For missense variants use REVEL with a score ≥ 0.644.
-
-
-For splice site variants use SpliceAI with a score ≥ 0.2.",Clarification
-TCF4 (HGNC:11634),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-TCF4 (HGNC:11634),PP4,Supporting,"Phenotype specific for disease with single genetic etiology.
-
-
-
-
-See gene specific clinical phenotype guidelines.",Disease-specific
-TCF4 (HGNC:11634),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-TCF4 (HGNC:11634),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-TCF4 (HGNC:11634),BA1,Stand Alone,"Allele frequency above 0.05%.
-
-
-
-
-Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-TCF4 (HGNC:11634),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-TCF4 (HGNC:11634),BS1,Strong,"Allele frequency greater than expected for disease.
-
-
-
-
-Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-TCF4 (HGNC:11634),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-TCF4 (HGNC:11634),BS2,Strong,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-2 unaffected (related or unrelated) heterozygotes",Strength
-TCF4 (HGNC:11634),BS2,Supporting,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-1 unaffected (related or unrelated) heterozygote",Strength
-TCF4 (HGNC:11634),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-TCF4 (HGNC:11634),BS3,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.
-
-
-
-
-RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.
-
-
-Not applicable for other functional studies.",Disease-specific
-TCF4 (HGNC:11634),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-TCF4 (HGNC:11634),BS4,Strong,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member, when seen in two or more families
-
-
-Need to confirm that the family member is ‘affected with a neurodevelopmental phenotype consistent with the gene’ at a minimum.",Strength
-TCF4 (HGNC:11634),BS4,Supporting,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member",Strength
-TCF4 (HGNC:11634),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-TCF4 (HGNC:11634),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-TCF4 (HGNC:11634),BP2,Supporting,"Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.
-
-
-
-
-Applicable for 
-TCF4
- for 
-in trans
- state",Disease-specific
-TCF4 (HGNC:11634),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-TCF4 (HGNC:11634),BP3,Supporting,"In-frame deletions/insertions in a repetitive region without a known function.
-
-
-
-
-BP3 is applicable if there are in-frame deletions/duplications in a repetitive region where other in-frame deletions/duplications have been observed with an overall frequency commensurate with the BA1 threshold for this gene.",None
-TCF4 (HGNC:11634),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-TCF4 (HGNC:11634),BP4,Supporting,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
-
-
-
-
-For missense variants use REVEL with a score ≤ 0.290.
-
-
-For splice site variants use SpliceAI with a score ≤ 0.1.",General recommendation
-TCF4 (HGNC:11634),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-TCF4 (HGNC:11634),BP5,Strong,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-≥3 cases with alternate molecular basis for disease.",Strength
-TCF4 (HGNC:11634),BP5,Moderate,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-2 cases with alternate molecular basis for disease.",Strength
-TCF4 (HGNC:11634),BP5,Supporting,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-1 case with alternate molecular basis for disease.",Disease-specific
-TCF4 (HGNC:11634),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-TCF4 (HGNC:11634),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-TCF4 (HGNC:11634),BP7,Supporting,"A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
-
-
-
-
-Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.
-
-
-For splice site variants use SpliceAI with a score ≤ 0.1.",None
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforUBE3AVersion3.0.0_version=3.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforUBE3AVersion3.0.0_version=3.0.0.csv
deleted file mode 100644
index 7739c453feffc41bc82101269da0bdee879de438..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforUBE3AVersion3.0.0_version=3.0.0.csv
+++ /dev/null
@@ -1,298 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-UBE3A (HGNC:12496),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-UBE3A (HGNC:12496),PVS1,Very Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-Use as defined by ClinGen SVI working group (PMID:30192042).
-
-
-PVS1 is applicable for any truncating variant up to p.K841, for any frameshift variant that results in a read-through of the stop codon, for initiation codon variants, for canonical splice site variants predicted to result in an out-of-frame product, and for intragenic deletions/duplications predicted to result in an out-of-frame product.",Disease-specific
-UBE3A (HGNC:12496),PVS1,Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Strong is applicable for any truncating variant from p.K842 to p.G850 and for canonical splice site variants that flank exons 7, 8 (in-frame exons).",Disease-specific
-UBE3A (HGNC:12496),PVS1,Moderate,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Moderate is applicable for any truncating variant distal of p.G850.",Disease-specific
-UBE3A (HGNC:12496),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-UBE3A (HGNC:12496),PS1,Strong,Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.,None
-UBE3A (HGNC:12496),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-UBE3A (HGNC:12496),PS2,Very Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-≥2 independent occurrences of PS2.
-
-
-≥2 independent occurrences of PM6 and one occurrence of PS2.
-
-
-Evidence from literature must be fully evaluated to support independent events.",None
-UBE3A (HGNC:12496),PS2,Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-1 occurrence of PS2.",None
-UBE3A (HGNC:12496),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-UBE3A (HGNC:12496),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an out-offrame transcript.
-
-
-Do not use for canonical splice site variants and when PVS1 is used.",Disease-specific
-UBE3A (HGNC:12496),PS3,Supporting,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).
-
-
-See included table for acceptable functional studies.",Disease-specific
-UBE3A (HGNC:12496),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-UBE3A (HGNC:12496),PS4,Strong,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-5+ observations.",Strength
-UBE3A (HGNC:12496),PS4,Moderate,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-3-4 observations.",Strength
-UBE3A (HGNC:12496),PS4,Supporting,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-Use for 2nd independent occurrence.",Strength
-UBE3A (HGNC:12496),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-UBE3A (HGNC:12496),PM1,Moderate,"Located in a mutational hot spot and/or critical and well-established functional domain.
-
-
-
-
-3’ cysteine binding site: aa 820 (PMID 9887341)",Disease-specific
-UBE3A (HGNC:12496),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-UBE3A (HGNC:12496),PM2,Supporting,"Absent/rare from controls in an ethnically-matched cohort population sample.
-
-
-
-
-Use if absent, zero observations in control databases.",Strength
-UBE3A (HGNC:12496),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-UBE3A (HGNC:12496),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-UBE3A (HGNC:12496),PM4,Strong,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-PM4_Strong is applicable to stop-loss variants in UBE3A, as several stop loss variants in this gene has been described in affected individuals PMID 25212744.",Disease-specific
-UBE3A (HGNC:12496),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,Disease-specific
-UBE3A (HGNC:12496),PM4,Supporting,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domain for this gene).",Strength
-UBE3A (HGNC:12496),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-UBE3A (HGNC:12496),PM5,Strong,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-≥2 different missense changes affecting the amino acid residue.
-
-
-Do not apply PM1 in these situations.",Strength
-UBE3A (HGNC:12496),PM5,Moderate,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-Applicable to all genes as written.
-
-
-A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",None
-UBE3A (HGNC:12496),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-UBE3A (HGNC:12496),PM6,Very Strong,"Assumed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",Strength
-UBE3A (HGNC:12496),PM6,Strong,"Assumed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥2 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",Strength
-UBE3A (HGNC:12496),PM6,Moderate,"Assumed de novo without confirmation of paternity and maternity.
-
-
-
-
-1 occurrence of PM6.",None
-UBE3A (HGNC:12496),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-UBE3A (HGNC:12496),PP1,Strong,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-≥5 informative meiosis.",Strength
-UBE3A (HGNC:12496),PP1,Moderate,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-3-4 informative meiosis.",Strength
-UBE3A (HGNC:12496),PP1,Supporting,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-2 informative meiosis.",Strength
-UBE3A (HGNC:12496),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-UBE3A (HGNC:12496),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-UBE3A (HGNC:12496),PP3,Supporting,"For missense variants use REVEL with a score ≥ 0.75.
-
-
-For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site).",None
-UBE3A (HGNC:12496),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-UBE3A (HGNC:12496),PP4,Supporting,"Phenotype specific for disease with single genetic etiology.
-
-
-
-
-See gene specific clinical phenotype guidelines.",Disease-specific
-UBE3A (HGNC:12496),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-UBE3A (HGNC:12496),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-UBE3A (HGNC:12496),BA1,Stand Alone,"Allele frequency above 0.05%.
-
-
-
-
-Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-UBE3A (HGNC:12496),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-UBE3A (HGNC:12496),BS1,Strong,"Allele frequency greater than expected for disorder.
-
-
-
-
-Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-UBE3A (HGNC:12496),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-UBE3A (HGNC:12496),BS2,Strong,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-4 unaffected (related and maternally inherited or unrelated) Het (UBE3A).",Strength
-UBE3A (HGNC:12496),BS2,Supporting,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-2 unaffected (related and maternally inherited or unrelated) Het (UBE3A),",Strength
-UBE3A (HGNC:12496),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-UBE3A (HGNC:12496),BS3,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.
-
-
-
-
-RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.
-
-
-Not applicable for other functional studies (see tables for other accepted functional studies).",Disease-specific
-UBE3A (HGNC:12496),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-UBE3A (HGNC:12496),BS4,Strong,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member, when seen in two or more families.",Strength
-UBE3A (HGNC:12496),BS4,Supporting,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member.",Strength
-UBE3A (HGNC:12496),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-UBE3A (HGNC:12496),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-UBE3A (HGNC:12496),BP2,Supporting,"Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.
-
-
-
-
-BP2 is not applicable for UBE3A in trans state.",Disease-specific
-UBE3A (HGNC:12496),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-UBE3A (HGNC:12496),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-UBE3A (HGNC:12496),BP4,Supporting,"For missense variants use REVEL with a score ≤ 0.15.
-
-
-For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site).",None
-UBE3A (HGNC:12496),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-UBE3A (HGNC:12496),BP5,Strong,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-≥3 cases with alternate molecular basis for disease.",Strength
-UBE3A (HGNC:12496),BP5,Supporting,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-≥1 cases with alternate molecular basis for disease.",Disease-specific
-UBE3A (HGNC:12496),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-UBE3A (HGNC:12496),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-UBE3A (HGNC:12496),BP7,Supporting,"A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
-
-
-
-
-Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",None
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforUBE3AVersion4.0.0_version=4.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforUBE3AVersion4.0.0_version=4.0.0.csv
deleted file mode 100644
index 782d97b9d46022cd84445b83e95e24762550b2e2..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforUBE3AVersion4.0.0_version=4.0.0.csv
+++ /dev/null
@@ -1,296 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-UBE3A (HGNC:12496),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-UBE3A (HGNC:12496),PVS1,Very Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-Use as defined by ClinGen SVI working group (PMID:30192042).
-
-
-PVS1 is applicable for any truncating variant up to p.K841
-5
-, for any frameshift variant that results in a read-through of the stop codon, for initiation codon variants, for canonical splice site variants predicted to result in an out-of-frame product, and for intragenic deletions/duplications predicted to result in an out-of-frame product.",Disease-specific
-UBE3A (HGNC:12496),PVS1,Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Strong is applicable for any truncating variant from p.K842 to p.G850 and for canonical splice site variants that flank exons 7, 8 (in-frame exons).",Disease-specific
-UBE3A (HGNC:12496),PVS1,Moderate,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Moderate is applicable for any truncating variant distal of p.G850.",Disease-specific
-UBE3A (HGNC:12496),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-UBE3A (HGNC:12496),PS1,Strong,Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.,None
-UBE3A (HGNC:12496),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-UBE3A (HGNC:12496),PS2,Very Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-≥2 independent occurrences of PS2.
-
-
-≥2 independent occurrences of PM6 and one occurrence of PS2.
-
-
-Evidence from literature must be fully evaluated to support independent events.",None
-UBE3A (HGNC:12496),PS2,Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-1 occurrence of PS2.",None
-UBE3A (HGNC:12496),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-UBE3A (HGNC:12496),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an out-of-frame transcript.
-
-
-Do not use for canonical splice site variants and when PVS1 is used.",Disease-specific
-UBE3A (HGNC:12496),PS3,Supporting,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).
-
-
-See included table for acceptable functional studies.",Disease-specific
-UBE3A (HGNC:12496),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-UBE3A (HGNC:12496),PS4,Strong,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-5+ observations.",Strength
-UBE3A (HGNC:12496),PS4,Moderate,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-3-4 observations.",Strength
-UBE3A (HGNC:12496),PS4,Supporting,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-Use for 2nd independent occurrence.",Strength
-UBE3A (HGNC:12496),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-UBE3A (HGNC:12496),PM1,Moderate,"Located in a mutational hot spot and/or critical and well-established functional domain.
-
-
-
-
-3’ cysteine binding site: aa 820
-5",Disease-specific
-UBE3A (HGNC:12496),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-UBE3A (HGNC:12496),PM2,Supporting,"Absent/rare from controls in an ethnically-matched cohort population sample.
-
-
-
-
-Use if absent, zero observations in control databases.",Strength
-UBE3A (HGNC:12496),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-UBE3A (HGNC:12496),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-UBE3A (HGNC:12496),PM4,Strong,"Protein length changes due to stop-loss variants.
-
-
-
-
-PM4_Strong is applicable to stop-loss variants in UBE3A, as several stop loss variants in this gene has been described in affected individuals.
-9",Disease-specific
-UBE3A (HGNC:12496),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region.,Disease-specific
-UBE3A (HGNC:12496),PM4,Supporting,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domain for this gene).",Strength
-UBE3A (HGNC:12496),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-UBE3A (HGNC:12496),PM5,Strong,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-≥2 different missense changes affecting the amino acid residue.
-
-
-Do not apply PM1 in these situations.",Strength
-UBE3A (HGNC:12496),PM5,Moderate,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",None
-UBE3A (HGNC:12496),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-UBE3A (HGNC:12496),PM6,Very Strong,"Assumed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",Strength
-UBE3A (HGNC:12496),PM6,Strong,"Assumed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥2 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",Strength
-UBE3A (HGNC:12496),PM6,Moderate,"Assumed de novo without confirmation of paternity and maternity.
-
-
-
-
-1 occurrence of PM6.",None
-UBE3A (HGNC:12496),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-UBE3A (HGNC:12496),PP1,Strong,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-≥5 informative meiosis.",Strength
-UBE3A (HGNC:12496),PP1,Moderate,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-3-4 informative meiosis.",Strength
-UBE3A (HGNC:12496),PP1,Supporting,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-2 informative meiosis.",Strength
-UBE3A (HGNC:12496),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-UBE3A (HGNC:12496),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-UBE3A (HGNC:12496),PP3,Supporting,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product.
-
-
-
-
-For missense variants use REVEL with a score ≥ 0.75.
-
-
-For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when all of the prediction programs support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of cryptic splice site).",General recommendation
-UBE3A (HGNC:12496),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-UBE3A (HGNC:12496),PP4,Supporting,"Phenotype specific for disease with single genetic etiology.
-
-
-
-
-See gene specific clinical phenotype guidelines.",Disease-specific
-UBE3A (HGNC:12496),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-UBE3A (HGNC:12496),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-UBE3A (HGNC:12496),BA1,Stand Alone,"Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-UBE3A (HGNC:12496),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-UBE3A (HGNC:12496),BS1,Strong,"Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-UBE3A (HGNC:12496),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-UBE3A (HGNC:12496),BS2,Strong,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-4 unaffected (related and maternally inherited or unrelated) heterozygotes",Strength
-UBE3A (HGNC:12496),BS2,Supporting,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-2 unaffected (related and maternally inherited or unrelated) heterozygotes",Strength
-UBE3A (HGNC:12496),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-UBE3A (HGNC:12496),BS3,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.
-
-
-
-
-RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.
-
-
-Not applicable for other functional studies (see tables for other accepted functional studies).",Disease-specific
-UBE3A (HGNC:12496),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-UBE3A (HGNC:12496),BS4,Strong,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member, when seen in two or more families.",Strength
-UBE3A (HGNC:12496),BS4,Supporting,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member.",Strength
-UBE3A (HGNC:12496),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-UBE3A (HGNC:12496),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-UBE3A (HGNC:12496),BP2,Supporting,"Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.
-
-
-
-
-BP2 is not applicable for UBE3A 
-in trans
- state.",Disease-specific
-UBE3A (HGNC:12496),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-UBE3A (HGNC:12496),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-UBE3A (HGNC:12496),BP4,Supporting,"For missense variants use REVEL with a score ≤ 0.15.
-
-
-For splice site variants use MaxEntScan, NNSPLICE and SpliceSiteFinder-like when the majority of the prediction programs do not support significant splicing alteration (significant splicing alterations defined as ≥15% decrease to the natural splice site and ≥70% gain in prediction strength of a cryptic splice site).",None
-UBE3A (HGNC:12496),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-UBE3A (HGNC:12496),BP5,Strong,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-≥3 cases with alternate molecular basis for disease.",Strength
-UBE3A (HGNC:12496),BP5,Supporting,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-1-2 cases with alternate molecular basis for disease.",Disease-specific
-UBE3A (HGNC:12496),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-UBE3A (HGNC:12496),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-UBE3A (HGNC:12496),BP7,Supporting,"A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
-
-
-
-
-Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.",None
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforUBE3AVersion5.0.0_version=5.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforUBE3AVersion5.0.0_version=5.0.0.csv
deleted file mode 100644
index 62e0faf4fee3f521aab1b4eb4a9fe1f0bb5fab0a..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforUBE3AVersion5.0.0_version=5.0.0.csv
+++ /dev/null
@@ -1,345 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-UBE3A (HGNC:12496),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-UBE3A (HGNC:12496),PVS1,Very Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-Use as defined by ClinGen SVI working group (PMID:30192042).
-
-
-PVS1 is applicable for:
-
-
-Any truncating variant up to p.K841
-3
-
-
-Any frameshift variant that results in a read-through of the stop codon
-
-
-Initiation codon variants
-
-
-Canonical splice site variants predicted to result in an out-of-frame product
-
-
-Intragenic deletions/duplications predicted to result in an out-of-frame product.
-
-
-Full gene deletion",Disease-specific
-UBE3A (HGNC:12496),PVS1,Strong,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Strong is applicable for:
-
-
-Any truncating variant from p.A842 to p.G850 
-
-
-Canonical splice site variants that flank exons 7, 8 (in-frame exons)","Disease-specific,Strength"
-UBE3A (HGNC:12496),PVS1,Moderate,"Null variant in a gene where loss of function is a known mechanism of disease.
-
-
-
-
-PVS1_Moderate is applicable for any truncating variant distal of p.G850.","Disease-specific,Strength"
-UBE3A (HGNC:12496),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-UBE3A (HGNC:12496),PS1,Strong,Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.,None
-UBE3A (HGNC:12496),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-UBE3A (HGNC:12496),PS2,Very Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-≥2 independent occurrences of PS2.
-
-
-≥2 independent occurrences of PM6 and one occurrence of PS2.
-
-
-Evidence from literature must be fully evaluated to support independent events.",None
-UBE3A (HGNC:12496),PS2,Strong,"De novo (maternity and paternity confirmed) in a patient with the disease and no family history.
-
-
-
-
-1 occurrence of PS2.",None
-UBE3A (HGNC:12496),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-UBE3A (HGNC:12496),PS3,Strong,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an out-of-frame transcript.
-
-
-Do not use for canonical splice site variants and when PVS1 is used.",Disease-specific
-UBE3A (HGNC:12496),PS3,Supporting,"Well-established in vitro or in vivo functional studies supportive of a damaging effect.
-
-
-
-
-RNA studies that demonstrate abnormal splicing and an inframe product (unless it affects an in-frame exon specified in the PVS1 section).
-
-
-See included table for acceptable functional studies.",Disease-specific
-UBE3A (HGNC:12496),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-UBE3A (HGNC:12496),PS4,Strong,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-5+ observations.",Strength
-UBE3A (HGNC:12496),PS4,Moderate,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-3-4 observations.",Strength
-UBE3A (HGNC:12496),PS4,Supporting,"The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.
-
-
-
-
-Use for 2nd independent occurrence.",Strength
-UBE3A (HGNC:12496),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-UBE3A (HGNC:12496),PM1,Moderate,"Located in a mutational hot spot and/or critical and well-established functional domain.
-
-
-
-
-3’ cysteine binding site: aa 820
-3",Disease-specific
-UBE3A (HGNC:12496),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-UBE3A (HGNC:12496),PM2,Supporting,"Absent/rare from controls in an ethnically-matched cohort population sample.
-
-
-
-
-Use if absent, zero observations in control databases.",Strength
-UBE3A (HGNC:12496),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-UBE3A (HGNC:12496),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-UBE3A (HGNC:12496),PM4,Strong,"Protein length changes due to stop-loss variants.
-
-
-
-
-PM4_Strong is applicable to stop-loss variants in UBE3A, as several stop loss variants in this gene has been described in affected individuals.
-4",Disease-specific
-UBE3A (HGNC:12496),PM4,Moderate,Protein length changes due to in-frame deletions/insertions in a non-repeat region.,Disease-specific
-UBE3A (HGNC:12496),PM4,Supporting,"Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
-
-
-
-
-Smaller in-frame events (< 3 amino acid residues) unless they occur in a functionally important region (see PM1 for functionally important domain for this gene).",Strength
-UBE3A (HGNC:12496),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-UBE3A (HGNC:12496),PM5,Strong,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-≥2 different missense changes affecting the amino acid residue.
-
-
-Do not apply PM1 in these situations.",Strength
-UBE3A (HGNC:12496),PM5,Moderate,"Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-
-
-
-
-A Grantham or BLOSUM score comparison can be used to determine if the variant is predicted to be as or more damaging than the established pathogenic variant.",None
-UBE3A (HGNC:12496),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-UBE3A (HGNC:12496),PM6,Very Strong,"Assumed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥4 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",Strength
-UBE3A (HGNC:12496),PM6,Strong,"Assumed de novo without confirmation of paternity and maternity.
-
-
-
-
-≥2 independent occurrences of PM6. Evidence from literature must be fully evaluated to support independent events.",Strength
-UBE3A (HGNC:12496),PM6,Moderate,"Assumed de novo without confirmation of paternity and maternity.
-
-
-
-
-1 occurrence of PM6.",None
-UBE3A (HGNC:12496),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-UBE3A (HGNC:12496),PP1,Strong,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-≥5 informative meiosis.",Strength
-UBE3A (HGNC:12496),PP1,Moderate,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-3-4 informative meiosis.",Strength
-UBE3A (HGNC:12496),PP1,Supporting,"Co-segregation with disease in multiple affected family members.
-
-
-
-
-2 informative meiosis.",Strength
-UBE3A (HGNC:12496),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-UBE3A (HGNC:12496),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-UBE3A (HGNC:12496),PP3,Supporting,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product.
-
-
-
-
-For missense variants use REVEL with a score ≥ 0.644.
-
-
-For splice site variants use SpliceAI with a score ≥ 0.2.",General recommendation
-UBE3A (HGNC:12496),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-UBE3A (HGNC:12496),PP4,Supporting,"Phenotype specific for disease with single genetic etiology.
-
-
-
-
-See gene specific clinical phenotype guidelines.",Disease-specific
-UBE3A (HGNC:12496),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-UBE3A (HGNC:12496),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-UBE3A (HGNC:12496),BA1,Stand Alone,"Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-UBE3A (HGNC:12496),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-UBE3A (HGNC:12496),BS1,Strong,"Use large population databases (i.e. gnomAD).
-
-
-Use if variant is present at ≥0.00008 (0.008%) and <0.0003 (0.03%) in any sub-population.
-
-
-Use if allele frequency is met in any general continental population dataset of at least 2,000 observed alleles.",Disease-specific
-UBE3A (HGNC:12496),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-UBE3A (HGNC:12496),BS2,Strong,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-4 unaffected (related and maternally inherited or unrelated) heterozygotes",Strength
-UBE3A (HGNC:12496),BS2,Moderate,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-3 unaffected (related and maternally inherited or unrelated) heterozygotes",Strength
-UBE3A (HGNC:12496),BS2,Supporting,"Observed in the heterozygous/hemizygous state in a healthy adult.
-
-
-
-
-2 unaffected (related and maternally inherited or unrelated) heterozygotes",Strength
-UBE3A (HGNC:12496),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-UBE3A (HGNC:12496),BS3,Strong,"Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.
-
-
-
-
-RNA functional studies that demonstrate no impact on splicing and transcript composition. It can be downgraded based on quality of data.
-
-
-Not applicable for other functional studies.",Disease-specific
-UBE3A (HGNC:12496),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-UBE3A (HGNC:12496),BS4,Strong,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member, when seen in two or more families.",Strength
-UBE3A (HGNC:12496),BS4,Supporting,"Lack of segregation in affected members of a family.
-
-
-
-
-Absent in a similarly affected family member.",Strength
-UBE3A (HGNC:12496),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-UBE3A (HGNC:12496),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-UBE3A (HGNC:12496),BP2,Supporting,"Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern.
-
-
-
-
-BP2 is not applicable for UBE3A 
-in trans
- state.",Disease-specific
-UBE3A (HGNC:12496),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-UBE3A (HGNC:12496),BP3,Supporting,"In-frame deletions/insertions in a repetitive region without a known function.
-
-
-
-
-BP3 is applicable if there are in-frame deletions/duplications in a repetitive region where other in-frame deletions/duplications have been observed with an overall frequency commensurate with the BA1 threshold for this gene.",None
-UBE3A (HGNC:12496),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-UBE3A (HGNC:12496),BP4,Supporting,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc).
-
-
-
-
-For missense variants use REVEL with a score ≤ 0.290.
-
-
-For splice site variants use SpliceAI with a score ≤ 0.1.",None
-UBE3A (HGNC:12496),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-UBE3A (HGNC:12496),BP5,Strong,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-≥3 cases with alternate molecular basis for disease.",Strength
-UBE3A (HGNC:12496),BP5,Moderate,"Variant found in a case with an alternate molecular basis for disease. 
-
-
-
-
-2 cases with alternate molecular basis for disease.",Strength
-UBE3A (HGNC:12496),BP5,Supporting,"Variant found in a case with an alternate molecular basis for disease.
-
-
-
-
-1 case with alternate molecular basis for disease.",Disease-specific
-UBE3A (HGNC:12496),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-UBE3A (HGNC:12496),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-UBE3A (HGNC:12496),BP7,Supporting,"A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
-
-
-
-
-Defined 'not highly conserved' regions in BP7 as those with PhastCons score <1 and/or PhyloP score <0.1 and/or the variant is the reference nucleotide in one primate and/or three mammal species.
-
-
-For splice site variants use SpliceAI with a score ≤ 0.1.",None
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforADAVersion1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforADAVersion1.0.0_version=1.0.0.csv
deleted file mode 100644
index eac6c0b0fad4b603ef1f6645b736e0cd200f2c4f..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforADAVersion1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,215 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-ADA (HGNC:186),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-ADA (HGNC:186),PVS1,Very Strong,"Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)).","General recommendation,Gene-specific"
-ADA (HGNC:186),PVS1,Strong,"Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification:
-
-
-
-
-For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein (i.e. variants in the last exon, exon 12, or variants in the last 50 nucleotides of the penultimate exon after c.1028, codon 343, in exon 11), at least one pathogenic variant 
-must be
- present downstream in order to apply PVS1_Strong.","General recommendation,Gene-specific"
-ADA (HGNC:186),PVS1,Moderate,"Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification:
-
-
-
-
-For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein (i.e. variants in the last exon, exon 12, or variants in the last 50 nucleotides of the penultimate exon after c.1028, codon 343, in exon 11), when at least one pathogenic variant is 
-not
- present downstream downgrade to PVS1_Moderate.",General recommendation
-ADA (HGNC:186),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-ADA (HGNC:186),PS1,Strong,"It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be pathogenic, can use PS1 for c.105+1G>T.
-
-
-Applicable if the previously established variant is classified as 
-pathogenic
- by SCID VCEP specifications for 
-ADA.",Gene-specific
-ADA (HGNC:186),PS1,Moderate,"It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be likely pathogenic, can use PS1 for c.105+1G>T
-
-
-Applicable if the previously established variant is classified as 
-likely pathogenic
- by SCID VCEP specifications for 
-ADA.","Gene-specific,Strength"
-ADA (HGNC:186),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-ADA (HGNC:186),PS2,Very Strong,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-ADA (HGNC:186),PS2,Strong,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-ADA (HGNC:186),PS2,Moderate,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-ADA (HGNC:186),PS2,Supporting,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-ADA (HGNC:186),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-ADA (HGNC:186),PS3,Strong,PS3 may potentially be applied at the default strength level of Strong for evidence from an animal model expressing the variant of interest and recapitulating the ADA-SCID phenotype.,Gene-specific
-ADA (HGNC:186),PS3,Moderate,"The strength of evidence from cellular models/
-in vitro
- studies is dependent upon the level of expressed ADA enzyme activity based on levels defined in Arredondo-Vega et al., 1998 (PMID: 9758612): 
-
-
-
-
-PS3_Moderate: ≤0.05% of wild-type activity (group I)
-
-
-
-
-At least one previously observed proband with the expressed ADA variant meeting PP4 is required to apply PS3 at any strength on the basis of a cellular model/in vitro study.",Gene-specific
-ADA (HGNC:186),PS3,Supporting,"The strength of evidence from cellular models/
-in vitro
- studies is dependent upon the level of expressed ADA enzyme activity based on levels defined in Arredondo-Vega et al., 1998 (PMID: 9758612):
-
-
-
-
-PS3_Supporting: 0.06-0.6% of wild-type activity (groups II and III)
-
-
-
-
-At least one previously observed proband with the expressed ADA variant meeting PP4 is required to apply PS3 at any strength on the basis of a cellular model/in vitro study.","Gene-specific,Strength"
-ADA (HGNC:186),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",NA
-ADA (HGNC:186),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-ADA (HGNC:186),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-ADA (HGNC:186),PM2,Supporting,"gnomAD popmax filtering allele frequency  <0.0001742
-
-
-
-
-An additional requirement is that 
-no homozygotes
- have been observed in gnomAD.",Gene-specific
-ADA (HGNC:186),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-ADA (HGNC:186),PM3,Very Strong,"Use ClinGen SVI recommendations for 
-in trans
- criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for 
-ADA.",General recommendation
-ADA (HGNC:186),PM3,Strong,"Use ClinGen SVI recommendations for 
-in trans
- criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for 
-ADA.",General recommendation
-ADA (HGNC:186),PM3,Moderate,"Use ClinGen SVI recommendations for 
-in trans
- criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for 
-ADA.",General recommendation
-ADA (HGNC:186),PM3,Supporting,"Use ClinGen SVI recommendations for 
-in trans
- criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for 
-ADA.",General recommendation
-ADA (HGNC:186),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-ADA (HGNC:186),PM4,Moderate,"When applied to deletion variants, the deleted region must contain a known 
-pathogenic
- or 
-likely pathogenic
- variant that is not predicted/observed to alter splicing.",Gene-specific
-ADA (HGNC:186),PM4,Supporting,"When applied to deletion variants, the deleted region must contain a known 
-VUS
- variant that is not predicted/observed to alter splicing.","Gene-specific,Strength"
-ADA (HGNC:186),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-ADA (HGNC:186),PM5,Moderate,"Applicable if a previously established variant is classified as 
-pathogenic
- by SCID VCEP specifications for 
-ADA.
- Previously established variant must be classified by SCID VCEP specifications for 
-ADA.",Gene-specific
-ADA (HGNC:186),PM5,Supporting,"Applicable if a previously established variant is classified as 
-likely pathogenic
- by SCID VCEP specifications for 
-ADA.
- Previously established variant must be classified by SCID VCEP specifications for 
-ADA.","Gene-specific,Strength"
-ADA (HGNC:186),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-ADA (HGNC:186),PM6,Strong,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-ADA (HGNC:186),PM6,Moderate,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-ADA (HGNC:186),PM6,Supporting,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-ADA (HGNC:186),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-ADA (HGNC:186),PP1,Strong,"Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations.",General recommendation
-ADA (HGNC:186),PP1,Moderate,"Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations.",General recommendation
-ADA (HGNC:186),PP1,Supporting,"Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations.",General recommendation
-ADA (HGNC:186),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-ADA (HGNC:186),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-ADA (HGNC:186),PP3,Supporting,"Only applicable to synonymous or intronic variants predicted to impact splicing by SpliceAI with a delta score greater than or equal to 0.2.
-
-
-Do not apply to missense variants.",General recommendation
-ADA (HGNC:186),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-ADA (HGNC:186),PP4,Strong,"A patient score of ≥ 9 points
-1
-. 
-
-
-1
-CNV (Copy number variation) testing is required to consider PP4_Strong in order to certify that the variant in question is the causative for the phenotype and not one CNV event corrected by gene therapy and not identified previously (see instructions below).","Disease-specific,Gene-specific"
-ADA (HGNC:186),PP4,Moderate,A patient score of 2-<9 points (see instructions below).,"Disease-specific,Gene-specific"
-ADA (HGNC:186),PP4,Supporting,A patient score of 1-<2 points (see instructions below).,"Disease-specific,Gene-specific"
-ADA (HGNC:186),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-ADA (HGNC:186),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-ADA (HGNC:186),BA1,Stand Alone,gnomAD popmax filtering allele frequency >0.00721.,Gene-specific
-ADA (HGNC:186),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-ADA (HGNC:186),BS1,Strong,"gnomAD popmax filtering allele frequency >0.00161
-1
-
-
-1
- Consider also bottleneck populations.",Gene-specific
-ADA (HGNC:186),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-ADA (HGNC:186),BS2,Supporting,Only to be used when the variant is observed in the homozygous state in a healthy adult.,Gene-specific
-ADA (HGNC:186),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-ADA (HGNC:186),BS3,Supporting,"The strength of evidence from cellular models/
-in vitro
- studies is dependent upon the level of expressed ADA enzyme activity based on levels defined in Arredondo-Vega et al., 1998 (PMID: 9758612): 
-
-
-
-
-BS3_Supporting: Expressed ADA enzyme activity ≥4.8% of wild-type activity (based on group IV).",Gene-specific
-ADA (HGNC:186),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-ADA (HGNC:186),BS4,Strong,Can be applied without additional specifications.,None
-ADA (HGNC:186),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-ADA (HGNC:186),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-ADA (HGNC:186),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-ADA (HGNC:186),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",NA
-ADA (HGNC:186),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-ADA (HGNC:186),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-ADA (HGNC:186),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-ADA (HGNC:186),BP7,Supporting,"Applicable to both synonymous variants and deep intronic variants affecting nucleotides at or beyond the +7 (donor) and -21 (acceptor) positions.
-
-
-The variant should be predicted not to impact splicing by at least two out of three 
-in silico
- tools (freely available tools include GeneSplicer, MaxEntScan, NNSplice, SpliceAI, Splicing Sequences Finder (SSF), and varSEAK).
-
-
-Given the potential for poor conservation of genes related to T cell and B cell development among vertebrates, nucleotide conservation is 
-not required
- in order to apply BP7.",General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDCLRE1CVersion1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDCLRE1CVersion1.0.0_version=1.0.0.csv
deleted file mode 100644
index d4b40bddcba43b4539c81e55c70892a0e6f15709..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDCLRE1CVersion1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,289 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-DCLRE1C (HGNC:17642),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-DCLRE1C (HGNC:17642),PVS1,Very Strong,"Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)).","General recommendation,Gene-specific"
-DCLRE1C (HGNC:17642),PVS1,Strong,"Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification:
-
-
-
-
-For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein (i.e. variants in the last exon, exon 14, or variants in the last 50 nucleotides of the penultimate exon after c.1106, codon 369, in exon 13), at least one pathogenic variant 
-must be
- present downstream in order to apply PVS1_Strong.
-
-
-
-
-Note: Exons 1-3 and exons 1-4 have been reported as a hot spot for deletion variants as a result of homologous recombination of the wild-type DCLRE1C gene with a DCLRE1C pseudogene (PMID: 19953608).","General recommendation,Gene-specific"
-DCLRE1C (HGNC:17642),PVS1,Moderate,"Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification:
-
-
-
-
-For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein (i.e. variants in the last exon, exon 14, or variants in the last 50 nucleotides of the penultimate exon after c.1106, codon 369, in exon 13), when at least one pathogenic variant is 
-not
- present downstream downgrade to PVS1_Moderate.
-
-
-
-
-Note: Exons 1-3 and exons 1-4 have been reported as a hot spot for deletion variants as a result of homologous recombination of the wild-type DCLRE1C gene with a DCLRE1C pseudogene (PMID: 19953608).",General recommendation
-DCLRE1C (HGNC:17642),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-DCLRE1C (HGNC:17642),PS1,Strong,"It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be pathogenic, can use PS1 for c.105+1G>T.
-
-
-Applicable if the previously established variant is classified as 
-pathogenic
- by SCID VCEP specifications for 
-DCLRE1C.",Gene-specific
-DCLRE1C (HGNC:17642),PS1,Moderate,"It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be likely pathogenic, can use PS1 for c.105+1G>T
-
-
-Applicable if the previously established variant is classified as 
-likely pathogenic
- by SCID VCEP specifications for 
-DCLRE1C.","Gene-specific,Strength"
-DCLRE1C (HGNC:17642),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-DCLRE1C (HGNC:17642),PS2,Very Strong,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-DCLRE1C (HGNC:17642),PS2,Strong,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-DCLRE1C (HGNC:17642),PS2,Moderate,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-DCLRE1C (HGNC:17642),PS2,Supporting,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-DCLRE1C (HGNC:17642),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-DCLRE1C (HGNC:17642),PS3,Strong,PS3 may potentially be applied at the default strength level of Strong for evidence from an animal model expressing the variant of interest and recapitulating the DCLRE1C-SCID phenotype. Animal models will be reviewed on a case-by-case basis by the VCEP to determine the appropriate strength level.,Gene-specific
-DCLRE1C (HGNC:17642),PS3,Moderate,"The strength of evidence from cellular models/
-in vitro
- studies is dependent upon abnormal results in 
-in vitro
- DNA repair activity and V(D)J recombination assays: 
-
-
-
-
-PS3_Moderate: Abnormal result in 
-both
- an 
-in vitro
- DNA repair activity assay AND an 
-in vitro
- V(D)J recombination assay (defined as <25% of wild-type activity for both assays).
-
-
-
-
-At least one previously observed proband with the DCLRE1C variant meeting PP4 is required to apply PS3 at any strength on the basis of a cellular model/in vitro study.
-
-
-
-
-Approved assay instances:
-
-
-DNA repair activity assay 
-
-
-Felgentreff et al., 2015 (PMID: 25917813)
-
-
-
-
-
-
-V(D)J recombination assay 
-
-
-Pannicke et al., 2004 (PMID: 15071507)
-
-
-Ege et al., 2005 (PMID: 15731174)
-
-
-Felgentreff et al., 2015 (PMID: 25917813)
-
-
-Volk et al., 2015 (PMID: 26476407)",Gene-specific
-DCLRE1C (HGNC:17642),PS3,Supporting,"The strength of evidence from cellular models/
-in vitro
- studies is dependent upon abnormal results in 
-in vitro
- DNA repair activity and V(D)J recombination assays: 
-
-
-
-
-PS3_Supporting: Abnormal result in an 
-in vitro
- V(D)J recombination assay (same threshold, <25% of wild-type activity).
-
-
-
-
-At least one previously observed proband with the DCLRE1C variant meeting PP4 is required to apply PS3 at any strength on the basis of a cellular model/in vitro study.
-
-
-
-
-Approved assay instances:
-
-
-DNA repair activity assay 
-
-
-Felgentreff et al., 2015 (PMID: 25917813)
-
-
-
-
-
-
-V(D)J recombination assay 
-
-
-Pannicke et al., 2004 (PMID: 15071507)
-
-
-Ege et al., 2005 (PMID: 15731174)
-
-
-Felgentreff et al., 2015 (PMID: 25917813)
-
-
-Volk et al., 2015 (PMID: 26476407)","Gene-specific,Strength"
-DCLRE1C (HGNC:17642),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",NA
-DCLRE1C (HGNC:17642),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-DCLRE1C (HGNC:17642),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-DCLRE1C (HGNC:17642),PM2,Supporting,"gnomAD popmax filtering allele frequency  <0.00003266 
-
-
-
-
-An additional requirement is that 
-no homozygotes
- have been observed in gnomAD.",Gene-specific
-DCLRE1C (HGNC:17642),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-DCLRE1C (HGNC:17642),PM3,Very Strong,"Use ClinGen SVI recommendations for 
-in trans
- criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for 
-DCLRE1C.",General recommendation
-DCLRE1C (HGNC:17642),PM3,Strong,"Use ClinGen SVI recommendations for 
-in trans
- criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for 
-DCLRE1C.",General recommendation
-DCLRE1C (HGNC:17642),PM3,Moderate,"Use ClinGen SVI recommendations for 
-in trans
- criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for 
-DCLRE1C.",General recommendation
-DCLRE1C (HGNC:17642),PM3,Supporting,"Use ClinGen SVI recommendations for 
-in trans
- criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for 
-DCLRE1C.",General recommendation
-DCLRE1C (HGNC:17642),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-DCLRE1C (HGNC:17642),PM4,Moderate,"When applied to deletion variants, the deleted region must contain a known 
-pathogenic
- or 
-likely pathogenic
- variant that is not predicted/observed to alter splicing.",Gene-specific
-DCLRE1C (HGNC:17642),PM4,Supporting,"When applied to deletion variants, the deleted region must contain a known 
-VUS
- variant that is not predicted/observed to alter splicing.","Gene-specific,Strength"
-DCLRE1C (HGNC:17642),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-DCLRE1C (HGNC:17642),PM5,Moderate,"Applicable if a previously established variant is classified as 
-pathogenic
- by SCID VCEP specifications for 
-DCLRE1C.
- Previously established variant must be classified by SCID VCEP specifications for 
-DCLRE1C.",Gene-specific
-DCLRE1C (HGNC:17642),PM5,Supporting,"Applicable if a previously established variant is classified as 
-likely pathogenic
- by SCID VCEP specifications for 
-DCLRE1C.
- Previously established variant must be classified by SCID VCEP specifications for 
-DCLRE1C.","Gene-specific,Strength"
-DCLRE1C (HGNC:17642),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-DCLRE1C (HGNC:17642),PM6,Strong,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-DCLRE1C (HGNC:17642),PM6,Moderate,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-DCLRE1C (HGNC:17642),PM6,Supporting,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-DCLRE1C (HGNC:17642),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-DCLRE1C (HGNC:17642),PP1,Strong,"Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations.",General recommendation
-DCLRE1C (HGNC:17642),PP1,Moderate,"Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations.",General recommendation
-DCLRE1C (HGNC:17642),PP1,Supporting,"Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations.",General recommendation
-DCLRE1C (HGNC:17642),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-DCLRE1C (HGNC:17642),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-DCLRE1C (HGNC:17642),PP3,Supporting,"Only applicable to synonymous or intronic variants predicted to impact splicing by SpliceAI with a delta score greater than or equal to 0.2.
-
-
-Do not apply to missense variants.",General recommendation
-DCLRE1C (HGNC:17642),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-DCLRE1C (HGNC:17642),PP4,Strong,"A patient score of ≥ 7 points
-1
-. 
-
-
-1
-CNV (Copy number variation) testing is required to consider PP4_Strong in order to certify that the variant in question is the causative for the phenotype and not one CNV event corrected by gene therapy and not identified previously (see instructions below).","Disease-specific,Gene-specific"
-DCLRE1C (HGNC:17642),PP4,Moderate,A patient score of 2-<7 points (see instructions below).,"Disease-specific,Gene-specific"
-DCLRE1C (HGNC:17642),PP4,Supporting,A patient score of 1-<2 points (see instructions below).,"Disease-specific,Gene-specific"
-DCLRE1C (HGNC:17642),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-DCLRE1C (HGNC:17642),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-DCLRE1C (HGNC:17642),BA1,Stand Alone,gnomAD popmax filtering allele frequency >0.00346.,Gene-specific
-DCLRE1C (HGNC:17642),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-DCLRE1C (HGNC:17642),BS1,Strong,"gnomAD popmax filtering allele frequency >0.00078
-1
-
-
-1
- Consider also bottleneck populations.",Gene-specific
-DCLRE1C (HGNC:17642),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-DCLRE1C (HGNC:17642),BS2,Supporting,Only to be used when the variant is observed in the homozygous state in a healthy adult.,"Disease-specific,Gene-specific"
-DCLRE1C (HGNC:17642),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-DCLRE1C (HGNC:17642),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-DCLRE1C (HGNC:17642),BS4,Strong,Can be applied without additional specifications.,None
-DCLRE1C (HGNC:17642),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-DCLRE1C (HGNC:17642),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-DCLRE1C (HGNC:17642),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-DCLRE1C (HGNC:17642),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",NA
-DCLRE1C (HGNC:17642),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-DCLRE1C (HGNC:17642),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-DCLRE1C (HGNC:17642),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-DCLRE1C (HGNC:17642),BP7,Supporting,"Applicable to both synonymous variants and deep intronic variants affecting nucleotides at or beyond the +7 (donor) and -21 (acceptor) positions.
-
-
-The variant should be predicted not to impact splicing by at least two out of three 
-in silico
- tools (freely available tools include GeneSplicer, MaxEntScan, NNSplice, SpliceAI, Splicing Sequences Finder (SSF), and varSEAK).
-
-
-Given the potential for poor conservation of genes related to T cell and B cell development among vertebrates, nucleotide conservation is 
-not required
- in order to apply BP7.",General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforFOXN1Version1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforFOXN1Version1.0.0_version=1.0.0.csv
deleted file mode 100644
index 233a382bef65411b04d3d9560d634d047c3525cf..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforFOXN1Version1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,159 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-FOXN1 (HGNC:12765),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-FOXN1 (HGNC:12765),PVS1,Very Strong,"Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification:
-
-
-
-
-PVS1 can be applied to variants not predicted to undergo nonsense-mediated decay but removing/altering the critical forkhead domain (amino acids 270-367; Newman et al., 2020; PMID: 31914405) based on recommendations from Walker et. al., 2023 (PMID: 37352859).","General recommendation,Gene-specific"
-FOXN1 (HGNC:12765),PVS1,Strong,"Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with two specifications:
-
-
-
-
-For variants not predicted to undergo nonsense-mediated decay, but removing >10% of protein, (i.e. variants in the last exon, exon 9, or variants in the last 50 nucleotides of the penultimate exon after c.1577, codon 526, in exon 8), at least one pathogenic variant must be present downstream in order to apply PVS1_Strong
-
-
-PVS1_Strong can be applied to variants not predicted to undergo nonsense-mediated decay but removing/altering the transactivation domain (amino acids 511-563; Schlake et al., 2000 PMID: 10767081).","General recommendation,Gene-specific"
-FOXN1 (HGNC:12765),PVS1,Moderate,"Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification:
-
-
-
-
-For variants not predicted to undergo nonsense-mediated decay, but removing >10% of protein, (i.e. variants in the last exon, exon 9, or variants in the last 50 nucleotides of the penultimate exon after c.1577, codon 526, in exon 8), when at least one pathogenic variant is not present downstream downgrade to PVS1_Moderate",General recommendation
-FOXN1 (HGNC:12765),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-FOXN1 (HGNC:12765),PS1,Strong,"Applicable for a same amino acid change if previously established variant is classified as pathogenic by SCID VCEP specifications for 
-FOXN1.
-
-
-Can also be applied for variants with the same predicted splicing event as a known Pathogenic variant (as classified by the SCID VCEP specifications for 
-FOXN1
-), only when the strength of the prediction for the variant under assessment is of similar or higher strength than the strength of the prediction for the comparison (Likely) Pathogenic variant (i.e., per in silico splicing tool SpliceAI). See attached instructions (from Table 2 of PMID: 
-37352859
-) for determining when PS1 should be applied at PS1_Strong, _Moderate, or _Supporting.",Gene-specific
-FOXN1 (HGNC:12765),PS1,Moderate,"Applicable for a same amino acid change if previously established variant is classified as likely pathogenic by SCID VCEP specifications for 
-FOXN1.
-
-
-Can also be applied for variants with the same predicted splicing event as a known (Likely) Pathogenic variant (as classified by the SCID VCEP specifications for 
-FOXN1
-), only when the strength of the prediction for the variant under assessment is of similar or higher strength than the strength of the prediction for the comparison (Likely) Pathogenic variant (i.e., per in silico splicing tool SpliceAI). See attached instructions (from Table 2 of PMID: 
-37352859
-) for determining when PS1 should be applied at PS1_Strong, _Moderate, or _Supporting.","Gene-specific,Strength"
-FOXN1 (HGNC:12765),PS1,Supporting,"Can be applied for variants with the same predicted splicing event as a known (Likely) Pathogenic variant (as classified by the SCID VCEP specifications for 
-FOXN1
-), only when the strength of the prediction for the variant under assessment is of similar or higher strength than the strength of the prediction for the comparison (Likely) Pathogenic variant (i.e., per in silico splicing tool SpliceAI). See attached instructions (from Table 2 of PMID: 
-37352859
-) for determining when PS1 should be applied at PS1_Strong, _Moderate, or _Supporting.","Gene-specific,Strength"
-FOXN1 (HGNC:12765),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-FOXN1 (HGNC:12765),PS2,Very Strong,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-FOXN1 (HGNC:12765),PS2,Strong,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-FOXN1 (HGNC:12765),PS2,Moderate,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-FOXN1 (HGNC:12765),PS2,Supporting,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-FOXN1 (HGNC:12765),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-FOXN1 (HGNC:12765),PS3,Strong,PS3 may be applied at the strong level for evidence from an animal model expressing the variant of interest and recapitulating FOXN1 deficiency (i.e. a mouse model with T cell lymphopenia).,Gene-specific
-FOXN1 (HGNC:12765),PS3,Moderate,"PS3 may be applied at the moderate level based on a luciferase assay showing reduced (<50%) activity, as part of a validated assay with pathogenic and benign controls (PMID: 37419334).","Gene-specific,Strength"
-FOXN1 (HGNC:12765),PS3,Supporting,"PS3 may be applied at the supporting level based on a luciferase assay, without sufficient validation controls, showing reduced (<50%) activity, such as those reported in PMIDs: 31566583, 33464451, 34860543.","Gene-specific,Strength"
-FOXN1 (HGNC:12765),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-FOXN1 (HGNC:12765),PS4,Very Strong,Sum of case scores ≥8 points (see instructions below),Disease-specific
-FOXN1 (HGNC:12765),PS4,Strong,Sum of case scores 4-7.75 points (see instructions below),Disease-specific
-FOXN1 (HGNC:12765),PS4,Moderate,Sum of case scores 2-3.75 points (see instructions below),Disease-specific
-FOXN1 (HGNC:12765),PS4,Supporting,Sum of case scores 1-1.75 points (see instructions below),Disease-specific
-FOXN1 (HGNC:12765),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-FOXN1 (HGNC:12765),PM1,Moderate,"Applicable for variants in the DNA binding forkhead domain (amino acids 270-367), which is a well-established functional domain (Newman et al., 2020; PMID: 31914405) of 
-FOXN1
- with low tolerance for benign variation.",Gene-specific
-FOXN1 (HGNC:12765),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-FOXN1 (HGNC:12765),PM2,Supporting,gnomAD Grpmax filtering allele frequency ≤0.00002412,Gene-specific
-FOXN1 (HGNC:12765),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-FOXN1 (HGNC:12765),PM3,Very Strong,Sum of case scores ≥8 points (see instructions below),General recommendation
-FOXN1 (HGNC:12765),PM3,Strong,Sum of case scores 4-7.75 points (see instructions below),General recommendation
-FOXN1 (HGNC:12765),PM3,Moderate,Sum of case scores 2-3.75 points (see instructions below),General recommendation
-FOXN1 (HGNC:12765),PM3,Supporting,Sum of case scores 1-1.75 points (see instructions below),General recommendation
-FOXN1 (HGNC:12765),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-FOXN1 (HGNC:12765),PM4,Moderate,"Additional requirement that when applied to deletion variants, the deleted region must contain a known pathogenic or likely pathogenic variant that is not predicted/observed to alter splicing.",Gene-specific
-FOXN1 (HGNC:12765),PM4,Supporting,"Additional requirement that when applied to deletion variants, the deleted region must contain a known VUS variant that is not predicted/observed to alter splicing.","Gene-specific,Strength"
-FOXN1 (HGNC:12765),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-FOXN1 (HGNC:12765),PM5,Moderate,"Applicable if previously established variant is classified as pathogenic by SCID VCEP specifications for 
-FOXN1.
- Previously established variant must be classified by SCID VCEP specifications for 
-FOXN1.",Gene-specific
-FOXN1 (HGNC:12765),PM5,Supporting,"Applicable if previously established variant is classified as likely pathogenic by SCID VCEP specifications for 
-FOXN1.
- Previously established variant must be classified by SCID VCEP specifications for 
-FOXN1.","Gene-specific,Strength"
-FOXN1 (HGNC:12765),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-FOXN1 (HGNC:12765),PM6,Strong,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-FOXN1 (HGNC:12765),PM6,Moderate,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-FOXN1 (HGNC:12765),PM6,Supporting,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-FOXN1 (HGNC:12765),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-FOXN1 (HGNC:12765),PP1,Strong,"Can be applied when there is a 32:1 likelihood ratio (LOD score ≥1.5, summed across all families with segregation evidence) per recommendations from PMID: 30311386 Table 4a. See instructions for calculating the estimated LOD score.",General recommendation
-FOXN1 (HGNC:12765),PP1,Moderate,"Can be applied when there is a 16:1 likelihood ratio (LOD score 1.2-<1.5, summed across all families with segregation evidence) per recommendations from PMID: 30311386 Table 4a. See instructions for calculating the estimated LOD score.",General recommendation
-FOXN1 (HGNC:12765),PP1,Supporting,"Can be applied when there is a 4:1 likelihood ratio (LOD score 0.6-<1.2, summed across all families with segregation evidence) per recommendations from PMID: 30311386 Table 4a. See instructions for calculating the estimated LOD score.",General recommendation
-FOXN1 (HGNC:12765),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-FOXN1 (HGNC:12765),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-FOXN1 (HGNC:12765),PP3,Moderate,"Moderate evidence can be applied for a REVEL score of ≥0.932, downgraded from the recommendation of Strong in Pejaver et al., 2022 (PMID: 36413997).",General recommendation
-FOXN1 (HGNC:12765),PP3,Supporting,"Supporting evidence can be applied for a REVEL score of ≥0.644 (to <0.932), based on recommendations of Pejaver et al., 2022 (PMID: 36413997).
-
-
-Also applicable to missense, synonymous, or intronic variants predicted to impact splicing by SpliceAI ∆ score ≥0.2",General recommendation
-FOXN1 (HGNC:12765),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-FOXN1 (HGNC:12765),PP4,Moderate,Patient score of ≥2 points (see instructions below),"Disease-specific,Gene-specific"
-FOXN1 (HGNC:12765),PP4,Supporting,Patient score of 1-<2 points (see instructions below),"Disease-specific,Gene-specific"
-FOXN1 (HGNC:12765),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-FOXN1 (HGNC:12765),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-FOXN1 (HGNC:12765),BA1,Stand Alone,gnomAD Grpmax filtering allele frequency >0.00447,Gene-specific
-FOXN1 (HGNC:12765),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-FOXN1 (HGNC:12765),BS1,Strong,gnomAD Grpmax filtering allele frequency >0.00141 OR a bottle-necked population with a MAF >0.00141 may be used for this criterion. Caveat: If the variant is known to be a founder variant in the bottle-necked population do not consider the frequency in that population for BS1.,Gene-specific
-FOXN1 (HGNC:12765),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",NA
-FOXN1 (HGNC:12765),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-FOXN1 (HGNC:12765),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-FOXN1 (HGNC:12765),BS4,Strong,"Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",None
-FOXN1 (HGNC:12765),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-FOXN1 (HGNC:12765),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-FOXN1 (HGNC:12765),BP2,Supporting,"Applicable only when observed in cis with a pathogenic variant in any inheritance pattern, with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for 
-FOXN1.",Disease-specific
-FOXN1 (HGNC:12765),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-FOXN1 (HGNC:12765),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-FOXN1 (HGNC:12765),BP4,Supporting,"•Supporting evidence can be applied for a REVEL score of <0.290 based on recommendations of Pejaver et al., 2022 (PMID: 36413997).
-
-
-•Also applicable to synonymous or intronic variants not predicted to impact splicing by SpliceAI ∆ score ≤0.1",General recommendation
-FOXN1 (HGNC:12765),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-FOXN1 (HGNC:12765),BP5,Supporting,Use with no specification.,None
-FOXN1 (HGNC:12765),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-FOXN1 (HGNC:12765),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-FOXN1 (HGNC:12765),BP7,Supporting,"A synonymous variant, or deep intronic variant affecting nucleotides at or beyond the +7 (donor) and -21 (acceptor) positions, for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site (SpliceAI ∆ score ≤0.1) AND the nucleotide is not highly conserved.",General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforIL2RGVersion1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforIL2RGVersion1.0.0_version=1.0.0.csv
deleted file mode 100644
index d134464d4c319b6e85d3d931a564b056bc5f9bef..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforIL2RGVersion1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,259 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-IL2RG (HGNC:6010),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-IL2RG (HGNC:6010),PVS1,Very Strong,"Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification:
-
-
-
-
-PVS1 at default strength (Very Strong) can be applied to variants not predicted to undergo nonsense-mediated decay but truncating the transmembrane domain (which begins at amino acid 255) or any distal region (i.e. cytoplasmic domain) due to the lack of functionality of the protein expressed with this defect.","General recommendation,Gene-specific"
-IL2RG (HGNC:6010),PVS1,Strong,"Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification:
-
-
-
-
-For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein (i.e. variants in the last exon, exon 8, or variants in the last 50 nucleotides of the penultimate exon after c.874, codon 292, in exon 7), at least one pathogenic variant 
-must be
- present downstream in order to apply PVS1_Strong","General recommendation,Gene-specific"
-IL2RG (HGNC:6010),PVS1,Moderate,"Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification:
-
-
-
-
-For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein (i.e. variants in the last exon, exon 8, or variants in the last 50 nucleotides of the penultimate exon after c.874, codon 292, in exon 7), when at least one pathogenic variant is 
-not
- present downstream downgrade to PVS1_Moderate.",General recommendation
-IL2RG (HGNC:6010),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-IL2RG (HGNC:6010),PS1,Strong,"It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be pathogenic, can use PS1 for c.105+1G>T.
-
-
-Applicable if the previously established variant is classified as 
-pathogenic
- by SCID VCEP specifications for 
-IL2RG
-.",Gene-specific
-IL2RG (HGNC:6010),PS1,Moderate,"It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be likely pathogenic, can use PS1 for c.105+1G>T
-
-
-Applicable if the previously established variant is classified as 
-likely pathogenic
- by SCID VCEP specifications for 
-IL2RG.","Gene-specific,Strength"
-IL2RG (HGNC:6010),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-IL2RG (HGNC:6010),PS2,Very Strong,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-IL2RG (HGNC:6010),PS2,Strong,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-IL2RG (HGNC:6010),PS2,Moderate,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-IL2RG (HGNC:6010),PS2,Supporting,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-IL2RG (HGNC:6010),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-IL2RG (HGNC:6010),PS3,Strong,PS3 may potentially be applied at the default strength level of strong for evidence from an animal model expressing the variant of interest and recapitulating the IL2RG-SCID phenotype. Animal models will be reviewed on a case-by-case basis by the VCEP to determine the appropriate strength level.,Gene-specific
-IL2RG (HGNC:6010),PS3,Supporting,"PS3_Supporting can be applied based on an abnormal result in 
-at least
- one approved 
-in vitro
- assay.
-
-
-
-
-Approved assay instances:
-
-
-Phosphorylation of JAK3/Co-Immunoprecipitation with JAK3
-
-
-Sharfe et al., 1997 (PMID: 9399950)
-
-
-Kumaki et al., 1999 (PMID: 9933465)
-
-
-Arcas-García et al., 2020 (PMID: 31799703)
-
-
-
-
-
-
-Cytokine binding
-
-
-Sharfe et al., 1997 (PMID: 9399950)
-
-
-Kumaki et al., 1995 (PMID: 7632950)
-
-
-
-
-
-
-Surface expression of the gamma chain
-
-
-Kumaki et al., 1995 (PMID: 7632950)
-
-
-
-
-
-
-Interaction profiling-BioID
-
-
-Tuovinen et al., 2020 (PMID: 32072341)
-
-
-
-
-
-
-
-
-
-
-
-
-At least one previously observed proband with the IL2RG variant meeting PP4 is required to apply PS3 at any strength on the basis of a cellular model/in vitro study.",Gene-specific
-IL2RG (HGNC:6010),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-IL2RG (HGNC:6010),PS4,Very Strong,Sum of case scores >16 points (see instructions below),Disease-specific
-IL2RG (HGNC:6010),PS4,Strong,Sum of case scores 4.5-16 points (see instructions below),Disease-specific
-IL2RG (HGNC:6010),PS4,Moderate,Sum of case scores 2.5-4 points (see instructions below),Disease-specific
-IL2RG (HGNC:6010),PS4,Supporting,Sum of case scores 1-2 points (see instructions below),Disease-specific
-IL2RG (HGNC:6010),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-IL2RG (HGNC:6010),PM1,Strong,"Defined to include missense alterations of the following positions:
-
-
-Affecting a conserved cysteine residue: Cys62 , Cys72 , Cys102, Cys115
-
-
-Affecting CpG dinucleotides: c.684C (Arg224), c.690C (Arg226), c.691G (Arg691), c.868G (Arg285) (PMID: 7668284)
-
-
-Affecting the WSxWS motif: Trp237, Ser238, Glu239, Trp240, Ser241
-
-
-Affecting a transmembrane domain residue by introducing a charged or polar residue (Asn, Asp, Arg, Cys, His, Glu, Gln, Lys, Ser, Thr, Tyr): amino acids 263-283","Gene-specific,Strength"
-IL2RG (HGNC:6010),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-IL2RG (HGNC:6010),PM2,Supporting,"gnomAD popmax filtering allele frequency <0.000124 
-
-
-
-
-Additional requirement that no 
-hemizygotes
- have been observed in gnomAD.","Gene-specific,Strength"
-IL2RG (HGNC:6010),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-IL2RG (HGNC:6010),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-IL2RG (HGNC:6010),PM4,Moderate,"When applied to deletion variants, the deleted region must contain a known 
-pathogenic
- or 
-likely pathogenic
- variant that is not predicted/observed to alter splicing.",Gene-specific
-IL2RG (HGNC:6010),PM4,Supporting,"When applied to deletion variants, the deleted region must contain a known 
-VUS
- variant that is not predicted/observed to alter splicing.","Gene-specific,Strength"
-IL2RG (HGNC:6010),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-IL2RG (HGNC:6010),PM5,Moderate,"Applicable if a previously established variant is classified as 
-pathogenic
- by SCID VCEP specifications for 
-IL2RG.
- Previously established variant must be classified by SCID VCEP specifications for 
-IL2RG.",Gene-specific
-IL2RG (HGNC:6010),PM5,Supporting,"Applicable if a previously established variant is classified as 
-likely pathogenic
- by SCID VCEP specifications for 
-IL2RG.
- Previously established variant must be classified by SCID VCEP specifications for 
-IL2RG.","Gene-specific,Strength"
-IL2RG (HGNC:6010),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-IL2RG (HGNC:6010),PM6,Strong,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-IL2RG (HGNC:6010),PM6,Moderate,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-IL2RG (HGNC:6010),PM6,Supporting,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-IL2RG (HGNC:6010),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-IL2RG (HGNC:6010),PP1,Strong,"Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations.",General recommendation
-IL2RG (HGNC:6010),PP1,Moderate,"Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations.",General recommendation
-IL2RG (HGNC:6010),PP1,Supporting,"Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations.",General recommendation
-IL2RG (HGNC:6010),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-IL2RG (HGNC:6010),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-IL2RG (HGNC:6010),PP3,Supporting,"Only applicable to synonymous or intronic variants predicted to impact splicing by SpliceAI with a delta score greater than or equal to 0.2.
-
-
-
-
-Do not apply to missense variants.",General recommendation
-IL2RG (HGNC:6010),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-IL2RG (HGNC:6010),PP4,Strong,"A patient score of ≥ 8 points
-1
-. 
-
-
-1
-CNV (Copy number variation) testing is required to consider PP4_Strong in order to certify that the variant in question is the causative for the phenotype and not one CNV event corrected by gene therapy and not identified previously (see instructions below).","Disease-specific,Gene-specific"
-IL2RG (HGNC:6010),PP4,Moderate,A patient score of ≥2-7 points (see instructions below).,"Disease-specific,Gene-specific"
-IL2RG (HGNC:6010),PP4,Supporting,A patient score of 1-<2 points (see instructions below).,"Disease-specific,Gene-specific"
-IL2RG (HGNC:6010),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-IL2RG (HGNC:6010),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-IL2RG (HGNC:6010),BA1,Stand Alone,gnomAD popmax filtering allele frequency >0.01110.,Gene-specific
-IL2RG (HGNC:6010),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-IL2RG (HGNC:6010),BS1,Strong,"gnomAD popmax filtering allele frequency >0.00249
-1
-
-
-1
- Consider also bottleneck populations.",Gene-specific
-IL2RG (HGNC:6010),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-IL2RG (HGNC:6010),BS2,Strong,BS2_Strong: Observed in >=3 (3 or more) hemizygotes in gnomAD.,Gene-specific
-IL2RG (HGNC:6010),BS2,Supporting,BS2_Supporting: Can be applied at Supporting level of evidence if observed at least 2 hemizygotes in gnomAD.,Gene-specific
-IL2RG (HGNC:6010),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-IL2RG (HGNC:6010),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-IL2RG (HGNC:6010),BS4,Strong,Can be applied without additional specifications.,None
-IL2RG (HGNC:6010),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-IL2RG (HGNC:6010),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-IL2RG (HGNC:6010),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-IL2RG (HGNC:6010),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",NA
-IL2RG (HGNC:6010),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-IL2RG (HGNC:6010),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-IL2RG (HGNC:6010),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-IL2RG (HGNC:6010),BP7,Supporting,"Applicable to both synonymous variants and deep intronic variants affecting nucleotides at or beyond the +7 (donor) and -21 (acceptor) positions.
-
-
-The variant should be predicted not to impact splicing by at least two out of three 
-in silico
- tools (freely available tools include GeneSplicer, MaxEntScan, NNSplice, SpliceAI, Splicing Sequences Finder (SSF), and varSEAK).
-
-
-Given the potential for poor conservation of genes related to T cell and B cell development among vertebrates, nucleotide conservation is 
-not required
- in order to apply BP7.",General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforIL7RVersion1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforIL7RVersion1.0.0_version=1.0.0.csv
deleted file mode 100644
index 7d81a69cf36c13af2854b3436949a10b2ccb6e36..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforIL7RVersion1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,233 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-IL7R (HGNC:6024),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-IL7R (HGNC:6024),PVS1,Very Strong,"Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)).","General recommendation,Gene-specific"
-IL7R (HGNC:6024),PVS1,Strong,"Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with two specifications:
-
-
-
-
-For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein (i.e. variants in the last exon, exon 8, or variants in the last 50 nucleotides of the penultimate exon after c.826, codon 276, in exon 7), at least one pathogenic variant 
-must be
- present downstream in order to apply PVS1_Strong.
-
-
-PVS1_Strong can be applied to variants not predicted to undergo nonsense-mediated decay but causing truncation of the transmembrane domain (which begins at amino acid 240) or any distal region (i.e. cytoplasmatic domain).","General recommendation,Gene-specific"
-IL7R (HGNC:6024),PVS1,Moderate,"Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification:
-
-
-
-
-For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein (i.e. variants in the last exon, exon 8, or variants in the last 50 nucleotides of the penultimate exon after c.826, codon 276, in exon 7), when at least one pathogenic variant is 
-not
- present downstream downgrade to PVS1_Moderate.",General recommendation
-IL7R (HGNC:6024),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-IL7R (HGNC:6024),PS1,Strong,"It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be pathogenic, can use PS1 for c.105+1G>T.
-
-
-Applicable if the previously established variant is classified as 
-pathogenic
- by SCID VCEP specifications for 
-IL7R.",Gene-specific
-IL7R (HGNC:6024),PS1,Moderate,"It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be likely pathogenic, can use PS1 for c.105+1G>T
-
-
-Applicable if the previously established variant is classified as 
-likely pathogenic
- by SCID VCEP specifications for 
-IL7R.","Gene-specific,Strength"
-IL7R (HGNC:6024),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-IL7R (HGNC:6024),PS2,Very Strong,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-IL7R (HGNC:6024),PS2,Strong,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-IL7R (HGNC:6024),PS2,Moderate,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-IL7R (HGNC:6024),PS2,Supporting,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-IL7R (HGNC:6024),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-IL7R (HGNC:6024),PS3,Strong,PS3 may potentially be applied at the default strength level of strong for evidence from an animal model expressing the variant of interest and recapitulating the IL7R-SCID phenotype. Animal models will be reviewed on a case-by-case basis by the VCEP to determine the appropriate strength level.,Gene-specific
-IL7R (HGNC:6024),PS3,Supporting,"PS3_Supporting can be applied based on an abnormal result in 
-at least
- 
-one
- approved 
-in vitro
- assay (IL-7-induced Jak3 phosphorylation assay, IL-7 binding assay, IL-7-induced STAT5 DNA binding/transcriptional induction).
-
-
-
-
-Approved assay instances:
-
-
-IL-7-induced Jak3 phosphorylation assay
-
-
-Roifman et al., 2000 (PMID: 11023514)
-
-
-
-
-
-
-IL-7 binding assay
-
-
-Puel et al., 1998 (PMID: 9843216)
-
-
-
-
-
-
-IL-7-induced STAT5 DNA binding/transcriptional induction
-
-
-Puel et al., 1998 (PMID: 9843216)
-
-
-
-
-
-
-
-
-
-
-
-
-At least one previously observed proband with the expressed IL7R variant meeting PP4 is required to apply PS3 at any strength on the basis of a cellular model/in vitro study.","Gene-specific,Strength"
-IL7R (HGNC:6024),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",NA
-IL7R (HGNC:6024),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-IL7R (HGNC:6024),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-IL7R (HGNC:6024),PM2,Supporting,"gnomAD popmax filtering allele frequency <0.00004129.
-
-
-
-
-An additional requirement is that 
-no homozygotes
- have been observed in gnomAD.",Gene-specific
-IL7R (HGNC:6024),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-IL7R (HGNC:6024),PM3,Very Strong,"Use ClinGen SVI recommendations for 
-in trans
- criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for 
-IL7R.",General recommendation
-IL7R (HGNC:6024),PM3,Strong,"Use ClinGen SVI recommendations for 
-in trans
- criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for 
-IL7R.",General recommendation
-IL7R (HGNC:6024),PM3,Moderate,"Use ClinGen SVI recommendations for 
-in trans
- criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for 
-IL7R.",General recommendation
-IL7R (HGNC:6024),PM3,Supporting,"Use ClinGen SVI recommendations for 
-in trans
- criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for 
-IL7R.",General recommendation
-IL7R (HGNC:6024),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-IL7R (HGNC:6024),PM4,Moderate,"When applied to deletion variants, the deleted region must contain a known 
-pathogenic
- or 
-likely pathogenic
- variant that is not predicted/observed to alter splicing.",Gene-specific
-IL7R (HGNC:6024),PM4,Supporting,"When applied to deletion variants, the deleted region must contain a known 
-VUS
- variant that is not predicted/observed to alter splicing.","Gene-specific,Strength"
-IL7R (HGNC:6024),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-IL7R (HGNC:6024),PM5,Moderate,"Applicable if a previously established variant is classified as 
-pathogenic
- by SCID VCEP specifications for 
-IL7R.
- Previously established variant must be classified by SCID VCEP specifications for 
-IL7R.",Gene-specific
-IL7R (HGNC:6024),PM5,Supporting,"Applicable if a previously established variant is classified as 
-likely pathogenic
- by SCID VCEP specifications for 
-IL7R.
- Previously established variant must be classified by SCID VCEP specifications for 
-IL7R.","Gene-specific,Strength"
-IL7R (HGNC:6024),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-IL7R (HGNC:6024),PM6,Strong,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-IL7R (HGNC:6024),PM6,Moderate,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-IL7R (HGNC:6024),PM6,Supporting,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-IL7R (HGNC:6024),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-IL7R (HGNC:6024),PP1,Strong,"Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations.",General recommendation
-IL7R (HGNC:6024),PP1,Moderate,"Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations.",General recommendation
-IL7R (HGNC:6024),PP1,Supporting,"Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations.",General recommendation
-IL7R (HGNC:6024),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-IL7R (HGNC:6024),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-IL7R (HGNC:6024),PP3,Supporting,"Only applicable to synonymous or intronic variants predicted to impact splicing by SpliceAI with a delta score greater than or equal to 0.2.
-
-
-Do not apply to missense variants.",General recommendation
-IL7R (HGNC:6024),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-IL7R (HGNC:6024),PP4,Strong,"A patient score of ≥ 6 points
-1
-. 
-
-
-1
-CNV (Copy number variation) testing is required to consider PP4_Strong in order to certify that the variant in question is the causative for the phenotype and not one CNV event corrected by gene therapy and not identified previously (see instructions below).","Disease-specific,Gene-specific"
-IL7R (HGNC:6024),PP4,Moderate,A patient score of 2-<6 points (see instructions below).,"Disease-specific,Gene-specific"
-IL7R (HGNC:6024),PP4,Supporting,A patient score of 1-<2 points (see instructions below).,"Disease-specific,Gene-specific"
-IL7R (HGNC:6024),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-IL7R (HGNC:6024),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-IL7R (HGNC:6024),BA1,Stand Alone,gnomAD popmax filtering allele frequency >0.00566.,Gene-specific
-IL7R (HGNC:6024),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-IL7R (HGNC:6024),BS1,Strong,"gnomAD popmax filtering allele frequency >0.00126
-1
-
-
-1
-Consider also bottleneck populations.",Gene-specific
-IL7R (HGNC:6024),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-IL7R (HGNC:6024),BS2,Supporting,Only to be used when the variant is observed in the homozygous state in a healthy adult.,Strength
-IL7R (HGNC:6024),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-IL7R (HGNC:6024),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-IL7R (HGNC:6024),BS4,Strong,Can be applied without additional specifications.,None
-IL7R (HGNC:6024),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-IL7R (HGNC:6024),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-IL7R (HGNC:6024),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-IL7R (HGNC:6024),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",NA
-IL7R (HGNC:6024),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-IL7R (HGNC:6024),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-IL7R (HGNC:6024),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-IL7R (HGNC:6024),BP7,Supporting,"Applicable to both synonymous variants and deep intronic variants affecting nucleotides at or beyond the +7 (donor) and -21 (acceptor) positions.
-
-
-The variant should be predicted not to impact splicing by at least two out of three 
-in silico
- tools (freely available tools include GeneSplicer, MaxEntScan, NNSplice, SpliceAI, Splicing Sequences Finder (SSF), and varSEAK).
-
-
-Given the potential for poor conservation of genes related to T cell and B cell development among vertebrates, nucleotide conservation is not required in order to apply BP7.",Disease-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforJAK3Version1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforJAK3Version1.0.0_version=1.0.0.csv
deleted file mode 100644
index 462bb4f5d2e2265be4cb05d73268bf1e3f99a434..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforJAK3Version1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,193 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-JAK3 (HGNC:6193),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-JAK3 (HGNC:6193),PVS1,Very Strong,"Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)).","General recommendation,Gene-specific"
-JAK3 (HGNC:6193),PVS1,Strong,"Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification:
-
-
-
-
-For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein (i.e. variants in the last exon, exon 24, or variants in the last 50 nucleotides of the penultimate exon after c.3157, codon 1053, in exon 23), at least one pathogenic variant 
-must be
- present downstream in order to apply PVS1_Strong.","General recommendation,Gene-specific"
-JAK3 (HGNC:6193),PVS1,Moderate,"Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification:
-
-
-
-
-For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein (i.e. variants in the last exon, exon 24, or variants in the last 50 nucleotides of the penultimate exon after c.3157, codon 1053, in exon 23), when at least one pathogenic variant is 
-not
- present downstream downgrade to PVS1_Moderate.",General recommendation
-JAK3 (HGNC:6193),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-JAK3 (HGNC:6193),PS1,Strong,"It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be pathogenic, can use PS1 for c.105+1G>T.
-
-
-Applicable if the previously established variant is classified as 
-pathogenic
- by SCID VCEP specifications for 
-JAK3.",Gene-specific
-JAK3 (HGNC:6193),PS1,Moderate,"It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be likely pathogenic, can use PS1 for c.105+1G>T
-
-
-Applicable if the previously established variant is classified as 
-likely pathogenic
- by SCID VCEP specifications for 
-JAK3.","Gene-specific,Strength"
-JAK3 (HGNC:6193),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-JAK3 (HGNC:6193),PS2,Very Strong,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-JAK3 (HGNC:6193),PS2,Strong,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-JAK3 (HGNC:6193),PS2,Moderate,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-JAK3 (HGNC:6193),PS2,Supporting,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-JAK3 (HGNC:6193),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-JAK3 (HGNC:6193),PS3,Strong,PS3 may potentially be applied at the default strength level of strong for evidence from an animal model expressing the variant of interest and recapitulating the JAK3-SCID phenotype. Animal models will be reviewed on a case-by-case basis by the VCEP to determine the appropriate strength level.,Gene-specific
-JAK3 (HGNC:6193),PS3,Supporting,"PS3_Supporting can be applied based on an abnormal result in an 
-in vitro
- kinase activity assay.
-
-
-
-
-Approved assay instance: Roberts et al., 2004 (PMID: 14615376).
-
-
-
-
-At least one previously observed proband with the JAK3 variant meeting PP4 is required to apply PS3 at any strength on the basis of a cellular model/in vitro study.","Gene-specific,Strength"
-JAK3 (HGNC:6193),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",NA
-JAK3 (HGNC:6193),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-JAK3 (HGNC:6193),PM1,Moderate,Defined to include missense alterations of two JH2 domain residues: R651W and C759R (PMID: 11668610).,Gene-specific
-JAK3 (HGNC:6193),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-JAK3 (HGNC:6193),PM2,Supporting,"gnomAD popmax filtering allele frequency  <0.000115
-
-
-
-
-An additional requirement is that 
-no homozygotes
- have been observed in gnomAD.",Gene-specific
-JAK3 (HGNC:6193),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-JAK3 (HGNC:6193),PM3,Very Strong,"Use ClinGen SVI recommendations for 
-in trans
- criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for 
-JAK3.",General recommendation
-JAK3 (HGNC:6193),PM3,Strong,"Use ClinGen SVI recommendations for 
-in trans
- criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for 
-JAK3.",General recommendation
-JAK3 (HGNC:6193),PM3,Moderate,"Use ClinGen SVI recommendations for 
-in trans
- criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for 
-JAK3.",General recommendation
-JAK3 (HGNC:6193),PM3,Supporting,"Use ClinGen SVI recommendations for 
-in trans
- criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for 
-JAK3.",General recommendation
-JAK3 (HGNC:6193),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-JAK3 (HGNC:6193),PM4,Moderate,"When applied to deletion variants, the deleted region must contain a known 
-pathogenic
- or 
-likely pathogenic
- variant that is not predicted/observed to alter splicing.",Gene-specific
-JAK3 (HGNC:6193),PM4,Supporting,"When applied to deletion variants, the deleted region must contain a known 
-VUS
- variant that is not predicted/observed to alter splicing.","Gene-specific,Strength"
-JAK3 (HGNC:6193),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-JAK3 (HGNC:6193),PM5,Moderate,"Applicable if a previously established variant is classified as 
-pathogenic
- by SCID VCEP specifications for 
-JAK3.
- Previously established variant must be classified by SCID VCEP specifications for 
-JAK3.",Gene-specific
-JAK3 (HGNC:6193),PM5,Supporting,"Applicable if a previously established variant is classified as 
-likely pathogenic
- by SCID VCEP specifications for 
-JAK3.
- Previously established variant must be classified by SCID VCEP specifications for 
-JAK3.","Gene-specific,Strength"
-JAK3 (HGNC:6193),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-JAK3 (HGNC:6193),PM6,Strong,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-JAK3 (HGNC:6193),PM6,Moderate,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-JAK3 (HGNC:6193),PM6,Supporting,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-JAK3 (HGNC:6193),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-JAK3 (HGNC:6193),PP1,Strong,"Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations.",General recommendation
-JAK3 (HGNC:6193),PP1,Moderate,"Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations.",General recommendation
-JAK3 (HGNC:6193),PP1,Supporting,"Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations.",General recommendation
-JAK3 (HGNC:6193),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-JAK3 (HGNC:6193),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-JAK3 (HGNC:6193),PP3,Supporting,"Only applicable to synonymous or intronic variants predicted to impact splicing by SpliceAI with a delta score greater than or equal to 0.2.
-
-
-Do not apply to missense variants.",General recommendation
-JAK3 (HGNC:6193),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-JAK3 (HGNC:6193),PP4,Strong,"A patient score of ≥ 6 points
-1
-. 
-
-
-1
-CNV (Copy number variation) testing is required to consider PP4_Strong in order to certify that the variant in question is the causative for the phenotype and not one CNV event corrected by gene therapy and not identified previously (see instructions below).","Disease-specific,Gene-specific"
-JAK3 (HGNC:6193),PP4,Moderate,A patient score of 2-<6 points (see instructions below).,"Disease-specific,Gene-specific"
-JAK3 (HGNC:6193),PP4,Supporting,A patient score of 1-<2 points (see instructions below).,"Disease-specific,Gene-specific"
-JAK3 (HGNC:6193),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-JAK3 (HGNC:6193),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-JAK3 (HGNC:6193),BA1,Stand Alone,gnomAD popmax filtering allele frequency >0.00447,Gene-specific
-JAK3 (HGNC:6193),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-JAK3 (HGNC:6193),BS1,Strong,"gnomAD popmax filtering allele frequency >0.00100
-1
-
-
-1
-Consider also bottleneck populations.",Gene-specific
-JAK3 (HGNC:6193),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-JAK3 (HGNC:6193),BS2,Supporting,Only to be used when the variant is observed in the homozygous state in a healthy adult.,Strength
-JAK3 (HGNC:6193),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-JAK3 (HGNC:6193),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-JAK3 (HGNC:6193),BS4,Strong,Can be applied without additional specifications.,"General recommendation,None"
-JAK3 (HGNC:6193),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-JAK3 (HGNC:6193),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-JAK3 (HGNC:6193),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-JAK3 (HGNC:6193),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",NA
-JAK3 (HGNC:6193),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-JAK3 (HGNC:6193),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-JAK3 (HGNC:6193),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-JAK3 (HGNC:6193),BP7,Supporting,"Applicable to both synonymous variants and deep intronic variants affecting nucleotides at or beyond the +7 (donor) and -21 (acceptor) positions.
-
-
-The variant should be predicted not to impact splicing by at least two out of three 
-in silico
- tools (freely available tools include GeneSplicer, MaxEntScan, NNSplice, SpliceAI, Splicing Sequences Finder (SSF), and varSEAK).
-
-
-Given the potential for poor conservation of genes related to T cell and B cell development among vertebrates, nucleotide conservation is not required in order to apply BP7.",Disease-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRAG1Version1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRAG1Version1.0.0_version=1.0.0.csv
deleted file mode 100644
index b32a1022450af229c84d32985e339a4d7e7cdded..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRAG1Version1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,250 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-RAG1 (HGNC:9831),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-RAG1 (HGNC:9831),PVS1,Very Strong,"Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with two specifications:
-
-
-
-
-Given that the 
-RAG1
- protein is encoded by a single exon (based on MANE Select transcript NM_000448.3) and nonsense-mediated decay is not predicted for nonsense or frameshift variants, PVS1 cannot be applied at the default strength to RAG1 variants (indicated by the red boxes in the Flowchart attached), 
-except
- in the case of full gene deletion 
-or
- removing/altering critical domain for the protein (NBD domain, DDBD domain, and core domain, indicated by the purple in the Flowchart).
-
-
-PVS1 can be applied to variants not predicted to undergo nonsense-mediated decay when removing/altering the critical NBD domain (aa 394-460), DDBD domain (aa 461-517), and core domain (aa 387-1011) based on recommendations from Walker et al., preprint.","General recommendation,Gene-specific"
-RAG1 (HGNC:9831),PVS1,Strong,"Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification:
-
-
-
-
-For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein, at least one pathogenic variant 
-must be
- present downstream in order to apply PVS1_Strong.","General recommendation,Gene-specific"
-RAG1 (HGNC:9831),PVS1,Moderate,"Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification:
-
-
-
-
-For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein, when at least one pathogenic variant is 
-not
- present downstream, downgrade to PVS1_Moderate.",General recommendation
-RAG1 (HGNC:9831),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RAG1 (HGNC:9831),PS1,Strong,"It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be pathogenic, can use PS1 for c.105+1G>T.
-
-
-Applicable if the previously established variant is classified as 
-pathogenic
- by SCID VCEP specifications for 
-RAG1.",Gene-specific
-RAG1 (HGNC:9831),PS1,Moderate,"It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be likely pathogenic, can use PS1 for c.105+1G>T
-
-
-Applicable if the previously established variant is classified as 
-likely pathogenic
- by SCID VCEP specifications for 
-RAG1.","Gene-specific,Strength"
-RAG1 (HGNC:9831),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-RAG1 (HGNC:9831),PS2,Very Strong,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-RAG1 (HGNC:9831),PS2,Strong,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-RAG1 (HGNC:9831),PS2,Moderate,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-RAG1 (HGNC:9831),PS2,Supporting,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-RAG1 (HGNC:9831),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-RAG1 (HGNC:9831),PS3,Strong,PS3 may potentially be applied at the default strength level of strong for evidence from an animal model expressing the variant of interest and recapitulating the RAG1-SCID phenotype.,Gene-specific
-RAG1 (HGNC:9831),PS3,Moderate,"The strength of evidence from cellular models/
-in vitro
- studies is dependent upon the abnormal result in a V(D)J recombination assay:
-
-
-
-
-PS3_Moderate: <25% of wild-type activity in Lee et al., 2014 (PMID: 24290284);
-
-
-
-
-At least one previously observed proband with the expressed RAG1 variant meeting PP4 is required to apply PS3 at any strength.",Gene-specific
-RAG1 (HGNC:9831),PS3,Supporting,"The strength of evidence from cellular models/
-in vitro
- studies is dependent upon the abnormal result in a V(D)J recombination assay:
-
-
-
-
-PS3_Supporting:
-
-
-25-60% of wild-type activity in Lee et al., 2014 (PMID: 24290284) 
-OR
-
-
-Reduced activity compared to wild type in Corneo et al., 2001 (PMID: 11313270);
-
-
-
-
-
-
-
-
-At least one previously observed proband with the expressed RAG1 variant meeting PP4 is required to apply PS3 at any strength.","Gene-specific,Strength"
-RAG1 (HGNC:9831),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",NA
-RAG1 (HGNC:9831),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-RAG1 (HGNC:9831),PM1,Moderate,"Strength is dependent upon the location of the variant within specific functional domains (PMID: 26996199):
-
-
-
-
-PM1_Moderate: missense variant located in the 
-NBD domain
- (amino acids 394-460) and 
-DDBD domain
- (amino acids 461-517).",Gene-specific
-RAG1 (HGNC:9831),PM1,Supporting,"Strength is dependent upon the location of the variant within specific functional domains (PMID: 26996199):
-
-
-
-
-PM1_Supporting: missense variant located elsewhere in the 
-core domain
- (amino acids 387-1011)",Gene-specific
-RAG1 (HGNC:9831),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-RAG1 (HGNC:9831),PM2,Supporting,"gnomAD popmax filtering allele frequency  <0.000102 
-
-
-
-
-An additional requirement is that 
-no homozygotes
- have been observed in gnomAD.",Gene-specific
-RAG1 (HGNC:9831),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-RAG1 (HGNC:9831),PM3,Very Strong,"Use ClinGen SVI recommendations for 
-in trans
- criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for 
-RAG1.",General recommendation
-RAG1 (HGNC:9831),PM3,Strong,"Use ClinGen SVI recommendations for 
-in trans
- criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for 
-RAG1.",General recommendation
-RAG1 (HGNC:9831),PM3,Moderate,"Use ClinGen SVI recommendations for 
-in trans
- criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for 
-RAG1.",General recommendation
-RAG1 (HGNC:9831),PM3,Supporting,"Use ClinGen SVI recommendations for 
-in trans
- criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for 
-RAG1.",General recommendation
-RAG1 (HGNC:9831),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-RAG1 (HGNC:9831),PM4,Moderate,"When applied to deletion variants, the deleted region must contain a known 
-pathogenic
- or 
-likely pathogenic
- variant that is not predicted/observed to alter splicing.",Gene-specific
-RAG1 (HGNC:9831),PM4,Supporting,"When applied to deletion variants, the deleted region must contain a known 
-VUS
- variant that is not predicted/observed to alter splicing.","Gene-specific,Strength"
-RAG1 (HGNC:9831),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RAG1 (HGNC:9831),PM5,Moderate,"Applicable if a previously established variant is classified as 
-pathogenic
- by SCID VCEP specifications for 
-RAG1.
- Previously established variant must be classified by SCID VCEP specifications for 
-RAG1.",Gene-specific
-RAG1 (HGNC:9831),PM5,Supporting,"Applicable if a previously established variant is classified as 
-likely pathogenic
- by SCID VCEP specifications for 
-RAG1.
- Previously established variant must be classified by SCID VCEP specifications for 
-RAG1.","Gene-specific,Strength"
-RAG1 (HGNC:9831),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-RAG1 (HGNC:9831),PM6,Strong,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-RAG1 (HGNC:9831),PM6,Moderate,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-RAG1 (HGNC:9831),PM6,Supporting,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-RAG1 (HGNC:9831),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-RAG1 (HGNC:9831),PP1,Strong,"Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations.",General recommendation
-RAG1 (HGNC:9831),PP1,Moderate,"Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations.",General recommendation
-RAG1 (HGNC:9831),PP1,Supporting,"Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations.",General recommendation
-RAG1 (HGNC:9831),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-RAG1 (HGNC:9831),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-RAG1 (HGNC:9831),PP3,Supporting,"Only applicable to synonymous or intronic variants predicted to impact splicing by SpliceAI with a delta score greater than or equal to 0.2.
-
-
-Do not apply to missense variants.",General recommendation
-RAG1 (HGNC:9831),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-RAG1 (HGNC:9831),PP4,Strong,"A patient score of ≥ 4 points
-1
-. 
-
-
-1
-CNV (Copy number variation) testing is required to consider PP4_Strong in order to certify that the variant in question is the causative for the phenotype and not one CNV event corrected by gene therapy and not identified previously (see instructions below).","Disease-specific,Gene-specific"
-RAG1 (HGNC:9831),PP4,Moderate,A patient score of ≥2-<4 points (see instructions below).,"Disease-specific,Gene-specific"
-RAG1 (HGNC:9831),PP4,Supporting,A patient score of 1-<2 points (see instructions below).,"Disease-specific,Gene-specific"
-RAG1 (HGNC:9831),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RAG1 (HGNC:9831),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-RAG1 (HGNC:9831),BA1,Stand Alone,gnomAD popmax filtering allele frequency >0.00872.,Gene-specific
-RAG1 (HGNC:9831),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-RAG1 (HGNC:9831),BS1,Strong,"gnomAD popmax filtering allele frequency  >0.00195
-1
-
-
-1
- Consider also bottleneck populations.",Gene-specific
-RAG1 (HGNC:9831),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-RAG1 (HGNC:9831),BS2,Supporting,Only to be used when the variant is observed in the homozygous state in a healthy adult.,Strength
-RAG1 (HGNC:9831),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-RAG1 (HGNC:9831),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-RAG1 (HGNC:9831),BS4,Strong,Can be applied without additional specifications.,None
-RAG1 (HGNC:9831),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-RAG1 (HGNC:9831),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-RAG1 (HGNC:9831),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-RAG1 (HGNC:9831),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",NA
-RAG1 (HGNC:9831),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-RAG1 (HGNC:9831),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RAG1 (HGNC:9831),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-RAG1 (HGNC:9831),BP7,Supporting,"Applicable to both synonymous variants and deep intronic variants affecting nucleotides at or beyond the +7 (donor) and -21 (acceptor) positions.
-
-
-The variant should be predicted not to impact splicing by at least two out of three 
-in silico
- tools (freely available tools include GeneSplicer, MaxEntScan, NNSplice, SpliceAI, Splicing Sequences Finder (SSF), and varSEAK).
-
-
-Given the potential for poor conservation of genes related to T cell and B cell development among vertebrates, nucleotide conservation is 
-not required
- in order to apply BP7.",General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRAG2Version1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRAG2Version1.0.0_version=1.0.0.csv
deleted file mode 100644
index f7f48be88bed07a673ce9727f2e355669de0d328..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRAG2Version1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,248 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-RAG2 (HGNC:9832),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-RAG2 (HGNC:9832),PVS1,Very Strong,"Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with two specifications:
-
-
-
-
-Given that the 
-RAG2
- protein is encoded by a single exon (based on MANE Select transcript NM_000536.4) and nonsense-mediated decay is not predicted for nonsense or frameshift variants, PVS1 cannot be applied at the default strength to RAG2 variants (indicated by the red boxes in the Flowchart), 
-except
- in the case of full gene deletion 
-or
- removing/altering critical domain: the PHD domain and core domain (indicated by the purple in the Flowchart). 
-
-
-PVS1 can be applied to variants not predicted to undergo nonsense-mediated decay when removing/altering the critical PHD domain (spanning amino acids 414-487) and core domain (amino acids 1-383)  based on recommendations from Walker et al., preprint.","General recommendation,Gene-specific"
-RAG2 (HGNC:9832),PVS1,Strong,"Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification:
-
-
-
-
-For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein, at least one pathogenic variant 
-must be
- present downstream in order to apply PVS1_Strong.","General recommendation,Gene-specific"
-RAG2 (HGNC:9832),PVS1,Moderate,"Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification:
-
-
-
-
-For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein, when at least one pathogenic variant is 
-not
- present downstream, downgrade to PVS1_Moderate.",General recommendation
-RAG2 (HGNC:9832),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RAG2 (HGNC:9832),PS1,Strong,"It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be pathogenic, can use PS1 for c.105+1G>T.
-
-
-Applicable if the previously established variant is classified as 
-pathogenic
- by SCID VCEP specifications for 
-RAG2.",Gene-specific
-RAG2 (HGNC:9832),PS1,Moderate,"It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be likely pathogenic, can use PS1 for c.105+1G>T
-
-
-Applicable if the previously established variant is classified as 
-likely pathogenic
- by SCID VCEP specifications for 
-RAG2.","Gene-specific,Strength"
-RAG2 (HGNC:9832),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-RAG2 (HGNC:9832),PS2,Very Strong,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-RAG2 (HGNC:9832),PS2,Strong,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-RAG2 (HGNC:9832),PS2,Moderate,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-RAG2 (HGNC:9832),PS2,Supporting,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-RAG2 (HGNC:9832),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-RAG2 (HGNC:9832),PS3,Strong,PS3 may potentially be applied at the default strength level of strong for evidence from an animal model expressing the variant of interest and recapitulating the RAG2-SCID phenotype.,Gene-specific
-RAG2 (HGNC:9832),PS3,Moderate,"Strength of evidence from cellular models/
-in vitro
- studies is dependent upon abnormal result in a V(D)J recombination assay:
-
-
-
-
-PS3_Moderate: <25% of wild-type activity in Tirosh et al., 2019 (PMID: 29772310)
-
-
-
-
-At least one previously observed proband with the expressed RAG2 variant meeting PP4 is required to apply PS3 at any strength.","Gene-specific,Strength"
-RAG2 (HGNC:9832),PS3,Supporting,"Strength of evidence from cellular models/
-in vitro
- studies is dependent upon abnormal result in a V(D)J recombination assay:
-
-
-
-
-PS3_Supporting: 
-
-
-25-60% of wild-type activity in Tirosh et al., 2019 (PMID: 29772310) 
-OR
-
-
-Reduced activity compared to wild type in Couëdel et al., 2010 (PMID: 20234091)
-
-
-
-
-
-
-
-
-At least one previously observed proband with the expressed RAG2 variant meeting PP4 is required to apply PS3 at any strength.","Gene-specific,Strength"
-RAG2 (HGNC:9832),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",NA
-RAG2 (HGNC:9832),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-RAG2 (HGNC:9832),PM1,Moderate,"Strength is dependent upon the location of the variant within specific functional domains (PMID: 26996199):
-
-
-
-
-PM1_Moderate: missense variant located in the 
-PHD domain
- (amino acids 414-487);",Gene-specific
-RAG2 (HGNC:9832),PM1,Supporting,"Strength is dependent upon the location of the variant within specific functional domains (PMID: 26996199):
-
-
-
-
-PM1_Supporting: missense variant located in the 
-core domain
- (amino acids 1-383);",Gene-specific
-RAG2 (HGNC:9832),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-RAG2 (HGNC:9832),PM2,Supporting,"gnomAD popmax filtering allele frequency <0.0000588  
-
-
-
-
-An additional requirement is that 
-no homozygotes
- have been observed in gnomAD.",Gene-specific
-RAG2 (HGNC:9832),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-RAG2 (HGNC:9832),PM3,Very Strong,"Use ClinGen SVI recommendations for 
-in trans
- criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for 
-RAG2.",General recommendation
-RAG2 (HGNC:9832),PM3,Strong,"Use ClinGen SVI recommendations for 
-in trans
- criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for 
-RAG2.",General recommendation
-RAG2 (HGNC:9832),PM3,Moderate,"Use ClinGen SVI recommendations for 
-in trans
- criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for 
-RAG2.",General recommendation
-RAG2 (HGNC:9832),PM3,Supporting,"Use ClinGen SVI recommendations for 
-in trans
- criterion with the additional requirement that the co-occurring variant must be classified using the SCID VCEP specifications for 
-RAG2.",General recommendation
-RAG2 (HGNC:9832),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-RAG2 (HGNC:9832),PM4,Moderate,"When applied to deletion variants, the deleted region must contain a known 
-pathogenic
- or 
-likely pathogenic
- variant that is not predicted/observed to alter splicing.",Gene-specific
-RAG2 (HGNC:9832),PM4,Supporting,"When applied to deletion variants, the deleted region must contain a known 
-VUS
- variant that is not predicted/observed to alter splicing.","Gene-specific,Strength"
-RAG2 (HGNC:9832),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-RAG2 (HGNC:9832),PM5,Moderate,"Applicable if a previously established variant is classified as 
-pathogenic
- by SCID VCEP specifications for 
-RAG2.
- Previously established variant must be classified by SCID VCEP specifications for 
-RAG2.",Gene-specific
-RAG2 (HGNC:9832),PM5,Supporting,"Applicable if a previously established variant is classified as 
-likely pathogenic
- by SCID VCEP specifications for 
-RAG2.
- Previously established variant must be classified by SCID VCEP specifications for 
-RAG2.","Gene-specific,Strength"
-RAG2 (HGNC:9832),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-RAG2 (HGNC:9832),PM6,Strong,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-RAG2 (HGNC:9832),PM6,Moderate,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-RAG2 (HGNC:9832),PM6,Supporting,"Use ClinGen SVI recommendations for 
-de novo
- criteria (see instructions below).","General recommendation,Gene-specific"
-RAG2 (HGNC:9832),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-RAG2 (HGNC:9832),PP1,Strong,"Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations.",General recommendation
-RAG2 (HGNC:9832),PP1,Moderate,"Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations.",General recommendation
-RAG2 (HGNC:9832),PP1,Supporting,"Use recommendations for co-segregation criterion from PMID: 30311386, with strength dependent on number of affected segregations.",General recommendation
-RAG2 (HGNC:9832),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-RAG2 (HGNC:9832),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-RAG2 (HGNC:9832),PP3,Supporting,"Only applicable to synonymous or intronic variants predicted to impact splicing by SpliceAI with a delta score greater than or equal to 0.2.
-
-
-Do not apply to missense variants.",General recommendation
-RAG2 (HGNC:9832),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-RAG2 (HGNC:9832),PP4,Strong,"A patient score of ≥ 4 points
-1
-. 
-
-
-1
-CNV (Copy number variation) testing is required to consider PP4_Strong in order to certify that the variant in question is the causative for the phenotype and not one CNV event corrected by gene therapy and not identified previously (see instructions below).","Disease-specific,Gene-specific"
-RAG2 (HGNC:9832),PP4,Moderate,A patient score of ≥2-<4 points (see instructions below).,"Disease-specific,Gene-specific"
-RAG2 (HGNC:9832),PP4,Supporting,A patient score of 1-<2 points (see instructions below).,"Disease-specific,Gene-specific"
-RAG2 (HGNC:9832),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RAG2 (HGNC:9832),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-RAG2 (HGNC:9832),BA1,Stand Alone,gnomAD popmax filtering allele frequency >0.00872,Gene-specific
-RAG2 (HGNC:9832),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-RAG2 (HGNC:9832),BS1,Strong,"gnomAD popmax filtering allele frequency  >0.00195
-1
-
-
-1
- Consider also bottleneck populations.",Gene-specific
-RAG2 (HGNC:9832),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-RAG2 (HGNC:9832),BS2,Supporting,Only to be used when the variant is observed in the homozygous state in a healthy adult.,Strength
-RAG2 (HGNC:9832),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-RAG2 (HGNC:9832),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-RAG2 (HGNC:9832),BS4,Strong,Can be applied without additional specifications.,"General recommendation,None"
-RAG2 (HGNC:9832),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-RAG2 (HGNC:9832),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-RAG2 (HGNC:9832),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-RAG2 (HGNC:9832),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",NA
-RAG2 (HGNC:9832),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-RAG2 (HGNC:9832),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-RAG2 (HGNC:9832),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-RAG2 (HGNC:9832),BP7,Supporting,"Applicable to both synonymous variants and deep intronic variants affecting nucleotides at or beyond the +7 (donor) and -21 (acceptor) positions.
-
-
-The variant should be predicted not to impact splicing by at least two out of three 
-in silico
- tools (freely available tools include GeneSplicer, MaxEntScan, NNSplice, SpliceAI, Splicing Sequences Finder (SSF), and varSEAK).
-
-
-Given the potential for poor conservation of genes related to T cell and B cell development among vertebrates, nucleotide conservation is 
-not required
- in order to apply BP7.",General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.2_version=1.2.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.2_version=1.2.0.csv
deleted file mode 100644
index 3c57044a088e070b150e62cadf5f42d1e2083ccb..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.2_version=1.2.0.csv
+++ /dev/null
@@ -1,192 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-TP53 (HGNC:11998),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-TP53 (HGNC:11998),PVS1,Very Strong,Defer to SVI recommendations,
-TP53 (HGNC:11998),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-TP53 (HGNC:11998),PS1,Strong,Must confirm there is no difference in splicing using RNA data. Can only compare to variants asserted as pathogenic by the ClinGen TP53 EP.,
-TP53 (HGNC:11998),PS1,Moderate,"Must confirm there is no difference in splicing using in silico modeling data using a splice metapredictor (SpliceAI, VarSEAK, etc). Can only compare to variants asserted as pathogenic by the ClinGen TP53 EP.",
-TP53 (HGNC:11998),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-TP53 (HGNC:11998),PS2,Very Strong,"Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.
- ≥4 points (ex. – 2 cancers in two probands from the strong criteria list or 4 cancers from 4 probands from the moderate criteria). For probands with multiple cancers, use the most specific/highest weight cancer to determine point for that proband.",
-TP53 (HGNC:11998),PS2,Strong,"Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.
- 2-3 points (ex. – 1 cancer from the strong criteria list or 2 from the moderate criteria list)",
-TP53 (HGNC:11998),PS2,Moderate,"Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.
- 1 point (for 1 cancer from the moderate criteria list)",
-TP53 (HGNC:11998),PS2,Supporting,"Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.
-0.5 point (1 cancer from the moderate criteria list)",
-TP53 (HGNC:11998),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-TP53 (HGNC:11998),PS3,Strong,"Transactivation assays in yeast (IARC classification based on data from Kato et al, 2003) that demonstrate a low functioning allele (<= 20% activity) AND:
-
-
-
-
-Evidence of dominant negative effect (DNE) + evidence of LOF from Giacomelli, et al data
-  OR 
-
-
-There is a 2nd assay showing low function (colony formation assays, apoptosis assays, tetramer assays, knock-in mouse models and growth suppression assays)
-Do not use code with conflicting evidence",
-TP53 (HGNC:11998),PS3,Moderate,"(A) Transactivation assays in yeast (IARC classification based on data from Kato et al, 2003) that demonstrate a partially functioning allele (>20-and <=75% activity) AND:
-
-
-
-
-Evidence of DNE + evidence of LOF from Giacomelli, et al data.
-  OR 
-
-
-There is a 2nd assay showing low function.
- Do not use code with conflicting evidence.
- (B) No transactivation assays (IARC classification based on data Kato et al, 2003) available BUT:
-
-
-Evidence of DNE + evidence of LOF from Giacomelli, et al data.
-  AND 
-
-
-There is a 2nd assay showing low function
-Do not use code with conflicting evidence.",
-TP53 (HGNC:11998),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-TP53 (HGNC:11998),PS4,Strong,"Use proband counting system described below in text.
-PS4 = 4+ points",
-TP53 (HGNC:11998),PS4,Moderate,"Use proband counting point system described in text below.
-PS4_moderate = 2-3 points",
-TP53 (HGNC:11998),PS4,Supporting,"Use proband counting point system described in text below.
- PS4_Suppporting = 1 point",
-TP53 (HGNC:11998),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-TP53 (HGNC:11998),PM1,Moderate,"This rule can be applied to variants in hot spots (codons 175, 245, 248, 249, 273, 282), but not to variants within functional domains. Use transcript NM_000546.4. Also use rule for variants with ≥10 somatic observations cancerhotspots.org (v2)",
-TP53 (HGNC:11998),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-TP53 (HGNC:11998),PM2,Supporting,"Variant needs to be absent from controls.
-The variant must be absent from population databases. gnomAD is the preferred population database at this time (
-http://gnomad.broadinstitute.org
-). The most recent version of gnomAD with a non-cancer subpopulation should be used; however, other versions may be utilized if there is reason to believe they would provide necessary information for curating the variant.",
-TP53 (HGNC:11998),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-TP53 (HGNC:11998),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,NA
-TP53 (HGNC:11998),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-TP53 (HGNC:11998),PM5,Moderate,Multiple pathogenic variants (≥2) at that residue using the requirements specified below (excluding known hot spots) would be required. Grantham should be used to compare the variants. At least one of the new variants must be equal or worse than known pathogenic variant. Splicing should be ruled out. Can only compare to variants asserted as pathogenic by the ClinGen TP53 EP. Rule cannot be used in conjunction with PM1.,
-TP53 (HGNC:11998),PM5,Supporting,Grantham should be used to compare variants. The new variant must be equal or worse than known mutation. Splicing should be ruled out. Rule cannot be used in conjunction with PM1.,
-TP53 (HGNC:11998),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-TP53 (HGNC:11998),PM6,Very Strong,"Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.
- ≥4 points (ex. – 2 cancers in two probands from the strong criteria list or 4 cancers from 4 probands from the moderate criteria). For probands with multiple cancers, use the most specific/highest weight cancer to determine point for that proband.",
-TP53 (HGNC:11998),PM6,Strong,"Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.
- 2-3 points (ex. – 1 cancer from the strong criteria list or 2 from the moderate criteria list)",
-TP53 (HGNC:11998),PM6,Moderate,"Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.
- 1 point (for 1 cancer from the moderate criteria list)",
-TP53 (HGNC:11998),PM6,Supporting,"Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.
-0.5 point (1 cancer from the moderate criteria list)",
-TP53 (HGNC:11998),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-TP53 (HGNC:11998),PP1,Strong,Cosegregation must be observed ≥7 meioses in >1 family in to apply this rule.,
-TP53 (HGNC:11998),PP1,Moderate,Cosegregation must be observed in 5-6 meioses in 1 family to apply this rule.,
-TP53 (HGNC:11998),PP1,Supporting,Cosegregation must be observed in 3-4 meioses in 1 family to apply this rule,
-TP53 (HGNC:11998),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-TP53 (HGNC:11998),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-TP53 (HGNC:11998),PP3,Moderate,"PolyPhen2 and SIFT in silico modeling programs should not be used for this gene.
-Missense variants: aGVGD (Zebrafish; Class C65 required) and BayesDel (score ≥ 0.16)",
-TP53 (HGNC:11998),PP3,Supporting,"PolyPhen2 and SIFT in silico modeling programs should not be used for this gene. Concordance of two predictors is recommended for this gene:
-
-
-
-
-Missense variants: aGVGD (Zebrafish; Class C25 and higher are considered evidence of pathogenicity) and BayesDel (scores ≥ 0.16 are considered evidence of pathogenic)
-
-
-Splicing variants: Evidence of splice effect on a splice metapredictor (SpliceAI, VarSEAK, etc).",
-TP53 (HGNC:11998),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-TP53 (HGNC:11998),PP4,Supporting,Use modified PS4 criteria instead of PP4 code,
-TP53 (HGNC:11998),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-TP53 (HGNC:11998),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-TP53 (HGNC:11998),BA1,Stand Alone,Frequency cutoff of 0.1% minimum of 5 alleles present in the population,
-TP53 (HGNC:11998),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-TP53 (HGNC:11998),BS1,Strong,"Frequency cutoff of 0.03%; minimum of 5 alleles present in the population.
-
-
-
-
-Use a minor allele frequency cutoff of >0.0003 but <0.001 (99.99% CI, sub-population must have a minimum of 5 alleles present in the sub-population) based on the Whiffen-Ware calculator.
-
-
-To set the strong benign MAF cutoff, we used a prevalence of 1 in 5,000 from Lalloo, et a 2006 (PMID:16644204). We set the genetic and allelic heterogeneity at 100% and penetrance at 30%.",
-TP53 (HGNC:11998),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-TP53 (HGNC:11998),BS2,Strong,"Observed in ≥8 cancer free 60+ year old females obtained from the same data source.
-Using TP53 multigene panel testing results from two diagnostic labs, we compared the proportion of cancer-free individuals by age 60 in TP53 carriers versus TP53-negative controls. Based on the correspondence between likelihood ratios of pathogenicity and different levels of strengths for ACMG/AMP rules in the study by Tavtigian et al., 2018 (PMID: 29300386), our most conservative results support the following:
-
-
-
-
-This evidence code can be used when a variant is observed in ≥8 females who have reached at least 60 years of age without cancer. These individuals all must have come from a single source (single lab, database, etc). Cases cannot be counted across sources.",
-TP53 (HGNC:11998),BS2,Supporting,"Observed in 2-7 cancer free 60+ year old females obtained from the same data source.
-Using TP53 multigene panel testing results from two diagnostic labs, we compared the proportion of cancer-free individuals by age 60 in TP53 carriers versus TP53-negative controls. Based on the correspondence between likelihood ratios of pathogenicity and different levels of strengths for ACMG/AMP rules in the study by Tavtigian et al., 2018 (PMID: 29300386), our most conservative results support the following:
-
-
-
-
-This evidence code can be used when a variant is observed in 2-7 females who have reached at least 60 years of age without cancer. These individuals all must have come from a single source (single lab, database, etc). Cases cannot be counted across sources.",
-TP53 (HGNC:11998),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-TP53 (HGNC:11998),BS3,Strong,"Transactivation assays in yeast (IARC classification based on data from Kato et al, 2003) that show retained function (76-140% activity) or supertransactivation function AND:
-
-
-
-
-No evidence of DNE + no evidence of LOF from Giacomelli, et al data.
-OR
-There is a 2nd assay, including colony formation assays, apoptosis assays, tetramer assays, growth suppression and knock-in mouse models demonstrating retained function.
-Do not use code with conflicting evidence",
-TP53 (HGNC:11998),BS3,Supporting,"Transactivation assays in yeast (IARC classification based on data from Kato et al, 2003) that demonstrate a partially functioning allele (>20% and <=75% activity) AND:
-
-
-
-
-No evidence of DNE + no evidence of LOF from Giacomelli, et al data.
-OR
-
-
-There is a 2nd assay demonstrating retained function
-Do not use code with conflicting evidence.
-No transactivation assays in yeast (IARC classification based on data from Kato et al, 2003) available BUT:
-
-
-No evidence of DNE + no evidence of LOF from Giacomelli, et al data.
-AND 
- There is a 2nd assay showing retained function
-Do not use code with conflicting evidence",
-TP53 (HGNC:11998),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-TP53 (HGNC:11998),BS4,Strong,"Variant segregates to opposite side of the family who meets LFS criteria.
-OR
-Variant is present in ≥3 living unaffected individuals (at least 2 of which should be female) above 55 years of age.",
-TP53 (HGNC:11998),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-TP53 (HGNC:11998),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-TP53 (HGNC:11998),BP2,Supporting,"This evidence code can be applied in either scenario below:
-
-
-
-
-Variant is observed in trans with a pathogenic or likely pathogenic TP53 variant (phase confirmed), or
-
-
-When there are 3 or more observations with a pathogenic or likely pathogenic variant when phase is unknown. In this scenario, the variant must be seen with at least two different pathogenic/likely pathogenic TP53 variants.",
-TP53 (HGNC:11998),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-TP53 (HGNC:11998),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-TP53 (HGNC:11998),BP4,Supporting,"Missense: aGVGD (zebrafish; Class C0 or C15 is considered evidence of non-pathogenicity) and BayesDel <0.16 is considered evidence on non-pathogenicity
-Splicing: Evidence of splice effect on a splice metapredictor (SpliceAI, VarSEAK, etc).",
-TP53 (HGNC:11998),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-TP53 (HGNC:11998),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-TP53 (HGNC:11998),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-TP53 (HGNC:11998),BP7,Supporting,"Evidence of splice effect on a splice metapredictor (SpliceAI, VarSEAK, etc). If a new alternate site is predicted, compare strength to native site in interpretation.",
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version1.0.0_version=1.0.0.csv
deleted file mode 100644
index e683e2b881b4fdcc16141c5766ef61bdf794bf3a..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,239 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-TP53 (HGNC:11998),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-TP53 (HGNC:11998),PVS1,Very Strong,Defer to SVI recommendations.,"Disease-specific,Strength"
-TP53 (HGNC:11998),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-TP53 (HGNC:11998),PS1,Strong,"Must confirm there is no difference in splicing using RNA data. Can only compare to variants asserted as pathogenic by the ClinGen TP53 EP.
-
-
-
-
-This rule code can only be used to compare to variants asserted as pathogenic by the ClinGen TP53 EP.
-
-
-Must confirm there is no difference in splicing using RNA data.","Disease-specific,Strength"
-TP53 (HGNC:11998),PS1,Moderate,"Must confirm there is no difference in splicing using in silico modeling data.
-
-
-
-
-This rule code can be used if there is no difference in splicing using in silico modeling data.
-
-
-This rule code can only be used to compare to variants asserted as pathogenic by the ClinGen TP53 EP.","Disease-specific,Strength"
-TP53 (HGNC:11998),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-TP53 (HGNC:11998),PS2,Very Strong,"Use SVI point system table. *See Cancer Criteria List & TP53 Point Table at end of document.
->4 points (ex. – 2 cancers in two probands from the strong criteria list or 4 cancers from 4 probands from the moderate criteria). For probands with multiple cancers, use the most specific/highest weight cancer to determine point for that proband.","Disease-specific,Strength"
-TP53 (HGNC:11998),PS2,Strong,"Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.
-2-3 points (ex. – 1 cancer from the strong criteria list or 2 from the moderate criteria list)","Disease-specific,Strength"
-TP53 (HGNC:11998),PS2,Moderate,"Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.
-1 point (for 1 cancer from the moderate criteria list)","Disease-specific,Strength"
-TP53 (HGNC:11998),PS2,Supporting,"Use SVI point system table. *See Cancer Criteria List & TP53 Point Table at end of document.
-0.5 point (1 cancer from the moderate criteria list)","Disease-specific,Strength"
-TP53 (HGNC:11998),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-TP53 (HGNC:11998),PS3,Strong,"Transactivation assays in yeast (IARC classification based on data from Kato et al, 2003) that demonstrate a low functioning allele (<20% activity) AND:
-
-
-
-
-Evidence of dominant negative effect (DNE) + evidence of LOF from Giacomelli, et al data
--OR-
-
-
-There is a 2nd assay showing low function (colony formation assays, apoptosis assays, tetramer assays, knock-in mouse models and growth suppression assays)","Disease-specific,Strength"
-TP53 (HGNC:11998),PS3,Moderate,"A) Transactivation assays in yeast (IARC classification based on data from Kato et al, 2003) that demonstrate a partially functioning allele (>20-and <=75% activity) AN
-
-
-
-
-Evidence of DNE + evidence of LOF from Giacomelli, et al data. OR
-
-
-There is a 2nd assay showing low function
-Do not use code with conflicting evidence.
-
-
-
-
-B) No transactivation assays (IARC classification based on data Kato et al, 2003) available BUT:  
-
-
-
-
-Evidence of DNE + evidence of LOF from Giacomelli, et al data. AND
-
-
-There is a 2nd assay showing low function
-Do not use code with conflicting evidence.","Disease-specific,Strength"
-TP53 (HGNC:11998),PS3,Supporting,"PS3
-
-
-
-
-Kato et al, 2003 (PMID: 12826609) data performed the best on our test set of variants. These data thus remain the main functional assay underlying the classification.
-
-
-Giacomelli et al, 2018 (PMID: 30224644) assays are systematic and are available for more than 8000 mutants. When using cut-offs derived from original publication data (optimal cut-offs separating silent and common cancer variants), they show good concordance with other ssays.
-The combination of two assays (DNE + LOF) show better performance than LOF alone (0.88 vs 0.73) and DNE alone (0.88 vs 0.70) when tested on the test set of variants. The performance of DNE+LOF was close to the one of Kato data (0.88 vs 0.94). There are >5900 variants included in Giacomelli dataset (including 378 silent and 414 stopgain variants) that have no Kato data. Over 400 of these variants have at least one entry in the IARC database (somatic). Giacomelli DNE+LOF class can thus be used to support and complement Kato data. Giacomelli DNE+LOF data could be used when there is no Kato data but with a moderate code because of the less robust cut-offs of the assays.
-
-
-Non-systematic assays are harder to interpret but if there are several of them and if all suggest benign or pathogenic, they should be taken into account. A large proportion of these assays is documented in the IARC database and thus be easily found by curators.
-- Kotler data are available for a large number of mutants, but only for mutants within the DNA binding domain. They will be used as other non-systematic LOF assay.
-- For variants that are partially functional by Kato, Giacomelli LOF/DNE can be used as results correlate well with Kotler data and quantitative model outputs.
-Data supporting Functional classes:
-
-
-IARC Transactivation class: IARC classification based on transactivation assays in yeast from Kato et al., (2003): non-functional is <=20% activity; partially functional is >20% and <=75% activity; functional and supertrans are >75% activity.
-
-
-Giacomelli et al. (2018): IARC classification based on growth suppression assays in A549 human cells; DNE+LOF is p53WTNutlin3 Z-score >= 0.61 and Etoposide Z-score <= -0.21; noDNE+noLOF is p53WTNutlin3 Z-score < 0.61 and Etoposide Z-score > -0.21.
-
-
-Other assays (available in IARC database or original publications): in vitro growth assays in H1299 human cells from Kotler et al., (2018) with RFS score >= -1.0 for LOF and RFS score <1 for noLOF; or colony formation assays, growth suppression assays, apoptosis assays, tetramer assays, knock-in mouse models.","Disease-specific,Strength"
-TP53 (HGNC:11998),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-TP53 (HGNC:11998),PS4,Strong,"Use proband counting system described below in text.
-PS4 = 4+ points","Disease-specific,Strength"
-TP53 (HGNC:11998),PS4,Moderate,"Use proband counting point system described in text below.
-PS4_moderate = 2-3 points.","Disease-specific,Strength"
-TP53 (HGNC:11998),PS4,Supporting,"Use proband counting point system described in text below.
-PS4_Suppporting = 1 point.","Disease-specific,Strength"
-TP53 (HGNC:11998),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-TP53 (HGNC:11998),PM1,Moderate,"This rule can be applied to variants in hot spots (codons 175, 248, 273, 248, 245, 282, 249), but not to variants within functional domains. Use transcript NM_000546.4.
-Also use rule for variants with >10 somatic observations cancerhotspots.org (v2).","Disease-specific,Strength"
-TP53 (HGNC:11998),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-TP53 (HGNC:11998),PM2,Supporting,Variant needs to be absent from controls.,"Disease-specific,General recommendation"
-TP53 (HGNC:11998),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-TP53 (HGNC:11998),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,NA
-TP53 (HGNC:11998),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-TP53 (HGNC:11998),PM5,Moderate,Multiple pathogenic variants (>2) at that residue using the requirements specified below (excluding known hot spots) would be required. Grantham or BLOSUM should be used to compare the variants. New variant must be equal or worse than known pathogenic variant. Splicing should be ruled out. Can only compare to variants asserted as pathogenic by the ClinGen TP53 EP.,"Disease-specific,Strength"
-TP53 (HGNC:11998),PM5,Supporting,Grantham or BLOSUM should be used to compare variants. The new variant must be equal or worse than known mutation. Splicing should be ruled out. This rule cannot be used for hot spots.,"Disease-specific,Strength"
-TP53 (HGNC:11998),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-TP53 (HGNC:11998),PM6,Strong,"Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.
-2-3 points (ex. – 1 cancer from the strong criteria list or 2 from the moderate criteria list).",Strength
-TP53 (HGNC:11998),PM6,Moderate,"Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.
-1 point (for 1 cancer from the moderate criteria list)",Strength
-TP53 (HGNC:11998),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-TP53 (HGNC:11998),PP1,Strong,Cosegregation must be observed in ≥ 7 meioses across > 1 family,"Disease-specific,Strength"
-TP53 (HGNC:11998),PP1,Moderate,Cosegregation must be observed in 5-6 meioses in 1 family to apply this rule.,"Disease-specific,Strength"
-TP53 (HGNC:11998),PP1,Supporting,Cosegregation must be observed in 3-4 meioses in 1 family to apply this rule.,"Disease-specific,Strength"
-TP53 (HGNC:11998),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-TP53 (HGNC:11998),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-TP53 (HGNC:11998),PP3,Moderate,"Missense variants
- 
-(See flowchart for application of PP3 and BP4 rules for missense variants)
-
-
-aGVGD Class C65 and BayesDel score ≥ 0.16","Disease-specific,Strength"
-TP53 (HGNC:11998),PP3,Supporting,"PolyPhen2 and SIFT in silico modeling programs should not be used for this gene. Concordance of two predictors is recommended for this gene:
-
-
-
-
-Missense variants: aGVGD (Zebrafish; Class C15 and higher are considered evidence of pathogenicity) and BayesDel (scores > 0.16 are considered evidence of pathogenic)
-
-
-Splicing variants: MaxEntScan and HSF","Disease-specific,Strength"
-TP53 (HGNC:11998),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-TP53 (HGNC:11998),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-TP53 (HGNC:11998),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-TP53 (HGNC:11998),BA1,Stand Alone,"Frequency cutoff of 0.1% minimum of 5 alleles present in the population.
-
-
-
-
-Use a minor allele frequency cutoff of >0.001 or 0.1% (99.99% CI, sub-population must have a minimum of 5 alleles present in the sub-population) based on the Whiffen-Ware calculator.
-
-
-To set the stand-alone benign MAF cutoff, we used the MAF cutoff established for BS1 (see below) and increased 0.0003 one order of magnitude to come to a value of 0.001.",Disease-specific
-TP53 (HGNC:11998),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-TP53 (HGNC:11998),BS1,Strong,"Frequency cutoff of 0.03%; minimum of 5 alleles present in the population.
-
-
-
-
-Use a minor allele frequency cutoff of >0.0003 but <0.001 (99.99% CI, sub-population must have a minimum of 5 alleles present in the sub-population) based on the Whiffen-Ware
-calculator.
-
-
-To set the strong benign MAF cutoff, we used a prevalence of 1 in 5,000 from Lalloo, et a 2006 (PMID:16644204). We set the genetic and allelic heterogeneity at 100% and penetrance at 30%.",Disease-specific
-TP53 (HGNC:11998),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-TP53 (HGNC:11998),BS2,Strong,Observed in >8 cancer free 60+ year old females.,Disease-specific
-TP53 (HGNC:11998),BS2,Supporting,Observed in 2-7 cancer free 60+ year old females.,Disease-specific
-TP53 (HGNC:11998),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-TP53 (HGNC:11998),BS3,Strong,"Transactivation assays in yeast (IARC classification based on data from Kato et al, 2003) that show retained function (76-140% activity) or supertransactivation function AND:
-
-
-
-
-No evidence of DNE + no evidence of LOF from Giacomelli, et al data.
--OR-
-
-
-There is a 2nd assay, including colony formation assays, apoptosis assays, tetramer assays, growth suppression and knock-in mouse models demonstrating retained function.","Disease-specific,Strength"
-TP53 (HGNC:11998),BS3,Supporting,"Transactivation assays in yeast (IARC classification based on data from Kato et al, 2003) that demonstrate a partially functioning allele (>20% and <=75% activity) AND:  
-
-
-
-
-No evidence of DNE + no evidence of LOF from Giacomelli, et al data. OR
-
-
-There is a 2nd assay demonstrating retained function.
-
-
-
-
-Do not use code with conflicting evidence.
-
-
-No transactivation assays in yeast (IARC classification based on data from Kato et al, 2003) available BUT:  
-
-
-
-
-No evidence of DNE + no evidence of LOF from Giacomelli, et al data. AND
-
-
-There is a 2nd assay showing retained function
-
-
-
-
-Do not use code with conflicting evidence","Disease-specific,Strength"
-TP53 (HGNC:11998),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-TP53 (HGNC:11998),BS4,Strong,"Variant segregates to opposite side of the family who meets LFS criteria OR 
-
-
-Variant is present in ≥3 living unaffected individuals (at least 2 of 3 should be female) above 55 years of age.",Disease-specific
-TP53 (HGNC:11998),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-TP53 (HGNC:11998),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-TP53 (HGNC:11998),BP2,Supporting,"Variant is observed in trans with a pathogenic or likely pathogenic TP53 variant (phase confirmed) OR
-
-
-3 or more observations when phase is unknown with at least two different pathogenic/likely pathogenic TP53 variants",Disease-specific
-TP53 (HGNC:11998),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-TP53 (HGNC:11998),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-TP53 (HGNC:11998),BP4,Supporting,"Missense: aGVGD (zebrafish; Class C0 or C15 is considered evidence of non-pathogenicity) and BayesDel <0.16 is considered evidence on non-pathogenicity
-Splicing: MaxEntScan and HSF","Disease-specific,Strength"
-TP53 (HGNC:11998),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-TP53 (HGNC:11998),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-TP53 (HGNC:11998),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-TP53 (HGNC:11998),BP7,Supporting,"Concordance of MaxEntScan and HSF; If a new alternate site is predicted, compare strength to native site in interpretation.",Disease-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version1.3.0_version=1.3.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version1.3.0_version=1.3.0.csv
deleted file mode 100644
index 323b7005c2773127d05bb7499908fcbd46696eda..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version1.3.0_version=1.3.0.csv
+++ /dev/null
@@ -1,191 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-TP53 (HGNC:11998),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-TP53 (HGNC:11998),PVS1,Very Strong,Defer to SVI recommendations,General recommendation
-TP53 (HGNC:11998),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-TP53 (HGNC:11998),PS1,Strong,Must confirm there is no difference in splicing using RNA data. Can only compare to variants asserted as pathogenic by the ClinGen TP53 EP.,Strength
-TP53 (HGNC:11998),PS1,Moderate,"Must confirm there is no difference in splicing using in silico modeling data using a splice metapredictor (SpliceAI, VarSEAK, etc). Can only compare to variants asserted as pathogenic by the ClinGen TP53 EP.",Strength
-TP53 (HGNC:11998),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-TP53 (HGNC:11998),PS2,Very Strong,"Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.
- ≥4 points (ex. – 2 cancers in two probands from the strong criteria list or 4 cancers from 4 probands from the moderate criteria). For probands with multiple cancers, use the most specific/highest weight cancer to determine point for that proband.",Strength
-TP53 (HGNC:11998),PS2,Strong,"Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.
- 2-3 points (ex. – 1 cancer from the strong criteria list or 2 from the moderate criteria list)",Strength
-TP53 (HGNC:11998),PS2,Moderate,"Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.
- 1 point (for 1 cancer from the moderate criteria list)",Strength
-TP53 (HGNC:11998),PS2,Supporting,"Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.
-0.5 point (1 cancer from the moderate criteria list)",Strength
-TP53 (HGNC:11998),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-TP53 (HGNC:11998),PS3,Strong,"Transactivation assays in yeast (IARC classification based on data from Kato et al, 2003) that demonstrate a low functioning allele (<= 20% activity) AND:
-
-
-
-
-Evidence of dominant negative effect (DNE) + evidence of LOF from Giacomelli, et al data
-  OR 
-
-
-There is a 2nd assay showing low function (colony formation assays, apoptosis assays, tetramer assays, knock-in mouse models and growth suppression assays)
-Do not use code with conflicting evidence",Strength
-TP53 (HGNC:11998),PS3,Moderate,"(A) Transactivation assays in yeast (IARC classification based on data from Kato et al, 2003) that demonstrate a partially functioning allele (>20-and <=75% activity) AND:
-
-
-
-
-Evidence of DNE + evidence of LOF from Giacomelli, et al data.
-  OR 
-
-
-There is a 2nd assay showing low function.
- Do not use code with conflicting evidence.
- (B) No transactivation assays (IARC classification based on data Kato et al, 2003) available BUT:
-
-
-Evidence of DNE + evidence of LOF from Giacomelli, et al data.
-  AND 
-
-
-There is a 2nd assay showing low function
-Do not use code with conflicting evidence.",Strength
-TP53 (HGNC:11998),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-TP53 (HGNC:11998),PS4,Strong,"Use proband counting system described below in text.
-PS4 = 4+ points",Strength
-TP53 (HGNC:11998),PS4,Moderate,"Use proband counting point system described in text below.
-PS4_moderate = 2-3 points",Strength
-TP53 (HGNC:11998),PS4,Supporting,"Use proband counting point system described in text below.
- PS4_Suppporting = 1 point",Strength
-TP53 (HGNC:11998),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-TP53 (HGNC:11998),PM1,Moderate,"This rule can be applied to variants in hot spots (codons 175, 245, 248, 249, 273, 282), but not to variants within functional domains. Use transcript NM_000546.4. Also use rule for variants with ≥10 somatic observations cancerhotspots.org (v2)","Disease-specific,Strength"
-TP53 (HGNC:11998),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-TP53 (HGNC:11998),PM2,Supporting,"Variant needs to be absent from controls.
-The variant must be absent from population databases. gnomAD is the preferred population database at this time (
-http://gnomad.broadinstitute.org
-). The most recent version of gnomAD with a non-cancer subpopulation should be used; however, other versions may be utilized if there is reason to believe they would provide necessary information for curating the variant.","Disease-specific,General recommendation"
-TP53 (HGNC:11998),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-TP53 (HGNC:11998),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,NA
-TP53 (HGNC:11998),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-TP53 (HGNC:11998),PM5,Moderate,Multiple pathogenic variants (≥2) at that residue using the requirements specified below (excluding known hot spots) would be required. Grantham should be used to compare the variants. At least one of the new variants must be equal or worse than known pathogenic variant. Splicing should be ruled out. Can only compare to variants asserted as pathogenic by the ClinGen TP53 EP. Rule cannot be used in conjunction with PM1.,Strength
-TP53 (HGNC:11998),PM5,Supporting,Grantham should be used to compare variants. The new variant must be equal or worse than known mutation. Splicing should be ruled out. Rule cannot be used in conjunction with PM1.,Strength
-TP53 (HGNC:11998),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-TP53 (HGNC:11998),PM6,Very Strong,"Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.
- ≥4 points (ex. – 2 cancers in two probands from the strong criteria list or 4 cancers from 4 probands from the moderate criteria). For probands with multiple cancers, use the most specific/highest weight cancer to determine point for that proband.",Strength
-TP53 (HGNC:11998),PM6,Strong,"Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.
- 2-3 points (ex. – 1 cancer from the strong criteria list or 2 from the moderate criteria list)",Strength
-TP53 (HGNC:11998),PM6,Moderate,"Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.
- 1 point (for 1 cancer from the moderate criteria list)",Strength
-TP53 (HGNC:11998),PM6,Supporting,"Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.
-0.5 point (1 cancer from the moderate criteria list)",Strength
-TP53 (HGNC:11998),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-TP53 (HGNC:11998),PP1,Strong,Cosegregation must be observed ≥7 meioses in >1 family in to apply this rule.,Strength
-TP53 (HGNC:11998),PP1,Moderate,Cosegregation must be observed in 5-6 meioses in 1 family to apply this rule.,Strength
-TP53 (HGNC:11998),PP1,Supporting,Cosegregation must be observed in 3-4 meioses in 1 family to apply this rule,Strength
-TP53 (HGNC:11998),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-TP53 (HGNC:11998),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-TP53 (HGNC:11998),PP3,Moderate,"PolyPhen2 and SIFT in silico modeling programs should not be used for this gene.
-Missense variants: aGVGD (Zebrafish; Class C65 required) and BayesDel (score ≥ 0.16)",Strength
-TP53 (HGNC:11998),PP3,Supporting,"PolyPhen2 and SIFT in silico modeling programs should not be used for this gene. Concordance of two predictors is recommended for this gene:
-
-
-
-
-Missense variants: aGVGD (Zebrafish; Class C25 and higher are considered evidence of pathogenicity) and BayesDel (scores ≥ 0.16 are considered evidence of pathogenic)
-
-
-Splicing variants: Evidence of splice effect on a splice metapredictor (SpliceAI, VarSEAK, etc).",Strength
-TP53 (HGNC:11998),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-TP53 (HGNC:11998),PP4,Supporting,Use modified PS4 criteria instead of PP4 code,Disease-specific
-TP53 (HGNC:11998),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-TP53 (HGNC:11998),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-TP53 (HGNC:11998),BA1,Stand Alone,Frequency cutoff of 0.1% minimum of 5 alleles present in the population,Disease-specific
-TP53 (HGNC:11998),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-TP53 (HGNC:11998),BS1,Strong,"Frequency cutoff of 0.03%; minimum of 5 alleles present in the population.
-
-
-
-
-Use a minor allele frequency cutoff of >0.0003 but <0.001 (99.99% CI, sub-population must have a minimum of 5 alleles present in the sub-population) based on the Whiffen-Ware calculator.
-
-
-To set the strong benign MAF cutoff, we used a prevalence of 1 in 5,000 from Lalloo, et a 2006 (PMID:16644204). We set the genetic and allelic heterogeneity at 100% and penetrance at 30%.",Disease-specific
-TP53 (HGNC:11998),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-TP53 (HGNC:11998),BS2,Strong,"Observed in ≥8 cancer free 60+ year old females obtained from the same data source.
-Using TP53 multigene panel testing results from two diagnostic labs, we compared the proportion of cancer-free individuals by age 60 in TP53 carriers versus TP53-negative controls. Based on the correspondence between likelihood ratios of pathogenicity and different levels of strengths for ACMG/AMP rules in the study by Tavtigian et al., 2018 (PMID: 29300386), our most conservative results support the following:
-
-
-
-
-This evidence code can be used when a variant is observed in ≥8 females who have reached at least 60 years of age without cancer. These individuals all must have come from a single source (single lab, database, etc). Cases cannot be counted across sources.",Disease-specific
-TP53 (HGNC:11998),BS2,Supporting,"Observed in 2-7 cancer free 60+ year old females obtained from the same data source.
-Using TP53 multigene panel testing results from two diagnostic labs, we compared the proportion of cancer-free individuals by age 60 in TP53 carriers versus TP53-negative controls. Based on the correspondence between likelihood ratios of pathogenicity and different levels of strengths for ACMG/AMP rules in the study by Tavtigian et al., 2018 (PMID: 29300386), our most conservative results support the following:
-
-
-
-
-This evidence code can be used when a variant is observed in 2-7 females who have reached at least 60 years of age without cancer. These individuals all must have come from a single source (single lab, database, etc). Cases cannot be counted across sources.",Disease-specific
-TP53 (HGNC:11998),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-TP53 (HGNC:11998),BS3,Strong,"Transactivation assays in yeast (IARC classification based on data from Kato et al, 2003) that show retained function (76-140% activity) or supertransactivation function AND:
-
-
-
-
-No evidence of DNE + no evidence of LOF from Giacomelli, et al data.
-OR
-There is a 2nd assay, including colony formation assays, apoptosis assays, tetramer assays, growth suppression and knock-in mouse models demonstrating retained function.
-Do not use code with conflicting evidence",Strength
-TP53 (HGNC:11998),BS3,Supporting,"Transactivation assays in yeast (IARC classification based on data from Kato et al, 2003) that demonstrate a partially functioning allele (>20% and <=75% activity) AND:
-
-
-
-
-No evidence of DNE + no evidence of LOF from Giacomelli, et al data.
-OR
-
-
-There is a 2nd assay demonstrating retained function
-Do not use code with conflicting evidence.
-No transactivation assays in yeast (IARC classification based on data from Kato et al, 2003) available BUT:
-
-
-No evidence of DNE + no evidence of LOF from Giacomelli, et al data.
-AND 
- There is a 2nd assay showing retained function
-Do not use code with conflicting evidence",Strength
-TP53 (HGNC:11998),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-TP53 (HGNC:11998),BS4,Strong,"Variant segregates to opposite side of the family who meets LFS criteria.
-OR
-Variant is present in ≥3 living unaffected individuals (at least 2 of which should be female) above 55 years of age.",Disease-specific
-TP53 (HGNC:11998),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-TP53 (HGNC:11998),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-TP53 (HGNC:11998),BP2,Supporting,"This evidence code can be applied in either scenario below:
-
-
-
-
-Variant is observed in trans with a pathogenic or likely pathogenic TP53 variant (phase confirmed), or
-
-
-When there are 3 or more observations with a pathogenic or likely pathogenic variant when phase is unknown. In this scenario, the variant must be seen with at least two different pathogenic/likely pathogenic TP53 variants.",Disease-specific
-TP53 (HGNC:11998),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-TP53 (HGNC:11998),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-TP53 (HGNC:11998),BP4,Supporting,"Missense: aGVGD (zebrafish; Class C0 or C15 is considered evidence of non-pathogenicity) and BayesDel <0.16 is considered evidence on non-pathogenicity Splicing: Evidence of no splice effect on a splice metapredictor (SpliceAI, VarSEAK, etc).",Disease-specific
-TP53 (HGNC:11998),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-TP53 (HGNC:11998),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-TP53 (HGNC:11998),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-TP53 (HGNC:11998),BP7,Supporting,"Evidence of no splice effect on a splice metapredictor (SpliceAI, VarSEAK, etc). If a new alternate site is predicted, compare strength to native site in interpretation.",Disease-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version1.4.0_version=1.4.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version1.4.0_version=1.4.0.csv
deleted file mode 100644
index 323b7005c2773127d05bb7499908fcbd46696eda..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version1.4.0_version=1.4.0.csv
+++ /dev/null
@@ -1,191 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-TP53 (HGNC:11998),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-TP53 (HGNC:11998),PVS1,Very Strong,Defer to SVI recommendations,General recommendation
-TP53 (HGNC:11998),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-TP53 (HGNC:11998),PS1,Strong,Must confirm there is no difference in splicing using RNA data. Can only compare to variants asserted as pathogenic by the ClinGen TP53 EP.,Strength
-TP53 (HGNC:11998),PS1,Moderate,"Must confirm there is no difference in splicing using in silico modeling data using a splice metapredictor (SpliceAI, VarSEAK, etc). Can only compare to variants asserted as pathogenic by the ClinGen TP53 EP.",Strength
-TP53 (HGNC:11998),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-TP53 (HGNC:11998),PS2,Very Strong,"Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.
- ≥4 points (ex. – 2 cancers in two probands from the strong criteria list or 4 cancers from 4 probands from the moderate criteria). For probands with multiple cancers, use the most specific/highest weight cancer to determine point for that proband.",Strength
-TP53 (HGNC:11998),PS2,Strong,"Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.
- 2-3 points (ex. – 1 cancer from the strong criteria list or 2 from the moderate criteria list)",Strength
-TP53 (HGNC:11998),PS2,Moderate,"Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.
- 1 point (for 1 cancer from the moderate criteria list)",Strength
-TP53 (HGNC:11998),PS2,Supporting,"Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.
-0.5 point (1 cancer from the moderate criteria list)",Strength
-TP53 (HGNC:11998),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-TP53 (HGNC:11998),PS3,Strong,"Transactivation assays in yeast (IARC classification based on data from Kato et al, 2003) that demonstrate a low functioning allele (<= 20% activity) AND:
-
-
-
-
-Evidence of dominant negative effect (DNE) + evidence of LOF from Giacomelli, et al data
-  OR 
-
-
-There is a 2nd assay showing low function (colony formation assays, apoptosis assays, tetramer assays, knock-in mouse models and growth suppression assays)
-Do not use code with conflicting evidence",Strength
-TP53 (HGNC:11998),PS3,Moderate,"(A) Transactivation assays in yeast (IARC classification based on data from Kato et al, 2003) that demonstrate a partially functioning allele (>20-and <=75% activity) AND:
-
-
-
-
-Evidence of DNE + evidence of LOF from Giacomelli, et al data.
-  OR 
-
-
-There is a 2nd assay showing low function.
- Do not use code with conflicting evidence.
- (B) No transactivation assays (IARC classification based on data Kato et al, 2003) available BUT:
-
-
-Evidence of DNE + evidence of LOF from Giacomelli, et al data.
-  AND 
-
-
-There is a 2nd assay showing low function
-Do not use code with conflicting evidence.",Strength
-TP53 (HGNC:11998),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-TP53 (HGNC:11998),PS4,Strong,"Use proband counting system described below in text.
-PS4 = 4+ points",Strength
-TP53 (HGNC:11998),PS4,Moderate,"Use proband counting point system described in text below.
-PS4_moderate = 2-3 points",Strength
-TP53 (HGNC:11998),PS4,Supporting,"Use proband counting point system described in text below.
- PS4_Suppporting = 1 point",Strength
-TP53 (HGNC:11998),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-TP53 (HGNC:11998),PM1,Moderate,"This rule can be applied to variants in hot spots (codons 175, 245, 248, 249, 273, 282), but not to variants within functional domains. Use transcript NM_000546.4. Also use rule for variants with ≥10 somatic observations cancerhotspots.org (v2)","Disease-specific,Strength"
-TP53 (HGNC:11998),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-TP53 (HGNC:11998),PM2,Supporting,"Variant needs to be absent from controls.
-The variant must be absent from population databases. gnomAD is the preferred population database at this time (
-http://gnomad.broadinstitute.org
-). The most recent version of gnomAD with a non-cancer subpopulation should be used; however, other versions may be utilized if there is reason to believe they would provide necessary information for curating the variant.","Disease-specific,General recommendation"
-TP53 (HGNC:11998),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-TP53 (HGNC:11998),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,NA
-TP53 (HGNC:11998),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-TP53 (HGNC:11998),PM5,Moderate,Multiple pathogenic variants (≥2) at that residue using the requirements specified below (excluding known hot spots) would be required. Grantham should be used to compare the variants. At least one of the new variants must be equal or worse than known pathogenic variant. Splicing should be ruled out. Can only compare to variants asserted as pathogenic by the ClinGen TP53 EP. Rule cannot be used in conjunction with PM1.,Strength
-TP53 (HGNC:11998),PM5,Supporting,Grantham should be used to compare variants. The new variant must be equal or worse than known mutation. Splicing should be ruled out. Rule cannot be used in conjunction with PM1.,Strength
-TP53 (HGNC:11998),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-TP53 (HGNC:11998),PM6,Very Strong,"Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.
- ≥4 points (ex. – 2 cancers in two probands from the strong criteria list or 4 cancers from 4 probands from the moderate criteria). For probands with multiple cancers, use the most specific/highest weight cancer to determine point for that proband.",Strength
-TP53 (HGNC:11998),PM6,Strong,"Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.
- 2-3 points (ex. – 1 cancer from the strong criteria list or 2 from the moderate criteria list)",Strength
-TP53 (HGNC:11998),PM6,Moderate,"Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.
- 1 point (for 1 cancer from the moderate criteria list)",Strength
-TP53 (HGNC:11998),PM6,Supporting,"Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document.
-0.5 point (1 cancer from the moderate criteria list)",Strength
-TP53 (HGNC:11998),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-TP53 (HGNC:11998),PP1,Strong,Cosegregation must be observed ≥7 meioses in >1 family in to apply this rule.,Strength
-TP53 (HGNC:11998),PP1,Moderate,Cosegregation must be observed in 5-6 meioses in 1 family to apply this rule.,Strength
-TP53 (HGNC:11998),PP1,Supporting,Cosegregation must be observed in 3-4 meioses in 1 family to apply this rule,Strength
-TP53 (HGNC:11998),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-TP53 (HGNC:11998),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-TP53 (HGNC:11998),PP3,Moderate,"PolyPhen2 and SIFT in silico modeling programs should not be used for this gene.
-Missense variants: aGVGD (Zebrafish; Class C65 required) and BayesDel (score ≥ 0.16)",Strength
-TP53 (HGNC:11998),PP3,Supporting,"PolyPhen2 and SIFT in silico modeling programs should not be used for this gene. Concordance of two predictors is recommended for this gene:
-
-
-
-
-Missense variants: aGVGD (Zebrafish; Class C25 and higher are considered evidence of pathogenicity) and BayesDel (scores ≥ 0.16 are considered evidence of pathogenic)
-
-
-Splicing variants: Evidence of splice effect on a splice metapredictor (SpliceAI, VarSEAK, etc).",Strength
-TP53 (HGNC:11998),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-TP53 (HGNC:11998),PP4,Supporting,Use modified PS4 criteria instead of PP4 code,Disease-specific
-TP53 (HGNC:11998),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-TP53 (HGNC:11998),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-TP53 (HGNC:11998),BA1,Stand Alone,Frequency cutoff of 0.1% minimum of 5 alleles present in the population,Disease-specific
-TP53 (HGNC:11998),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-TP53 (HGNC:11998),BS1,Strong,"Frequency cutoff of 0.03%; minimum of 5 alleles present in the population.
-
-
-
-
-Use a minor allele frequency cutoff of >0.0003 but <0.001 (99.99% CI, sub-population must have a minimum of 5 alleles present in the sub-population) based on the Whiffen-Ware calculator.
-
-
-To set the strong benign MAF cutoff, we used a prevalence of 1 in 5,000 from Lalloo, et a 2006 (PMID:16644204). We set the genetic and allelic heterogeneity at 100% and penetrance at 30%.",Disease-specific
-TP53 (HGNC:11998),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-TP53 (HGNC:11998),BS2,Strong,"Observed in ≥8 cancer free 60+ year old females obtained from the same data source.
-Using TP53 multigene panel testing results from two diagnostic labs, we compared the proportion of cancer-free individuals by age 60 in TP53 carriers versus TP53-negative controls. Based on the correspondence between likelihood ratios of pathogenicity and different levels of strengths for ACMG/AMP rules in the study by Tavtigian et al., 2018 (PMID: 29300386), our most conservative results support the following:
-
-
-
-
-This evidence code can be used when a variant is observed in ≥8 females who have reached at least 60 years of age without cancer. These individuals all must have come from a single source (single lab, database, etc). Cases cannot be counted across sources.",Disease-specific
-TP53 (HGNC:11998),BS2,Supporting,"Observed in 2-7 cancer free 60+ year old females obtained from the same data source.
-Using TP53 multigene panel testing results from two diagnostic labs, we compared the proportion of cancer-free individuals by age 60 in TP53 carriers versus TP53-negative controls. Based on the correspondence between likelihood ratios of pathogenicity and different levels of strengths for ACMG/AMP rules in the study by Tavtigian et al., 2018 (PMID: 29300386), our most conservative results support the following:
-
-
-
-
-This evidence code can be used when a variant is observed in 2-7 females who have reached at least 60 years of age without cancer. These individuals all must have come from a single source (single lab, database, etc). Cases cannot be counted across sources.",Disease-specific
-TP53 (HGNC:11998),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-TP53 (HGNC:11998),BS3,Strong,"Transactivation assays in yeast (IARC classification based on data from Kato et al, 2003) that show retained function (76-140% activity) or supertransactivation function AND:
-
-
-
-
-No evidence of DNE + no evidence of LOF from Giacomelli, et al data.
-OR
-There is a 2nd assay, including colony formation assays, apoptosis assays, tetramer assays, growth suppression and knock-in mouse models demonstrating retained function.
-Do not use code with conflicting evidence",Strength
-TP53 (HGNC:11998),BS3,Supporting,"Transactivation assays in yeast (IARC classification based on data from Kato et al, 2003) that demonstrate a partially functioning allele (>20% and <=75% activity) AND:
-
-
-
-
-No evidence of DNE + no evidence of LOF from Giacomelli, et al data.
-OR
-
-
-There is a 2nd assay demonstrating retained function
-Do not use code with conflicting evidence.
-No transactivation assays in yeast (IARC classification based on data from Kato et al, 2003) available BUT:
-
-
-No evidence of DNE + no evidence of LOF from Giacomelli, et al data.
-AND 
- There is a 2nd assay showing retained function
-Do not use code with conflicting evidence",Strength
-TP53 (HGNC:11998),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-TP53 (HGNC:11998),BS4,Strong,"Variant segregates to opposite side of the family who meets LFS criteria.
-OR
-Variant is present in ≥3 living unaffected individuals (at least 2 of which should be female) above 55 years of age.",Disease-specific
-TP53 (HGNC:11998),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-TP53 (HGNC:11998),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-TP53 (HGNC:11998),BP2,Supporting,"This evidence code can be applied in either scenario below:
-
-
-
-
-Variant is observed in trans with a pathogenic or likely pathogenic TP53 variant (phase confirmed), or
-
-
-When there are 3 or more observations with a pathogenic or likely pathogenic variant when phase is unknown. In this scenario, the variant must be seen with at least two different pathogenic/likely pathogenic TP53 variants.",Disease-specific
-TP53 (HGNC:11998),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-TP53 (HGNC:11998),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-TP53 (HGNC:11998),BP4,Supporting,"Missense: aGVGD (zebrafish; Class C0 or C15 is considered evidence of non-pathogenicity) and BayesDel <0.16 is considered evidence on non-pathogenicity Splicing: Evidence of no splice effect on a splice metapredictor (SpliceAI, VarSEAK, etc).",Disease-specific
-TP53 (HGNC:11998),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-TP53 (HGNC:11998),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-TP53 (HGNC:11998),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-TP53 (HGNC:11998),BP7,Supporting,"Evidence of no splice effect on a splice metapredictor (SpliceAI, VarSEAK, etc). If a new alternate site is predicted, compare strength to native site in interpretation.",Disease-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.0.0_version=2.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.0.0_version=2.0.0.csv
deleted file mode 100644
index 46ff1ad39411a23c93a6351f8c5845f131aa309c..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.0.0_version=2.0.0.csv
+++ /dev/null
@@ -1,337 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-TP53 (HGNC:11998),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-TP53 (HGNC:11998),PVS1,Very Strong,"Please utilize the PVS1 decision tree for application of PVS1 code. The decision tree details the specific strengths each type of null variant may be applied at. Please see below for some additional helpful summary details for application of PVS1 code:
-
-
-
-
-Initiation codon:
-
-
-PVS1 may be applied to initiation codon variants
-
-
-
-
-
-
-Nonsense or frameshift variants:
-
-
-PVS1 applies to variants predicted to result in nonsense-mediated decay (NMD) for nonsense variants upstream of p.Lys351 and for frameshift induced premature termination codon (PTC) upstream of p.Lys351
-
-
-PVS1_Strong applies to variants not predicted to undergo NMD (nonsense variants downstream of p.Leu350 or frameshift induced PTC in exon 11 or in the 3’ most 50 nucleotides of exon 10) in variants located in the p.Lys351 to p.Ala 355 range
-
-
-PVS1_Moderate applies to variants not predicted to undergo NMD (nonsense variants downstream of p.Leu350 or frameshift induced PTC in exon 11 or in the 3’ most 50 nucleotides of exon 10) in variants located in the p.Gly356 to p.Asp393 range
-
-
-PVS1_Moderate may also be applied to frameshift induced PTC downstream of the natural stop codon
-
-
-
-
-
-
-Canonical splice variants (+/- 1,2 intronic positions): 
-
-
-PVS1 applies to predicted splicing alterations that are PTC resulting in NMD (or in-frame but targeting critical domains or residues)
-
-
-PVS1 applies to predicted splicing alterations that target the start codon (Exon 2 donor)
-
-
-PVS1_Moderate applied to splicing alterations that are predicted to shorten (<10% of the protein removed) or expand a 
-TP53
- C-terminal end of unknown function (E10 donor or E11 acceptor)
-
-
-
-
-
-
-Deletions
-
-
-Full gene deletions: PVS1
-
-
-Single- to multi-exon deletions that target the initiation codon, preserving the potential rescue ATG (p.Met40) in exon 4: PVS1
-
-
-Single- to multi-exon deletions that target the initiation codon and the potential rescue ATG (p.Met40) in exon 4: PVS1
-
-
-Single- to multi-exon deletion that disrupts the reading frame and is predicted to undergo NMD (nonsense or frameshift induced PTC upstream of p.Lys351): PVS1
-
-
-Single- to multi-exon deletion that disrupts the reading frame and is 
-NOT
- predicted to undergo NMD (nonsense or frameshift inducted PTC downstream of p.Leu350): PVS1
-
-
-Single- to multi-exon deletion including the last exon where the truncated/altered region is critical to protein function (any multi-exon combination targeting exon 11): PVS1
-
-
-If the role of the region in protein function is unknown, if the variant removed < 10% of the protein (deletion of exon 11): PVS1_Moderate
-
-
-
-
-
-
-Single- to multi-exon deletion that preserves the reading frame where the truncated/altered region is critical to protein function: PVS1
-
-
-
-
-
-
-Duplications (≥1 exon in size and must be completely contained within the 
-TP53
- gene)
-
-
-Proven in tandem. Reading frame is disrupted and NMD predicted to occur (nonsense upstream of p.Lys351 or frameshift-induced PTC upstream of p.Lys351): PVS1
-
-
-Presumed in tandem. Reading frame presumed disrupted and NMD predicted to occur (nonsense upstream of p.Lys351 or frameshift-induced PTC upstream of p.Lys351): PVS1_Strong
-
-
-
-
-
-
-
-
-For variants inducing aberrant transcripts identified via mRNA assay, apply as PVS1_Variable Weight (RNA) following recommendations from Walker et al., 2023 (PMID: 37352859), downgrading one strength level if the assay data indicates leakiness.
-
-
-Caveats
-: PS3 should not be applied at any strength if PVS1 is applied at full strength. PP3 should not be used in combination with PVS1.
-
-
-For the purposes of unified curation, the TP53 domains/important motifs by amino acid range are defined as:
-
-
-TAD1
-: aa 17-25
-
-
-TAD2
-: aa 48-56
-
-
-Proline residues
-: aa 64-92
-
-
-DNA binding domain
-: aa 100-292
-
-
-Hinge domain
-: aa 293-324
-
-
-Oligomerization domain
-: aa 325-356
-
-
-C-terminal domain (Basic domain)
-: aa 368-387
-
-
-A disease-specific PVS1 decision tree incorporating the above bullets as well as a supplemental file for 
-TP53
- PVS1 Splicing Worksheet is also included as an additional curation tool and has more granular details.","Disease-specific,Strength"
-TP53 (HGNC:11998),PVS1,Strong,See PVS1 flowchart for code application,"Disease-specific,Strength"
-TP53 (HGNC:11998),PVS1,Moderate,See PVS1 flowchart for code application,"Disease-specific,Strength"
-TP53 (HGNC:11998),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-TP53 (HGNC:11998),PS1,Strong,"Can be applied to variants asserted as Pathogenic following the 
-TP53
- VCEP’s specifications.","Disease-specific,Strength"
-TP53 (HGNC:11998),PS1,Moderate,"Can be applied to variants asserted as Likely Pathogenic following the 
-TP53
- VCEP’s specifications.","Disease-specific,Strength"
-TP53 (HGNC:11998),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-TP53 (HGNC:11998),PS2,Very Strong,≥ 8 points,"Disease-specific,Strength"
-TP53 (HGNC:11998),PS2,Strong,4-7 points,"Disease-specific,Strength"
-TP53 (HGNC:11998),PS2,Moderate,2-3 points,"Disease-specific,Strength"
-TP53 (HGNC:11998),PS2,Supporting,1 point,"Disease-specific,Strength"
-TP53 (HGNC:11998),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-TP53 (HGNC:11998),PS3,Strong,"Non-functional on Kato et al. data 
-AND
- loss of function (LOF) on Giacomelli et al. data 
-AND/OR
- LOF on another assay (e.g. Kotler or a second assay showing low function)","Disease-specific,Strength"
-TP53 (HGNC:11998),PS3,Moderate,"Partially functional on Kato et al. data 
-AND
- loss of function (LOF) on Giacomelli et al. data 
-AND/OR
- LOF on another assay  (e.g. Kotler or a second assay showing low function). Do not apply PS3_Moderate if any assay evidence is conflicting.","Disease-specific,Strength"
-TP53 (HGNC:11998),PS3,Supporting,"Non-functional on Kato et.al data 
-AND
- abnormal on Kawaguchi et al. data regardless of other assays. If no Kato et al. data is available: LOF on Kotler et al. data 
-AND
- LOF (or no data available) on Giacomelli et al. data.
-
-
-PS3_Supporting may also be applied to small deletions with available Kotler et al. data that demonstrates LOF.","Disease-specific,Strength"
-TP53 (HGNC:11998),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-TP53 (HGNC:11998),PS4,Very Strong,≥ 8 points,"Disease-specific,Strength"
-TP53 (HGNC:11998),PS4,Strong,≥ 4-7.5 points,"Disease-specific,Strength"
-TP53 (HGNC:11998),PS4,Moderate,2-3.5 points,"Disease-specific,Strength"
-TP53 (HGNC:11998),PS4,Supporting,1-1.5 points,"Disease-specific,Strength"
-TP53 (HGNC:11998),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-TP53 (HGNC:11998),PM1,Moderate,"Missense variants within the following codons using transcript NM_00546.4: 175, 245, 248, 249, 273, 282. This code weight can also be used for germline missense variants seen in cancerhotspots.org with ≥ 10 somatic occurrences for the same amino acid change.","Disease-specific,Strength"
-TP53 (HGNC:11998),PM1,Supporting,Missense variants seen in cancerhotspots.org with 2-9 somatic occurrences for the same amino acid change.,"Disease-specific,Strength"
-TP53 (HGNC:11998),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-TP53 (HGNC:11998),PM2,Supporting,"This rule should be applied at supporting level. Variant should have an allele frequency of less than 0.00003 (0.003%) in gnomAD or another large sequenced population. If multiple alleles are present within any genetic ancestry group, allele frequency in that group must be <0.00004 (0.004%). Genetic ancestry groups influenced by founder effects (such as Ashkenazi Jewish, Finnish, Amish, Middle Eastern, and “Remaining”) should be ignored. 
-
-
-If the variant being assessed does not meet any population rule codes (PM2, BA1, BS1) 
-AND
- has a total allele frequency >0.00003 with no single genetic ancestry group having multiple alleles with a frequency >0.0004, curators should recalculate the total allele frequency based on the number of alleles with variant allele fraction (VAF) >0.35 to assess whether PM2 may be met after excluding the low VAF alleles which are likely to represent clonal hematopoiesis of indeterminant potential (CHIP) contamination in the database. This can be done by visualizing the “allele balance” for heterozygotes under the genotype quality metrics for a given variant. By hovering over the histogram bars, the number of variant carriers for each bar between 0.35 and 0.65 can be totaled and this can be used to revise the allele count to determine the allele frequency that can be used to assess if PM2_Supporting can be met.
-
-
-In general, the most recent version of gnomAD should be used when available; however, other population databases or earlier versions of gnomAD may be utilized if they are able to provide information the curator deems necessary for optimal variant classification (e.g, they would provide superior information for a particular variant type; have a larger sample size; or better representation for certain subpopulations, etc.)","Disease-specific,General recommendation"
-TP53 (HGNC:11998),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-TP53 (HGNC:11998),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,NA
-TP53 (HGNC:11998),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-TP53 (HGNC:11998),PM5,Strong,"Missense variant at an amino acid residue where ≥2 different missense variants previously determined to be pathogenic according to the 
-TP53
- VCEP’s specifications have been seen before.","Disease-specific,Strength"
-TP53 (HGNC:11998),PM5,Moderate,"Missense variant at an amino acid residue where 1 different missense variant previously determined to be pathogenic according to the 
-TP53
- VCEP’s specifications has been seen before.","Disease-specific,Strength"
-TP53 (HGNC:11998),PM5,Supporting,"Missense variant at an amino acid residue where 1 different missense variant previously determined to be likely pathogenic according to the 
-TP53
- VCEP’s specifications has been seen before. The previously seen likely pathogenic variant must have clinical data that demonstrates pathogenicity (i.e. PS2, PS4, PP1) in order for it to count towards PM5_Supporting code application.","Disease-specific,Strength"
-TP53 (HGNC:11998),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-TP53 (HGNC:11998),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-TP53 (HGNC:11998),PP1,Strong,Cosegregation must be observed in ≥ 7 meioses across > 1 family,"Disease-specific,Strength"
-TP53 (HGNC:11998),PP1,Moderate,Cosegregation must be observed in 5-6 meioses in/across 1 or more families,"Disease-specific,Strength"
-TP53 (HGNC:11998),PP1,Supporting,Cosegregation must be observed in 3-4 meioses in/across 1 or more families,"Disease-specific,Strength"
-TP53 (HGNC:11998),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-TP53 (HGNC:11998),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-TP53 (HGNC:11998),PP3,Moderate,"Missense variants
- 
-(See flowchart for application of PP3 and BP4 rules for missense variants)
-
-
-aGVGD Class C65 and BayesDel score ≥ 0.16","Disease-specific,Strength"
-TP53 (HGNC:11998),PP3,Supporting,"Missense variants
- 
-(See flowchart for application of PP3 and BP4 rules for missense variants)
-
-
-aGVGD class C25-C55 and BayesDel score ≥ 0.16
-
-
-Single amino acid inframe deletions
- 
-(See single aa BayesDel spreadsheet)
-
-
-BayesDel score ≥ 0.16
-
-
-Exonic (including silent variants and apparent “missense” variants or “single amino acid inframe deletions” for which there is a predicted splice effect) or Intronic Splice Variants (excluding ± 1,2 positions):
-
-
-SpliceAI ≥ 0.2","Disease-specific,Strength"
-TP53 (HGNC:11998),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-TP53 (HGNC:11998),PP4,Moderate,At least 2 independent observations of the variant with VAF 5-25%.,"Disease-specific,Strength"
-TP53 (HGNC:11998),PP4,Supporting,Observation of the variant with VAF at or below 35%.,"Disease-specific,Strength"
-TP53 (HGNC:11998),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-TP53 (HGNC:11998),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-TP53 (HGNC:11998),BA1,Stand Alone,"Filtering allele frequency (FAF) of ≥ 0.001 or 0.1% in gnomAD continental subpopulations of a single genetic ancestry group (excluding genetic ancestry groups influenced by founder effects, such as Ashkenazi Jewish, Finnish, Amish, Middle Eastern, and “Remaining”). Genetic ancestry group must have ≥2,000 alleles tested and a minimum of 2 alleles present. Caution should be exerted if the majority of alleles have a variant allele fraction (""allele balance"" in gnomAD) below 0.35.  To set the stand-alone benign FAF cutoff, we used the FAF cutoff established for BS1 (0.0003) and increased this cutoff by one order of magnitude to come to a value of 0.001. 
-
-
-In general, the most recent version of gnomAD should be used when available; however, other population databases or earlier versions of gnomAD may be utilized if they are able to provide information the curator deems necessary for optimal variant classification (e.g, they would provide superior information for a particular variant type; have a larger sample size; or better representation for certain subpopulations, etc.)",Disease-specific
-TP53 (HGNC:11998),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-TP53 (HGNC:11998),BS1,Strong,"Filtering allele frequency (FAF) of ≥ 0.0003 but < 0.001 in gnomAD continental subpopulations of a single genetic ancestry group (excluding genetic ancestry groups influenced by founder effects, such as Ashkenazi Jewish, Finnish, Amish, Middle Eastern, and “Remaining”). Genetic ancestry group must have ≥2,000 alleles tested and a minimum of 2 alleles present. Caution should be exerted if the majority of alleles have a variant allele fraction ( “allele balance” in gnomAD) below 0.35. To set the strong benign FAF cutoff, we used a Whiffin-Ware calculation using prevalence of 1 in 5,000 (Lalloo, et al., 2006 PMID: 16644204). Genetic and allelic heterogeneity were set at 100% and penetrance at 30%. 
-
-
-In general, the most recent version of gnomAD should be used when available; however, other population databases or earlier versions of gnomAD may be utilized if they are able to provide information the curator deems necessary for optimal variant classification (e.g, they would provide superior information for a particular variant type; have a larger sample size; or better representation for certain subpopulations, etc.)",Disease-specific
-TP53 (HGNC:11998),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-TP53 (HGNC:11998),BS2,Strong,"≥ 8 unrelated females who have reached at least 60 years of age without cancer. These individuals all must have come from a single source (single lab, database, etc). Cases cannot be counted across sources. Individuals with a diagnosis of sarcoma ≥ 61 years of age should not be counted towards the BS2 total.",Disease-specific
-TP53 (HGNC:11998),BS2,Moderate,"4-7 unrelated females who have reached at least 60 years of age without cancer. These individuals all must have come from a single source (single lab, database, etc). Cases cannot be counted across sources. Individuals with a diagnosis of sarcoma ≥ 61 years of age should not be counted towards the BS2 total.",Disease-specific
-TP53 (HGNC:11998),BS2,Supporting,"2-3 unrelated females who have reached at least 60 years of age without cancer. These individuals all must have come from a single source (single lab, database, etc). Cases cannot be counted across sources. Individuals with a diagnosis of sarcoma ≥ 61 years of age should not be counted towards the BS2 total.",Disease-specific
-TP53 (HGNC:11998),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-TP53 (HGNC:11998),BS3,Strong,"Functional on Kato et al. data 
-AND
- no loss of function (LOF) on Giacomelli et al. data 
-AND/OR
- no evidence of LOF on another assay (e.g. Kotler or a second assay)","Disease-specific,Strength"
-TP53 (HGNC:11998),BS3,Supporting,"Partially functional on Kato et al. data 
-AND
- no evidence of loss of function (LOF) on Giacomelli et al. data 
-AND
- no evidence of LOF on another assay (e.g. Kotler or other assay showing preserved function) 
-AND
- normal or no data on Kawaguchi et al. data. Do not apply BS3_Supporting if any assay evidence is conflicting. If no Kato et al. data is available: no evidence of LOF on Kotler et al. data 
-AND
- no evidence of LOF (or no data available) on Giacomelli et al. data. 
-
-
-BS3_Supporting may also be applied to small deletions with available Kotler et al. data that demonstrate no evidence of LOF.","Disease-specific,Strength"
-TP53 (HGNC:11998),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-TP53 (HGNC:11998),BS4,Strong,Lack of segregation in affected family members (i.e. family members diagnosed with LFS-associated cancers as described in Table of LFS Cancers and Points for PS2 and PP1 Code Application).,Disease-specific
-TP53 (HGNC:11998),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-TP53 (HGNC:11998),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-TP53 (HGNC:11998),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-TP53 (HGNC:11998),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-TP53 (HGNC:11998),BP4,Moderate,"Missense variants
- 
-(See flowchart for application of PP3 and BP4 rules for missense variants):
-
-
-BayesDel ≤ -0.008 irrespective of aGVGD score (except C65, in this case do not apply BP4_Moderate) AND no predicted differences in splicing (SpliceAI < 0.2)","Disease-specific,Strength"
-TP53 (HGNC:11998),BP4,Supporting,"Missense variants
- 
-(See flowchart for application of PP3 and BP4 rules for missense variants):
-
-
-BayesDel < 0.16 and > -0.008 irrespective of aGVGD score (except C65, this case do not apply BP4) AND no predicted differences in splicing (SpliceAI < 0.2)
-
-
-Single amino acid inframe deletions
- 
-(See single aa BayesDel spreadsheet):
-
-
-BayesDel score < 0.16 AND no predicted splicing impact (Splice AI < 0.2)
-
-
-Silent or Intronic Variants (outside ± 1,2 positions):
-
-
-SpliceAI ≤ 0.1","Disease-specific,Strength"
-TP53 (HGNC:11998),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-TP53 (HGNC:11998),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-TP53 (HGNC:11998),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-TP53 (HGNC:11998),BP7,Strong,"A (synonymous) silent or intronic variant for which RNA splicing assay data demonstrates no splicing aberration, as per recommendations from Walker et al., 2023 (PMID: 37352859). BP7 cannot be applied if BP4 is not met.",Disease-specific
-TP53 (HGNC:11998),BP7,Supporting,"A synonymous (silent) outside of the core splice motif (last three nucleotides and first nucleotide of the exon) or intronic variant at or beyond +7 to -21 positions for which SpliceAI predicts no impact to the splice consensus nor the creation of a new splice site (BP4 is met, SpliceAI ≤ 0.1). No requirement to assess for nucleotide conservation for rule application as per evidence and recommendations in Walker et al., 2023  (PMID: 37352859). BP7 cannot be applied if BP4 is not met.",Disease-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.1.0_version=2.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.1.0_version=2.1.0.csv
deleted file mode 100644
index 791714502de82c5406fb6a53005d02ca6bf15362..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.1.0_version=2.1.0.csv
+++ /dev/null
@@ -1,333 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-TP53 (HGNC:11998),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-TP53 (HGNC:11998),PVS1,Very Strong,"Please utilize the PVS1 decision tree for application of PVS1 code. The decision tree details the specific strengths each type of null variant may be applied at. Please see below for some additional helpful summary details for application of PVS1 code:
-
-
-
-
-Initiation codon:
-
-
-PVS1 may be applied to initiation codon variants
-
-
-
-
-
-
-Nonsense or frameshift variants:
-
-
-PVS1 applies to variants predicted to result in nonsense-mediated decay (NMD) for nonsense variants upstream of p.Lys351 and for frameshift induced premature termination codon (PTC) upstream of p.Lys351
-
-
-PVS1_Strong applies to variants not predicted to undergo NMD (nonsense variants downstream of p.Leu350 or frameshift induced PTC in exon 11 or in the 3’ most 50 nucleotides of exon 10) in variants located in the p.Lys351 to p.Ala 355 range
-
-
-PVS1_Moderate applies to variants not predicted to undergo NMD (nonsense variants downstream of p.Leu350 or frameshift induced PTC in exon 11 or in the 3’ most 50 nucleotides of exon 10) in variants located in the p.Gly356 to p.Asp393 range
-
-
-PVS1_Moderate may also be applied to frameshift induced PTC downstream of the natural stop codon
-
-
-
-
-
-
-Canonical splice variants (+/- 1,2 intronic positions): 
-
-
-PVS1 applies to predicted splicing alterations that are PTC resulting in NMD (or in-frame but targeting critical domains or residues)
-
-
-PVS1 applies to predicted splicing alterations that target the start codon (Exon 2 donor)
-
-
-PVS1_Moderate applied to splicing alterations that are predicted to shorten (<10% of the protein removed) or expand a 
-TP53
- C-terminal end of unknown function (E10 donor or E11 acceptor)
-
-
-
-
-
-
-Deletions
-
-
-Full gene deletions: PVS1
-
-
-Single- to multi-exon deletions that target the initiation codon, preserving the potential rescue ATG (p.Met40) in exon 4: PVS1
-
-
-Single- to multi-exon deletions that target the initiation codon and the potential rescue ATG (p.Met40) in exon 4: PVS1
-
-
-Single- to multi-exon deletion that disrupts the reading frame and is predicted to undergo NMD (nonsense or frameshift induced PTC upstream of p.Lys351): PVS1
-
-
-Single- to multi-exon deletion that disrupts the reading frame and is 
-NOT
- predicted to undergo NMD (nonsense or frameshift inducted PTC downstream of p.Leu350): PVS1
-
-
-Single- to multi-exon deletion including the last exon where the truncated/altered region is critical to protein function (any multi-exon combination targeting exon 11): PVS1
-
-
-If the role of the region in protein function is unknown, if the variant removed < 10% of the protein (deletion of exon 11): PVS1_Moderate
-
-
-
-
-
-
-Single- to multi-exon deletion that preserves the reading frame where the truncated/altered region is critical to protein function: PVS1
-
-
-
-
-
-
-Duplications (≥1 exon in size and must be completely contained within the 
-TP53
- gene)
-
-
-Proven in tandem. Reading frame is disrupted and NMD predicted to occur (nonsense upstream of p.Lys351 or frameshift-induced PTC upstream of p.Lys351): PVS1
-
-
-Presumed in tandem. Reading frame presumed disrupted and NMD predicted to occur (nonsense upstream of p.Lys351 or frameshift-induced PTC upstream of p.Lys351): PVS1_Strong
-
-
-
-
-
-
-
-
-For variants inducing aberrant transcripts identified via mRNA assay, apply as PVS1_Variable Weight (RNA) following recommendations from Walker et al., 2023 (PMID: 37352859), downgrading one strength level if the assay data indicates leakiness.
-
-
-Caveats
-: PS3 should not be applied at any strength if PVS1 is applied at full strength. PP3 should not be used in combination with PVS1.
-
-
-For the purposes of unified curation, the TP53 domains/important motifs by amino acid range are defined as:
-
-
-TAD1
-: aa 17-25
-
-
-TAD2
-: aa 48-56
-
-
-Proline residues
-: aa 64-92
-
-
-DNA binding domain
-: aa 100-292
-
-
-Hinge domain
-: aa 293-324
-
-
-Oligomerization domain
-: aa 325-356
-
-
-C-terminal domain (Basic domain)
-: aa 368-387
-
-
-A disease-specific PVS1 decision tree incorporating the above bullets as well as a supplemental file for 
-TP53
- PVS1 Splicing Worksheet is also included as an additional curation tool and has more granular details.","Disease-specific,Strength"
-TP53 (HGNC:11998),PVS1,Strong,See PVS1 flowchart for code application,"Disease-specific,Strength"
-TP53 (HGNC:11998),PVS1,Moderate,See PVS1 flowchart for code application,"Disease-specific,Strength"
-TP53 (HGNC:11998),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-TP53 (HGNC:11998),PS1,Strong,"Can be applied to variants asserted as Pathogenic following the 
-TP53
- VCEP’s specifications.","Disease-specific,Strength"
-TP53 (HGNC:11998),PS1,Moderate,"Can be applied to variants asserted as Likely Pathogenic following the 
-TP53
- VCEP’s specifications.","Disease-specific,Strength"
-TP53 (HGNC:11998),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-TP53 (HGNC:11998),PS2,Very Strong,≥ 8 points,"Disease-specific,Strength"
-TP53 (HGNC:11998),PS2,Strong,4-7 points,"Disease-specific,Strength"
-TP53 (HGNC:11998),PS2,Moderate,2-3 points,"Disease-specific,Strength"
-TP53 (HGNC:11998),PS2,Supporting,1 point,"Disease-specific,Strength"
-TP53 (HGNC:11998),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-TP53 (HGNC:11998),PS3,Strong,"Non-functional on Kato et al. data 
-AND
- loss of function (LOF) on another assay (e.g., Giacomelli et al., Kotler et al., or another assay showing low function)","Disease-specific,Strength"
-TP53 (HGNC:11998),PS3,Moderate,"Partially functional on Kato et al. data 
-AND
- loss of function (LOF) on Giacomelli et al. data 
-AND/OR
- LOF on another assay  (e.g. Kotler or a second assay showing low function). Do not apply PS3_Moderate if any assay evidence is conflicting.","Disease-specific,Strength"
-TP53 (HGNC:11998),PS3,Supporting,"Non-functional on Kato et.al data 
-AND
- abnormal on Kawaguchi et al. data regardless of other assays. If no Kato et al. data is available: LOF on Kotler et al. data 
-AND
- LOF (or no data available) on Giacomelli et al. data.
-
-
-PS3_Supporting may also be applied to small deletions with available Kotler et al. data that demonstrates LOF.","Disease-specific,Strength"
-TP53 (HGNC:11998),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-TP53 (HGNC:11998),PS4,Very Strong,≥ 8 points,"Disease-specific,Strength"
-TP53 (HGNC:11998),PS4,Strong,≥ 4-7.5 points,"Disease-specific,Strength"
-TP53 (HGNC:11998),PS4,Moderate,2-3.5 points,"Disease-specific,Strength"
-TP53 (HGNC:11998),PS4,Supporting,1-1.5 points,"Disease-specific,Strength"
-TP53 (HGNC:11998),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-TP53 (HGNC:11998),PM1,Moderate,"Missense variants within the following codons using transcript NM_00546.4: 175, 245, 248, 249, 273, 282. This code weight can also be used for germline missense variants seen in cancerhotspots.org with ≥ 10 somatic occurrences for the same amino acid change.","Disease-specific,Strength"
-TP53 (HGNC:11998),PM1,Supporting,Missense variants seen in cancerhotspots.org with 2-9 somatic occurrences for the same amino acid change.,"Disease-specific,Strength"
-TP53 (HGNC:11998),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-TP53 (HGNC:11998),PM2,Supporting,"This rule should be applied at supporting level. Variant should have an allele frequency of less than 0.00003 (0.003%) in gnomAD or another large sequenced population. If multiple alleles are present within any genetic ancestry group, allele frequency in that group must be <0.00004 (0.004%). Genetic ancestry groups influenced by founder effects (such as Ashkenazi Jewish, Finnish, Amish, Middle Eastern, and “Remaining”) should be ignored. 
-
-
-If the variant being assessed does not meet any population rule codes (PM2, BA1, BS1) 
-AND
- has a total allele frequency >0.00003 with no single genetic ancestry group having multiple alleles with a frequency >0.0004, curators should recalculate the total allele frequency based on the number of alleles with variant allele fraction (VAF) >0.35 to assess whether PM2 may be met after excluding the low VAF alleles which are likely to represent clonal hematopoiesis of indeterminant potential (CHIP) contamination in the database. This can be done by visualizing the “allele balance” for heterozygotes under the genotype quality metrics for a given variant. By hovering over the histogram bars, the number of variant carriers for each bar between 0.35 and 0.65 can be totaled and this can be used to revise the allele count to determine the allele frequency that can be used to assess if PM2_Supporting can be met.
-
-
-In general, the most recent version of gnomAD should be used when available; however, other population databases or earlier versions of gnomAD may be utilized if they are able to provide information the curator deems necessary for optimal variant classification (e.g, they would provide superior information for a particular variant type; have a larger sample size; or better representation for certain subpopulations, etc.)","Disease-specific,General recommendation"
-TP53 (HGNC:11998),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-TP53 (HGNC:11998),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,NA
-TP53 (HGNC:11998),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-TP53 (HGNC:11998),PM5,Strong,"Missense variant at an amino acid residue where ≥2 different missense variants previously determined to be pathogenic according to the 
-TP53
- VCEP’s specifications have been seen before.","Disease-specific,Strength"
-TP53 (HGNC:11998),PM5,Moderate,"Missense variant at an amino acid residue where 1 different missense variant previously determined to be pathogenic according to the 
-TP53
- VCEP’s specifications has been seen before.","Disease-specific,Strength"
-TP53 (HGNC:11998),PM5,Supporting,"Missense variant at an amino acid residue where 1 different missense variant previously determined to be likely pathogenic according to the 
-TP53
- VCEP’s specifications has been seen before. The previously seen likely pathogenic variant must have clinical data that demonstrates pathogenicity (i.e. PS2, PS4, PP1) in order for it to count towards PM5_Supporting code application.","Disease-specific,Strength"
-TP53 (HGNC:11998),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-TP53 (HGNC:11998),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-TP53 (HGNC:11998),PP1,Strong,Cosegregation must be observed in ≥ 7 meioses across > 1 family,"Disease-specific,Strength"
-TP53 (HGNC:11998),PP1,Moderate,Cosegregation must be observed in 5-6 meioses in/across 1 or more families,"Disease-specific,Strength"
-TP53 (HGNC:11998),PP1,Supporting,Cosegregation must be observed in 3-4 meioses in/across 1 or more families,"Disease-specific,Strength"
-TP53 (HGNC:11998),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-TP53 (HGNC:11998),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-TP53 (HGNC:11998),PP3,Moderate,"Missense variants
- 
-(See flowchart for application of PP3 and BP4 rules for missense variants)
-
-
-aGVGD Class C65 and BayesDel score ≥ 0.16","Disease-specific,Strength"
-TP53 (HGNC:11998),PP3,Supporting,"Missense variants
- 
-(See flowchart for application of PP3 and BP4 rules for missense variants)
-
-
-aGVGD class C25-C55 and BayesDel score ≥ 0.16
-
-
-Single amino acid inframe deletions
- 
-(See single aa BayesDel spreadsheet)
-
-
-BayesDel score ≥ 0.16
-
-
-Exonic (including silent variants and apparent “missense” variants or “single amino acid inframe deletions” for which there is a predicted splice effect) or Intronic Splice Variants (excluding ± 1,2 positions):
-
-
-SpliceAI ≥ 0.2","Disease-specific,Strength"
-TP53 (HGNC:11998),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-TP53 (HGNC:11998),PP4,Moderate,At least 2 independent observations of the variant with VAF 5-25%.,"Disease-specific,Strength"
-TP53 (HGNC:11998),PP4,Supporting,Observation of the variant with VAF at or below 35%.,"Disease-specific,Strength"
-TP53 (HGNC:11998),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-TP53 (HGNC:11998),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-TP53 (HGNC:11998),BA1,Stand Alone,"Filtering allele frequency (FAF) of ≥ 0.001 or 0.1% in gnomAD continental subpopulations of a single genetic ancestry group (excluding genetic ancestry groups influenced by founder effects, such as Ashkenazi Jewish, Finnish, Amish, Middle Eastern, and “Remaining”). Genetic ancestry group must have ≥2,000 alleles tested and a minimum of 2 alleles present. Caution should be exerted if the majority of alleles have a variant allele fraction (""allele balance"" in gnomAD) below 0.35.  To set the stand-alone benign FAF cutoff, we used the FAF cutoff established for BS1 (0.0003) and increased this cutoff by one order of magnitude to come to a value of 0.001. 
-
-
-In general, the most recent version of gnomAD should be used when available; however, other population databases or earlier versions of gnomAD may be utilized if they are able to provide information the curator deems necessary for optimal variant classification (e.g, they would provide superior information for a particular variant type; have a larger sample size; or better representation for certain subpopulations, etc.)",Disease-specific
-TP53 (HGNC:11998),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-TP53 (HGNC:11998),BS1,Strong,"Filtering allele frequency (FAF) of ≥ 0.0003 but < 0.001 in gnomAD continental subpopulations of a single genetic ancestry group (excluding genetic ancestry groups influenced by founder effects, such as Ashkenazi Jewish, Finnish, Amish, Middle Eastern, and “Remaining”). Genetic ancestry group must have ≥2,000 alleles tested and a minimum of 2 alleles present. Caution should be exerted if the majority of alleles have a variant allele fraction ( “allele balance” in gnomAD) below 0.35. To set the strong benign FAF cutoff, we used a Whiffin-Ware calculation using prevalence of 1 in 5,000 (Lalloo, et al., 2006 PMID: 16644204). Genetic and allelic heterogeneity were set at 100% and penetrance at 30%. 
-
-
-In general, the most recent version of gnomAD should be used when available; however, other population databases or earlier versions of gnomAD may be utilized if they are able to provide information the curator deems necessary for optimal variant classification (e.g, they would provide superior information for a particular variant type; have a larger sample size; or better representation for certain subpopulations, etc.)",Disease-specific
-TP53 (HGNC:11998),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-TP53 (HGNC:11998),BS2,Strong,"≥ 8 unrelated females who have reached at least 60 years of age without cancer. These individuals all must have come from a single source (single lab, database, etc). Cases cannot be counted across sources. Individuals with a diagnosis of sarcoma ≥ 61 years of age should not be counted towards the BS2 total.",Disease-specific
-TP53 (HGNC:11998),BS2,Moderate,"4-7 unrelated females who have reached at least 60 years of age without cancer. These individuals all must have come from a single source (single lab, database, etc). Cases cannot be counted across sources. Individuals with a diagnosis of sarcoma ≥ 61 years of age should not be counted towards the BS2 total.",Disease-specific
-TP53 (HGNC:11998),BS2,Supporting,"2-3 unrelated females who have reached at least 60 years of age without cancer. These individuals all must have come from a single source (single lab, database, etc). Cases cannot be counted across sources. Individuals with a diagnosis of sarcoma ≥ 61 years of age should not be counted towards the BS2 total.",Disease-specific
-TP53 (HGNC:11998),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-TP53 (HGNC:11998),BS3,Strong,"Functional on Kato et al. data 
-AND
- no loss of function (LOF) on another assay (e.g., Giacomelli et al., Kotler et al., or another assay)","Disease-specific,Strength"
-TP53 (HGNC:11998),BS3,Supporting,"Partially functional on Kato et al. data 
-AND
- no evidence of loss of function (LOF) on Giacomelli et al. data 
-AND
- no evidence of LOF on another assay (e.g. Kotler or other assay showing preserved function) 
-AND
- normal or no data on Kawaguchi et al. data. Do not apply BS3_Supporting if any assay evidence is conflicting. If no Kato et al. data is available: no evidence of LOF on Kotler et al. data 
-AND
- no evidence of LOF (or no data available) on Giacomelli et al. data. 
-
-
-BS3_Supporting may also be applied to small deletions with available Kotler et al. data that demonstrate no evidence of LOF.","Disease-specific,Strength"
-TP53 (HGNC:11998),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-TP53 (HGNC:11998),BS4,Strong,Lack of segregation in affected family members (i.e. family members diagnosed with LFS-associated cancers as described in Table of LFS Cancers and Points for PS2 and PP1 Code Application).,Disease-specific
-TP53 (HGNC:11998),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-TP53 (HGNC:11998),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-TP53 (HGNC:11998),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-TP53 (HGNC:11998),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-TP53 (HGNC:11998),BP4,Moderate,"Missense variants
- 
-(See flowchart for application of PP3 and BP4 rules for missense variants):
-
-
-BayesDel ≤ -0.008 irrespective of aGVGD score (except C65, in this case do not apply BP4_Moderate) AND no predicted differences in splicing (SpliceAI < 0.2)","Disease-specific,Strength"
-TP53 (HGNC:11998),BP4,Supporting,"Missense variants
- 
-(See flowchart for application of PP3 and BP4 rules for missense variants):
-
-
-BayesDel < 0.16 and > -0.008 irrespective of aGVGD score (except C65, this case do not apply BP4) AND no predicted differences in splicing (SpliceAI < 0.2)
-
-
-Single amino acid inframe deletions
- 
-(See single aa BayesDel spreadsheet):
-
-
-BayesDel score < 0.16 AND no predicted splicing impact (Splice AI < 0.2)
-
-
-Silent or Intronic Variants (outside ± 1,2 positions):
-
-
-SpliceAI ≤ 0.1","Disease-specific,Strength"
-TP53 (HGNC:11998),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-TP53 (HGNC:11998),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-TP53 (HGNC:11998),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-TP53 (HGNC:11998),BP7,Strong,"A (synonymous) silent or intronic variant for which RNA splicing assay data demonstrates no splicing aberration, as per recommendations from Walker et al., 2023 (PMID: 37352859). BP7 cannot be applied if BP4 is not met.",Disease-specific
-TP53 (HGNC:11998),BP7,Supporting,"A synonymous (silent) outside of the core splice motif (last three nucleotides and first nucleotide of the exon) or intronic variant at or beyond +7 to -21 positions for which SpliceAI predicts no impact to the splice consensus nor the creation of a new splice site (BP4 is met, SpliceAI ≤ 0.1). No requirement to assess for nucleotide conservation for rule application as per evidence and recommendations in Walker et al., 2023  (PMID: 37352859). BP7 cannot be applied if BP4 is not met.",Disease-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.2.0_version=2.2.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.2.0_version=2.2.0.csv
deleted file mode 100644
index 791714502de82c5406fb6a53005d02ca6bf15362..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.2.0_version=2.2.0.csv
+++ /dev/null
@@ -1,333 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-TP53 (HGNC:11998),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-TP53 (HGNC:11998),PVS1,Very Strong,"Please utilize the PVS1 decision tree for application of PVS1 code. The decision tree details the specific strengths each type of null variant may be applied at. Please see below for some additional helpful summary details for application of PVS1 code:
-
-
-
-
-Initiation codon:
-
-
-PVS1 may be applied to initiation codon variants
-
-
-
-
-
-
-Nonsense or frameshift variants:
-
-
-PVS1 applies to variants predicted to result in nonsense-mediated decay (NMD) for nonsense variants upstream of p.Lys351 and for frameshift induced premature termination codon (PTC) upstream of p.Lys351
-
-
-PVS1_Strong applies to variants not predicted to undergo NMD (nonsense variants downstream of p.Leu350 or frameshift induced PTC in exon 11 or in the 3’ most 50 nucleotides of exon 10) in variants located in the p.Lys351 to p.Ala 355 range
-
-
-PVS1_Moderate applies to variants not predicted to undergo NMD (nonsense variants downstream of p.Leu350 or frameshift induced PTC in exon 11 or in the 3’ most 50 nucleotides of exon 10) in variants located in the p.Gly356 to p.Asp393 range
-
-
-PVS1_Moderate may also be applied to frameshift induced PTC downstream of the natural stop codon
-
-
-
-
-
-
-Canonical splice variants (+/- 1,2 intronic positions): 
-
-
-PVS1 applies to predicted splicing alterations that are PTC resulting in NMD (or in-frame but targeting critical domains or residues)
-
-
-PVS1 applies to predicted splicing alterations that target the start codon (Exon 2 donor)
-
-
-PVS1_Moderate applied to splicing alterations that are predicted to shorten (<10% of the protein removed) or expand a 
-TP53
- C-terminal end of unknown function (E10 donor or E11 acceptor)
-
-
-
-
-
-
-Deletions
-
-
-Full gene deletions: PVS1
-
-
-Single- to multi-exon deletions that target the initiation codon, preserving the potential rescue ATG (p.Met40) in exon 4: PVS1
-
-
-Single- to multi-exon deletions that target the initiation codon and the potential rescue ATG (p.Met40) in exon 4: PVS1
-
-
-Single- to multi-exon deletion that disrupts the reading frame and is predicted to undergo NMD (nonsense or frameshift induced PTC upstream of p.Lys351): PVS1
-
-
-Single- to multi-exon deletion that disrupts the reading frame and is 
-NOT
- predicted to undergo NMD (nonsense or frameshift inducted PTC downstream of p.Leu350): PVS1
-
-
-Single- to multi-exon deletion including the last exon where the truncated/altered region is critical to protein function (any multi-exon combination targeting exon 11): PVS1
-
-
-If the role of the region in protein function is unknown, if the variant removed < 10% of the protein (deletion of exon 11): PVS1_Moderate
-
-
-
-
-
-
-Single- to multi-exon deletion that preserves the reading frame where the truncated/altered region is critical to protein function: PVS1
-
-
-
-
-
-
-Duplications (≥1 exon in size and must be completely contained within the 
-TP53
- gene)
-
-
-Proven in tandem. Reading frame is disrupted and NMD predicted to occur (nonsense upstream of p.Lys351 or frameshift-induced PTC upstream of p.Lys351): PVS1
-
-
-Presumed in tandem. Reading frame presumed disrupted and NMD predicted to occur (nonsense upstream of p.Lys351 or frameshift-induced PTC upstream of p.Lys351): PVS1_Strong
-
-
-
-
-
-
-
-
-For variants inducing aberrant transcripts identified via mRNA assay, apply as PVS1_Variable Weight (RNA) following recommendations from Walker et al., 2023 (PMID: 37352859), downgrading one strength level if the assay data indicates leakiness.
-
-
-Caveats
-: PS3 should not be applied at any strength if PVS1 is applied at full strength. PP3 should not be used in combination with PVS1.
-
-
-For the purposes of unified curation, the TP53 domains/important motifs by amino acid range are defined as:
-
-
-TAD1
-: aa 17-25
-
-
-TAD2
-: aa 48-56
-
-
-Proline residues
-: aa 64-92
-
-
-DNA binding domain
-: aa 100-292
-
-
-Hinge domain
-: aa 293-324
-
-
-Oligomerization domain
-: aa 325-356
-
-
-C-terminal domain (Basic domain)
-: aa 368-387
-
-
-A disease-specific PVS1 decision tree incorporating the above bullets as well as a supplemental file for 
-TP53
- PVS1 Splicing Worksheet is also included as an additional curation tool and has more granular details.","Disease-specific,Strength"
-TP53 (HGNC:11998),PVS1,Strong,See PVS1 flowchart for code application,"Disease-specific,Strength"
-TP53 (HGNC:11998),PVS1,Moderate,See PVS1 flowchart for code application,"Disease-specific,Strength"
-TP53 (HGNC:11998),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-TP53 (HGNC:11998),PS1,Strong,"Can be applied to variants asserted as Pathogenic following the 
-TP53
- VCEP’s specifications.","Disease-specific,Strength"
-TP53 (HGNC:11998),PS1,Moderate,"Can be applied to variants asserted as Likely Pathogenic following the 
-TP53
- VCEP’s specifications.","Disease-specific,Strength"
-TP53 (HGNC:11998),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-TP53 (HGNC:11998),PS2,Very Strong,≥ 8 points,"Disease-specific,Strength"
-TP53 (HGNC:11998),PS2,Strong,4-7 points,"Disease-specific,Strength"
-TP53 (HGNC:11998),PS2,Moderate,2-3 points,"Disease-specific,Strength"
-TP53 (HGNC:11998),PS2,Supporting,1 point,"Disease-specific,Strength"
-TP53 (HGNC:11998),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-TP53 (HGNC:11998),PS3,Strong,"Non-functional on Kato et al. data 
-AND
- loss of function (LOF) on another assay (e.g., Giacomelli et al., Kotler et al., or another assay showing low function)","Disease-specific,Strength"
-TP53 (HGNC:11998),PS3,Moderate,"Partially functional on Kato et al. data 
-AND
- loss of function (LOF) on Giacomelli et al. data 
-AND/OR
- LOF on another assay  (e.g. Kotler or a second assay showing low function). Do not apply PS3_Moderate if any assay evidence is conflicting.","Disease-specific,Strength"
-TP53 (HGNC:11998),PS3,Supporting,"Non-functional on Kato et.al data 
-AND
- abnormal on Kawaguchi et al. data regardless of other assays. If no Kato et al. data is available: LOF on Kotler et al. data 
-AND
- LOF (or no data available) on Giacomelli et al. data.
-
-
-PS3_Supporting may also be applied to small deletions with available Kotler et al. data that demonstrates LOF.","Disease-specific,Strength"
-TP53 (HGNC:11998),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-TP53 (HGNC:11998),PS4,Very Strong,≥ 8 points,"Disease-specific,Strength"
-TP53 (HGNC:11998),PS4,Strong,≥ 4-7.5 points,"Disease-specific,Strength"
-TP53 (HGNC:11998),PS4,Moderate,2-3.5 points,"Disease-specific,Strength"
-TP53 (HGNC:11998),PS4,Supporting,1-1.5 points,"Disease-specific,Strength"
-TP53 (HGNC:11998),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-TP53 (HGNC:11998),PM1,Moderate,"Missense variants within the following codons using transcript NM_00546.4: 175, 245, 248, 249, 273, 282. This code weight can also be used for germline missense variants seen in cancerhotspots.org with ≥ 10 somatic occurrences for the same amino acid change.","Disease-specific,Strength"
-TP53 (HGNC:11998),PM1,Supporting,Missense variants seen in cancerhotspots.org with 2-9 somatic occurrences for the same amino acid change.,"Disease-specific,Strength"
-TP53 (HGNC:11998),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-TP53 (HGNC:11998),PM2,Supporting,"This rule should be applied at supporting level. Variant should have an allele frequency of less than 0.00003 (0.003%) in gnomAD or another large sequenced population. If multiple alleles are present within any genetic ancestry group, allele frequency in that group must be <0.00004 (0.004%). Genetic ancestry groups influenced by founder effects (such as Ashkenazi Jewish, Finnish, Amish, Middle Eastern, and “Remaining”) should be ignored. 
-
-
-If the variant being assessed does not meet any population rule codes (PM2, BA1, BS1) 
-AND
- has a total allele frequency >0.00003 with no single genetic ancestry group having multiple alleles with a frequency >0.0004, curators should recalculate the total allele frequency based on the number of alleles with variant allele fraction (VAF) >0.35 to assess whether PM2 may be met after excluding the low VAF alleles which are likely to represent clonal hematopoiesis of indeterminant potential (CHIP) contamination in the database. This can be done by visualizing the “allele balance” for heterozygotes under the genotype quality metrics for a given variant. By hovering over the histogram bars, the number of variant carriers for each bar between 0.35 and 0.65 can be totaled and this can be used to revise the allele count to determine the allele frequency that can be used to assess if PM2_Supporting can be met.
-
-
-In general, the most recent version of gnomAD should be used when available; however, other population databases or earlier versions of gnomAD may be utilized if they are able to provide information the curator deems necessary for optimal variant classification (e.g, they would provide superior information for a particular variant type; have a larger sample size; or better representation for certain subpopulations, etc.)","Disease-specific,General recommendation"
-TP53 (HGNC:11998),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-TP53 (HGNC:11998),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,NA
-TP53 (HGNC:11998),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-TP53 (HGNC:11998),PM5,Strong,"Missense variant at an amino acid residue where ≥2 different missense variants previously determined to be pathogenic according to the 
-TP53
- VCEP’s specifications have been seen before.","Disease-specific,Strength"
-TP53 (HGNC:11998),PM5,Moderate,"Missense variant at an amino acid residue where 1 different missense variant previously determined to be pathogenic according to the 
-TP53
- VCEP’s specifications has been seen before.","Disease-specific,Strength"
-TP53 (HGNC:11998),PM5,Supporting,"Missense variant at an amino acid residue where 1 different missense variant previously determined to be likely pathogenic according to the 
-TP53
- VCEP’s specifications has been seen before. The previously seen likely pathogenic variant must have clinical data that demonstrates pathogenicity (i.e. PS2, PS4, PP1) in order for it to count towards PM5_Supporting code application.","Disease-specific,Strength"
-TP53 (HGNC:11998),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-TP53 (HGNC:11998),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-TP53 (HGNC:11998),PP1,Strong,Cosegregation must be observed in ≥ 7 meioses across > 1 family,"Disease-specific,Strength"
-TP53 (HGNC:11998),PP1,Moderate,Cosegregation must be observed in 5-6 meioses in/across 1 or more families,"Disease-specific,Strength"
-TP53 (HGNC:11998),PP1,Supporting,Cosegregation must be observed in 3-4 meioses in/across 1 or more families,"Disease-specific,Strength"
-TP53 (HGNC:11998),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-TP53 (HGNC:11998),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-TP53 (HGNC:11998),PP3,Moderate,"Missense variants
- 
-(See flowchart for application of PP3 and BP4 rules for missense variants)
-
-
-aGVGD Class C65 and BayesDel score ≥ 0.16","Disease-specific,Strength"
-TP53 (HGNC:11998),PP3,Supporting,"Missense variants
- 
-(See flowchart for application of PP3 and BP4 rules for missense variants)
-
-
-aGVGD class C25-C55 and BayesDel score ≥ 0.16
-
-
-Single amino acid inframe deletions
- 
-(See single aa BayesDel spreadsheet)
-
-
-BayesDel score ≥ 0.16
-
-
-Exonic (including silent variants and apparent “missense” variants or “single amino acid inframe deletions” for which there is a predicted splice effect) or Intronic Splice Variants (excluding ± 1,2 positions):
-
-
-SpliceAI ≥ 0.2","Disease-specific,Strength"
-TP53 (HGNC:11998),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-TP53 (HGNC:11998),PP4,Moderate,At least 2 independent observations of the variant with VAF 5-25%.,"Disease-specific,Strength"
-TP53 (HGNC:11998),PP4,Supporting,Observation of the variant with VAF at or below 35%.,"Disease-specific,Strength"
-TP53 (HGNC:11998),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-TP53 (HGNC:11998),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-TP53 (HGNC:11998),BA1,Stand Alone,"Filtering allele frequency (FAF) of ≥ 0.001 or 0.1% in gnomAD continental subpopulations of a single genetic ancestry group (excluding genetic ancestry groups influenced by founder effects, such as Ashkenazi Jewish, Finnish, Amish, Middle Eastern, and “Remaining”). Genetic ancestry group must have ≥2,000 alleles tested and a minimum of 2 alleles present. Caution should be exerted if the majority of alleles have a variant allele fraction (""allele balance"" in gnomAD) below 0.35.  To set the stand-alone benign FAF cutoff, we used the FAF cutoff established for BS1 (0.0003) and increased this cutoff by one order of magnitude to come to a value of 0.001. 
-
-
-In general, the most recent version of gnomAD should be used when available; however, other population databases or earlier versions of gnomAD may be utilized if they are able to provide information the curator deems necessary for optimal variant classification (e.g, they would provide superior information for a particular variant type; have a larger sample size; or better representation for certain subpopulations, etc.)",Disease-specific
-TP53 (HGNC:11998),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-TP53 (HGNC:11998),BS1,Strong,"Filtering allele frequency (FAF) of ≥ 0.0003 but < 0.001 in gnomAD continental subpopulations of a single genetic ancestry group (excluding genetic ancestry groups influenced by founder effects, such as Ashkenazi Jewish, Finnish, Amish, Middle Eastern, and “Remaining”). Genetic ancestry group must have ≥2,000 alleles tested and a minimum of 2 alleles present. Caution should be exerted if the majority of alleles have a variant allele fraction ( “allele balance” in gnomAD) below 0.35. To set the strong benign FAF cutoff, we used a Whiffin-Ware calculation using prevalence of 1 in 5,000 (Lalloo, et al., 2006 PMID: 16644204). Genetic and allelic heterogeneity were set at 100% and penetrance at 30%. 
-
-
-In general, the most recent version of gnomAD should be used when available; however, other population databases or earlier versions of gnomAD may be utilized if they are able to provide information the curator deems necessary for optimal variant classification (e.g, they would provide superior information for a particular variant type; have a larger sample size; or better representation for certain subpopulations, etc.)",Disease-specific
-TP53 (HGNC:11998),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-TP53 (HGNC:11998),BS2,Strong,"≥ 8 unrelated females who have reached at least 60 years of age without cancer. These individuals all must have come from a single source (single lab, database, etc). Cases cannot be counted across sources. Individuals with a diagnosis of sarcoma ≥ 61 years of age should not be counted towards the BS2 total.",Disease-specific
-TP53 (HGNC:11998),BS2,Moderate,"4-7 unrelated females who have reached at least 60 years of age without cancer. These individuals all must have come from a single source (single lab, database, etc). Cases cannot be counted across sources. Individuals with a diagnosis of sarcoma ≥ 61 years of age should not be counted towards the BS2 total.",Disease-specific
-TP53 (HGNC:11998),BS2,Supporting,"2-3 unrelated females who have reached at least 60 years of age without cancer. These individuals all must have come from a single source (single lab, database, etc). Cases cannot be counted across sources. Individuals with a diagnosis of sarcoma ≥ 61 years of age should not be counted towards the BS2 total.",Disease-specific
-TP53 (HGNC:11998),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-TP53 (HGNC:11998),BS3,Strong,"Functional on Kato et al. data 
-AND
- no loss of function (LOF) on another assay (e.g., Giacomelli et al., Kotler et al., or another assay)","Disease-specific,Strength"
-TP53 (HGNC:11998),BS3,Supporting,"Partially functional on Kato et al. data 
-AND
- no evidence of loss of function (LOF) on Giacomelli et al. data 
-AND
- no evidence of LOF on another assay (e.g. Kotler or other assay showing preserved function) 
-AND
- normal or no data on Kawaguchi et al. data. Do not apply BS3_Supporting if any assay evidence is conflicting. If no Kato et al. data is available: no evidence of LOF on Kotler et al. data 
-AND
- no evidence of LOF (or no data available) on Giacomelli et al. data. 
-
-
-BS3_Supporting may also be applied to small deletions with available Kotler et al. data that demonstrate no evidence of LOF.","Disease-specific,Strength"
-TP53 (HGNC:11998),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-TP53 (HGNC:11998),BS4,Strong,Lack of segregation in affected family members (i.e. family members diagnosed with LFS-associated cancers as described in Table of LFS Cancers and Points for PS2 and PP1 Code Application).,Disease-specific
-TP53 (HGNC:11998),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-TP53 (HGNC:11998),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-TP53 (HGNC:11998),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-TP53 (HGNC:11998),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-TP53 (HGNC:11998),BP4,Moderate,"Missense variants
- 
-(See flowchart for application of PP3 and BP4 rules for missense variants):
-
-
-BayesDel ≤ -0.008 irrespective of aGVGD score (except C65, in this case do not apply BP4_Moderate) AND no predicted differences in splicing (SpliceAI < 0.2)","Disease-specific,Strength"
-TP53 (HGNC:11998),BP4,Supporting,"Missense variants
- 
-(See flowchart for application of PP3 and BP4 rules for missense variants):
-
-
-BayesDel < 0.16 and > -0.008 irrespective of aGVGD score (except C65, this case do not apply BP4) AND no predicted differences in splicing (SpliceAI < 0.2)
-
-
-Single amino acid inframe deletions
- 
-(See single aa BayesDel spreadsheet):
-
-
-BayesDel score < 0.16 AND no predicted splicing impact (Splice AI < 0.2)
-
-
-Silent or Intronic Variants (outside ± 1,2 positions):
-
-
-SpliceAI ≤ 0.1","Disease-specific,Strength"
-TP53 (HGNC:11998),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-TP53 (HGNC:11998),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-TP53 (HGNC:11998),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-TP53 (HGNC:11998),BP7,Strong,"A (synonymous) silent or intronic variant for which RNA splicing assay data demonstrates no splicing aberration, as per recommendations from Walker et al., 2023 (PMID: 37352859). BP7 cannot be applied if BP4 is not met.",Disease-specific
-TP53 (HGNC:11998),BP7,Supporting,"A synonymous (silent) outside of the core splice motif (last three nucleotides and first nucleotide of the exon) or intronic variant at or beyond +7 to -21 positions for which SpliceAI predicts no impact to the splice consensus nor the creation of a new splice site (BP4 is met, SpliceAI ≤ 0.1). No requirement to assess for nucleotide conservation for rule application as per evidence and recommendations in Walker et al., 2023  (PMID: 37352859). BP7 cannot be applied if BP4 is not met.",Disease-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
deleted file mode 100644
index 64298496deac006b89a0ca790484d8bed8635356..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
+++ /dev/null
@@ -1,333 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-TP53 (HGNC:11998),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-TP53 (HGNC:11998),PVS1,Very Strong,"Please utilize the PVS1 decision tree for application of PVS1 code. The decision tree details the specific strengths each type of null variant may be applied at. Please see below for some additional helpful summary details for application of PVS1 code:
-
-
-
-
-Initiation codon:
-
-
-PVS1 may be applied to initiation codon variants
-
-
-
-
-
-
-Nonsense or frameshift variants:
-
-
-PVS1 applies to variants predicted to result in nonsense-mediated decay (NMD) for nonsense variants upstream of p.Lys351 and for frameshift induced premature termination codon (PTC) upstream of p.Lys351
-
-
-PVS1_Strong applies to variants not predicted to undergo NMD (nonsense variants downstream of p.Leu350 or frameshift induced PTC in exon 11 or in the 3’ most 50 nucleotides of exon 10) in variants located in the p.Lys351 to p.Ala 355 range
-
-
-PVS1_Moderate applies to variants not predicted to undergo NMD (nonsense variants downstream of p.Leu350 or frameshift induced PTC in exon 11 or in the 3’ most 50 nucleotides of exon 10) in variants located in the p.Gly356 to p.Asp393 range
-
-
-PVS1_Moderate may also be applied to frameshift induced PTC downstream of the natural stop codon
-
-
-
-
-
-
-Canonical splice variants (+/- 1,2 intronic positions): 
-
-
-PVS1 applies to predicted splicing alterations that are PTC resulting in NMD (or in-frame but targeting critical domains or residues)
-
-
-PVS1 applies to predicted splicing alterations that target the start codon (Exon 2 donor)
-
-
-PVS1_Moderate applied to splicing alterations that are predicted to shorten (<10% of the protein removed) or expand a 
-TP53
- C-terminal end of unknown function (E10 donor or E11 acceptor)
-
-
-
-
-
-
-Deletions
-
-
-Full gene deletions: PVS1
-
-
-Single- to multi-exon deletions that target the initiation codon, preserving the potential rescue ATG (p.Met40) in exon 4: PVS1
-
-
-Single- to multi-exon deletions that target the initiation codon and the potential rescue ATG (p.Met40) in exon 4: PVS1
-
-
-Single- to multi-exon deletion that disrupts the reading frame and is predicted to undergo NMD (nonsense or frameshift induced PTC upstream of p.Lys351): PVS1
-
-
-Single- to multi-exon deletion that disrupts the reading frame and is 
-NOT
- predicted to undergo NMD (nonsense or frameshift inducted PTC downstream of p.Leu350): PVS1
-
-
-Single- to multi-exon deletion including the last exon where the truncated/altered region is critical to protein function (any multi-exon combination targeting exon 11): PVS1
-
-
-If the role of the region in protein function is unknown, if the variant removed < 10% of the protein (deletion of exon 11): PVS1_Moderate
-
-
-
-
-
-
-Single- to multi-exon deletion that preserves the reading frame where the truncated/altered region is critical to protein function: PVS1
-
-
-
-
-
-
-Duplications (≥1 exon in size and must be completely contained within the 
-TP53
- gene)
-
-
-Proven in tandem. Reading frame is disrupted and NMD predicted to occur (nonsense upstream of p.Lys351 or frameshift-induced PTC upstream of p.Lys351): PVS1
-
-
-Presumed in tandem. Reading frame presumed disrupted and NMD predicted to occur (nonsense upstream of p.Lys351 or frameshift-induced PTC upstream of p.Lys351): PVS1_Strong
-
-
-
-
-
-
-
-
-For variants inducing aberrant transcripts identified via mRNA assay, apply as PVS1_Variable Weight (RNA) following recommendations from Walker et al., 2023 (PMID: 37352859), downgrading one strength level if the assay data indicates leakiness.
-
-
-Caveats
-: PS3 should not be applied at any strength if PVS1 is applied at full strength. PP3 should not be used in combination with PVS1.
-
-
-For the purposes of unified curation, the TP53 domains/important motifs by amino acid range are defined as:
-
-
-TAD1
-: aa 17-25
-
-
-TAD2
-: aa 48-56
-
-
-Proline residues
-: aa 64-92
-
-
-DNA binding domain
-: aa 100-292
-
-
-Hinge domain
-: aa 293-324
-
-
-Oligomerization domain
-: aa 325-356
-
-
-C-terminal domain (Basic domain)
-: aa 368-387
-
-
-A disease-specific PVS1 decision tree incorporating the above bullets as well as a supplemental file for 
-TP53
- PVS1 Splicing Worksheet is also included as an additional curation tool and has more granular details.","Disease-specific,Strength"
-TP53 (HGNC:11998),PVS1,Strong,See PVS1 flowchart for code application,"Disease-specific,Strength"
-TP53 (HGNC:11998),PVS1,Moderate,See PVS1 flowchart for code application,"Disease-specific,Strength"
-TP53 (HGNC:11998),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-TP53 (HGNC:11998),PS1,Strong,"Can be applied to variants asserted as Pathogenic following the 
-TP53
- VCEP’s specifications.","Disease-specific,Strength"
-TP53 (HGNC:11998),PS1,Moderate,"Can be applied to variants asserted as Likely Pathogenic following the 
-TP53
- VCEP’s specifications.","Disease-specific,Strength"
-TP53 (HGNC:11998),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-TP53 (HGNC:11998),PS2,Very Strong,≥ 8 points,"Disease-specific,Strength"
-TP53 (HGNC:11998),PS2,Strong,4-7 points,"Disease-specific,Strength"
-TP53 (HGNC:11998),PS2,Moderate,2-3 points,"Disease-specific,Strength"
-TP53 (HGNC:11998),PS2,Supporting,1 point,"Disease-specific,Strength"
-TP53 (HGNC:11998),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-TP53 (HGNC:11998),PS3,Strong,"Non-functional on Kato et al. data 
-AND
- loss of function (LOF) on another assay (e.g., Giacomelli et al., Kotler et al., or another assay showing low function)","Disease-specific,Strength"
-TP53 (HGNC:11998),PS3,Moderate,"Partially functional on Kato et al. data 
-AND
- loss of function (LOF) on Giacomelli et al. data 
-AND/OR
- LOF on another assay  (e.g. Kotler or a second assay showing low function). Do not apply PS3_Moderate if any assay evidence is conflicting.","Disease-specific,Strength"
-TP53 (HGNC:11998),PS3,Supporting,"Non-functional on Kato et.al data 
-AND
- abnormal on Kawaguchi et al. data regardless of other assays. If no Kato et al. data is available: LOF on Kotler et al. data 
-AND
- LOF (or no data available) on Giacomelli et al. data.
-
-
-PS3_Supporting may also be applied to small deletions with available Kotler et al. data that demonstrates LOF.","Disease-specific,Strength"
-TP53 (HGNC:11998),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-TP53 (HGNC:11998),PS4,Very Strong,≥ 8 points,"Disease-specific,Strength"
-TP53 (HGNC:11998),PS4,Strong,≥ 4-7.5 points,"Disease-specific,Strength"
-TP53 (HGNC:11998),PS4,Moderate,2-3.5 points,"Disease-specific,Strength"
-TP53 (HGNC:11998),PS4,Supporting,1-1.5 points,"Disease-specific,Strength"
-TP53 (HGNC:11998),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-TP53 (HGNC:11998),PM1,Moderate,"Missense variants within the following codons using transcript NM_00546.4: 175, 245, 248, 249, 273, 282. This code weight can also be used for germline missense variants seen in cancerhotspots.org with ≥ 10 somatic occurrences for the same amino acid change.","Disease-specific,Strength"
-TP53 (HGNC:11998),PM1,Supporting,Missense variants seen in cancerhotspots.org with 2-9 somatic occurrences for the same amino acid change.,"Disease-specific,Strength"
-TP53 (HGNC:11998),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-TP53 (HGNC:11998),PM2,Supporting,"This rule should be applied at supporting level. Variant should have an allele frequency of less than 0.00003 (0.003%) in gnomAD or another large sequenced population. If multiple alleles are present within any genetic ancestry group, allele frequency in that group must be <0.00004 (0.004%). Genetic ancestry groups influenced by founder effects (such as Ashkenazi Jewish, Finnish, Amish, Middle Eastern, and “Remaining”) should be ignored. 
-
-
-If the variant being assessed does not meet any population rule codes (PM2, BA1, BS1) 
-AND
- has a total allele frequency >0.00003 with no single genetic ancestry group having multiple alleles with a frequency >0.00004, curators should recalculate the total allele frequency based on the number of alleles with variant allele fraction (VAF) >0.35 to assess whether PM2 may be met after excluding the low VAF alleles which are likely to represent clonal hematopoiesis of indeterminant potential (CHIP) contamination in the database. This can be done by visualizing the “allele balance” for heterozygotes under the genotype quality metrics for a given variant. By hovering over the histogram bars, the number of variant carriers for each bar between 0.35 and 0.65 can be totaled and this can be used to revise the allele count to determine the allele frequency that can be used to assess if PM2_Supporting can be met.
-
-
-In general, the most recent version of gnomAD should be used when available; however, other population databases or earlier versions of gnomAD may be utilized if they are able to provide information the curator deems necessary for optimal variant classification (e.g, they would provide superior information for a particular variant type; have a larger sample size; or better representation for certain subpopulations, etc.)","Disease-specific,General recommendation"
-TP53 (HGNC:11998),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-TP53 (HGNC:11998),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,NA
-TP53 (HGNC:11998),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-TP53 (HGNC:11998),PM5,Strong,"Missense variant at an amino acid residue where ≥2 different missense variants previously determined to be pathogenic according to the 
-TP53
- VCEP’s specifications have been seen before.","Disease-specific,Strength"
-TP53 (HGNC:11998),PM5,Moderate,"Missense variant at an amino acid residue where 1 different missense variant previously determined to be pathogenic according to the 
-TP53
- VCEP’s specifications has been seen before.","Disease-specific,Strength"
-TP53 (HGNC:11998),PM5,Supporting,"Missense variant at an amino acid residue where 1 different missense variant previously determined to be likely pathogenic according to the 
-TP53
- VCEP’s specifications has been seen before. The previously seen likely pathogenic variant must have clinical data that demonstrates pathogenicity (i.e. PS2, PS4, PP1) in order for it to count towards PM5_Supporting code application.","Disease-specific,Strength"
-TP53 (HGNC:11998),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-TP53 (HGNC:11998),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-TP53 (HGNC:11998),PP1,Strong,Cosegregation must be observed in ≥ 7 meioses across > 1 family,"Disease-specific,Strength"
-TP53 (HGNC:11998),PP1,Moderate,Cosegregation must be observed in 5-6 meioses in/across 1 or more families,"Disease-specific,Strength"
-TP53 (HGNC:11998),PP1,Supporting,Cosegregation must be observed in 3-4 meioses in/across 1 or more families,"Disease-specific,Strength"
-TP53 (HGNC:11998),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-TP53 (HGNC:11998),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-TP53 (HGNC:11998),PP3,Moderate,"Missense variants
- 
-(See flowchart for application of PP3 and BP4 rules for missense variants)
-
-
-aGVGD Class C65 and BayesDel score ≥ 0.16","Disease-specific,Strength"
-TP53 (HGNC:11998),PP3,Supporting,"Missense variants
- 
-(See flowchart for application of PP3 and BP4 rules for missense variants)
-
-
-aGVGD class C25-C55 and BayesDel score ≥ 0.16
-
-
-Single amino acid inframe deletions
- 
-(See single aa BayesDel spreadsheet)
-
-
-BayesDel score ≥ 0.16
-
-
-Exonic (including silent variants and apparent “missense” variants or “single amino acid inframe deletions” for which there is a predicted splice effect) or Intronic Splice Variants (excluding ± 1,2 positions):
-
-
-SpliceAI ≥ 0.2","Disease-specific,Strength"
-TP53 (HGNC:11998),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-TP53 (HGNC:11998),PP4,Moderate,At least 2 independent observations of the variant with VAF 5-25%.,"Disease-specific,Strength"
-TP53 (HGNC:11998),PP4,Supporting,"Observation of the variant with VAF 5-35% (i.e., once or multiple times with VAF >25-35% and/or once with VAF 5-25%)","Disease-specific,Strength"
-TP53 (HGNC:11998),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-TP53 (HGNC:11998),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-TP53 (HGNC:11998),BA1,Stand Alone,"Filtering allele frequency (FAF) of ≥ 0.001 or 0.1% in gnomAD continental subpopulations of a single genetic ancestry group (excluding genetic ancestry groups influenced by founder effects, such as Ashkenazi Jewish, Finnish, Amish, Middle Eastern, and “Remaining”). Genetic ancestry group must have ≥2,000 alleles tested and a minimum of 2 alleles present. Caution should be exerted if the majority of alleles have a variant allele fraction (""allele balance"" in gnomAD) below 0.35.  To set the stand-alone benign FAF cutoff, we used the FAF cutoff established for BS1 (0.0003) and increased this cutoff by one order of magnitude to come to a value of 0.001. 
-
-
-In general, the most recent version of gnomAD should be used when available; however, other population databases or earlier versions of gnomAD may be utilized if they are able to provide information the curator deems necessary for optimal variant classification (e.g, they would provide superior information for a particular variant type; have a larger sample size; or better representation for certain subpopulations, etc.)",Disease-specific
-TP53 (HGNC:11998),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-TP53 (HGNC:11998),BS1,Strong,"Filtering allele frequency (FAF) of ≥ 0.0003 but < 0.001 in gnomAD continental subpopulations of a single genetic ancestry group (excluding genetic ancestry groups influenced by founder effects, such as Ashkenazi Jewish, Finnish, Amish, Middle Eastern, and “Remaining”). Genetic ancestry group must have ≥2,000 alleles tested and a minimum of 2 alleles present. Caution should be exerted if the majority of alleles have a variant allele fraction ( “allele balance” in gnomAD) below 0.35. To set the strong benign FAF cutoff, we used a Whiffin-Ware calculation using prevalence of 1 in 5,000 (Lalloo, et al., 2006 PMID: 16644204). Genetic and allelic heterogeneity were set at 100% and penetrance at 30%. 
-
-
-In general, the most recent version of gnomAD should be used when available; however, other population databases or earlier versions of gnomAD may be utilized if they are able to provide information the curator deems necessary for optimal variant classification (e.g, they would provide superior information for a particular variant type; have a larger sample size; or better representation for certain subpopulations, etc.)",Disease-specific
-TP53 (HGNC:11998),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-TP53 (HGNC:11998),BS2,Strong,"≥ 8 unrelated females who have reached at least 60 years of age without cancer. These individuals all must have come from a single source (single lab, database, etc). Cases cannot be counted across sources. Individuals with a diagnosis of sarcoma ≥ 61 years of age should not be counted towards the BS2 total.",Disease-specific
-TP53 (HGNC:11998),BS2,Moderate,"4-7 unrelated females who have reached at least 60 years of age without cancer. These individuals all must have come from a single source (single lab, database, etc). Cases cannot be counted across sources. Individuals with a diagnosis of sarcoma ≥ 61 years of age should not be counted towards the BS2 total.",Disease-specific
-TP53 (HGNC:11998),BS2,Supporting,"2-3 unrelated females who have reached at least 60 years of age without cancer. These individuals all must have come from a single source (single lab, database, etc). Cases cannot be counted across sources. Individuals with a diagnosis of sarcoma ≥ 61 years of age should not be counted towards the BS2 total.",Disease-specific
-TP53 (HGNC:11998),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-TP53 (HGNC:11998),BS3,Strong,"Functional on Kato et al. data 
-AND
- no loss of function (LOF) on another assay (e.g., Giacomelli et al., Kotler et al., or another assay)","Disease-specific,Strength"
-TP53 (HGNC:11998),BS3,Supporting,"Partially functional on Kato et al. data 
-AND
- no evidence of loss of function (LOF) on Giacomelli et al. data 
-AND
- no evidence of LOF on another assay (e.g. Kotler or other assay showing preserved function) 
-AND
- normal or no data on Kawaguchi et al. data. Do not apply BS3_Supporting if any assay evidence is conflicting. If no Kato et al. data is available: no evidence of LOF on Kotler et al. data 
-AND
- no evidence of LOF (or no data available) on Giacomelli et al. data. 
-
-
-BS3_Supporting may also be applied to small deletions with available Kotler et al. data that demonstrate no evidence of LOF.","Disease-specific,Strength"
-TP53 (HGNC:11998),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-TP53 (HGNC:11998),BS4,Strong,Lack of segregation in affected family members (i.e. family members diagnosed with LFS-associated cancers as described in Table of LFS Cancers and Points for PS2 and PP1 Code Application).,Disease-specific
-TP53 (HGNC:11998),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-TP53 (HGNC:11998),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-TP53 (HGNC:11998),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-TP53 (HGNC:11998),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-TP53 (HGNC:11998),BP4,Moderate,"Missense variants
- 
-(See flowchart for application of PP3 and BP4 rules for missense variants):
-
-
-BayesDel ≤ -0.008 irrespective of aGVGD score (except C65, in this case do not apply BP4_Moderate) AND no predicted differences in splicing (SpliceAI < 0.2)","Disease-specific,Strength"
-TP53 (HGNC:11998),BP4,Supporting,"Missense variants
- 
-(See flowchart for application of PP3 and BP4 rules for missense variants):
-
-
-BayesDel < 0.16 and > -0.008 irrespective of aGVGD score (except C65, this case do not apply BP4) AND no predicted differences in splicing (SpliceAI < 0.2)
-
-
-Single amino acid inframe deletions
- 
-(See single aa BayesDel spreadsheet):
-
-
-BayesDel score < 0.16 AND no predicted splicing impact (Splice AI < 0.2)
-
-
-Silent or Intronic Variants (outside ± 1,2 positions):
-
-
-SpliceAI ≤ 0.1","Disease-specific,Strength"
-TP53 (HGNC:11998),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-TP53 (HGNC:11998),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-TP53 (HGNC:11998),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-TP53 (HGNC:11998),BP7,Strong,"A (synonymous) silent or intronic variant for which RNA splicing assay data demonstrates no splicing aberration, as per recommendations from Walker et al., 2023 (PMID: 37352859).",Disease-specific
-TP53 (HGNC:11998),BP7,Supporting,"A synonymous (silent) outside of the core splice motif (last three nucleotides and first nucleotide of the exon) or intronic variant at or beyond +7 to -21 positions for which SpliceAI predicts no impact to the splice consensus nor the creation of a new splice site (BP4 is met, SpliceAI ≤ 0.1). No requirement to assess for nucleotide conservation for rule application as per evidence and recommendations in Walker et al., 2023  (PMID: 37352859). BP7 cannot be applied if BP4 is not met.",Disease-specific
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenThrombosisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSERPINC1Version1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenThrombosisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSERPINC1Version1.0.0_version=1.0.0.csv
deleted file mode 100644
index 5a71a05cec7af38493056f45ff3264c18de62e11..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenThrombosisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSERPINC1Version1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,157 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-SERPINC1 (HGNC:775),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-SERPINC1 (HGNC:775),PVS1,Very Strong,Use decision tree as per SVI WG with specified “regions critical to protein function”.,Gene-specific
-SERPINC1 (HGNC:775),PVS1,Strong,Use decision tree as per SVI WG with specified “regions critical to protein function”.,Gene-specific
-SERPINC1 (HGNC:775),PVS1,Moderate,Use decision tree as per SVI WG with specified “regions critical to protein function”.,Gene-specific
-SERPINC1 (HGNC:775),PVS1,Supporting,Use decision tree as per SVI WG with specified “regions critical to protein function”.,Gene-specific
-SERPINC1 (HGNC:775),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SERPINC1 (HGNC:775),PS1,Strong,"Use with no specification except comparison variant must be classified as pathogenic using 
-SERPINC1
- rule specifications from the Thrombosis VCEP.",Gene-specific
-SERPINC1 (HGNC:775),PS1,Moderate,"Use with no specification except comparison variant must be classified as likely pathogenic using 
-SERPINC1
- rule specifications from the Thrombosis VCEP.",Gene-specific
-SERPINC1 (HGNC:775),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-SERPINC1 (HGNC:775),PS2,Very Strong,Use proposed SVI point recommendations for “Phenotype highly specific for gene.” See de novo rule code guidance attached. Required 4 points.,Disease-specific
-SERPINC1 (HGNC:775),PS2,Strong,Use proposed SVI point recommendations for “Phenotype highly specific for gene.” See de novo rule code guidance attached. Required 2 points.,Disease-specific
-SERPINC1 (HGNC:775),PS2,Moderate,Use proposed SVI point recommendations for “Phenotype highly specific for gene.” See de novo rule code guidance attached. Required 1 point.,Disease-specific
-SERPINC1 (HGNC:775),PS2,Supporting,Use proposed SVI point recommendations for “Phenotype highly specific for gene.” See de novo rule code guidance attached. Required 0.5 point.,Disease-specific
-SERPINC1 (HGNC:775),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-SERPINC1 (HGNC:775),PS3,Supporting,"See attached spreadsheet for list of approved assays to use for this rule code. Below is a general description of assays that can be used:
-
-
- - 
-In vitro
- functional studies in COS-1, HEK293T, HEK-EBNA cells demonstrating abnormal activity levels:
-
-
-
-
-Antithrombin activity levels measured by FXa inhibition activity assay
-
-
-Antithrombin activity levels measured by thrombin inhibition activity assay
-
-
-
-
-OR
-
-
-- 
-In vitro
- functional studies in COS-1, HEK293T, HEK-EBNA cells demonstrating abnormal antigen levels:
-
-
-
-
-Antithrombin antigen levels measured by ELISA
-
-
-Immunofluorescence assay – intracellular retention and secretion defects
-
-
-
-
-
-
-
-
-OR
-
-
-- 
-In vivo
- studies demonstrating rescue of antithrombin levels would be considered, but no studies are       known to be available at this time.",Disease-specific
-SERPINC1 (HGNC:775),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-SERPINC1 (HGNC:775),PS4,Very Strong,Appropriate to use code when there 8 or more proband points that meet the defined antithrombin deficiency laboratory phenotype.,Disease-specific
-SERPINC1 (HGNC:775),PS4,Strong,Appropriate to use code when there 4-7 proband points that meet the defined antithrombin deficiency laboratory phenotype.,Disease-specific
-SERPINC1 (HGNC:775),PS4,Moderate,Appropriate to use code when there 2-3 proband points that meet the defined antithrombin deficiency laboratory phenotype.,Disease-specific
-SERPINC1 (HGNC:775),PS4,Supporting,Appropriate to use code when there is 1 proband point that meets the defined antithrombin deficiency laboratory phenotype.,Disease-specific
-SERPINC1 (HGNC:775),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-SERPINC1 (HGNC:775),PM1,Moderate,"This code is applicable for variants disrupting cystine residues involved in disulfide bridges (Cys40, Cys53, Cys127, Cys160, Cys279, Cys462)
-1
-, variants that would impact heparin binding site residues (Ile39, Arg56, Pro73, Arg79) and variants involving reactive site residues (Ala414 and Ala416)
-2
-.",Gene-specific
-SERPINC1 (HGNC:775),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-SERPINC1 (HGNC:775),PM2,Supporting,Use code for variants with a popmax MAF of <0.00002 in gnomAD.,"Disease-specific,Gene-specific"
-SERPINC1 (HGNC:775),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-SERPINC1 (HGNC:775),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-SERPINC1 (HGNC:775),PM4,Moderate,No specification,None
-SERPINC1 (HGNC:775),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SERPINC1 (HGNC:775),PM5,Moderate,"Use code when previously reported variant reaches a pathogenic classification using the 
-SERPINC1
- rule specifications from the Thrombosis VCEP.",General recommendation
-SERPINC1 (HGNC:775),PM5,Supporting,"Use code when previously reported variant reaches a likely pathogenic classification using the 
-SERPINC1
- rule specifications from the Thrombosis VCEP.",General recommendation
-SERPINC1 (HGNC:775),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-SERPINC1 (HGNC:775),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-SERPINC1 (HGNC:775),PP1,Strong,Appropriate to use there are 7 or more meioses across more than one family.,Disease-specific
-SERPINC1 (HGNC:775),PP1,Moderate,Appropriate to use there are 4-6 meioses across one or more families.,Disease-specific
-SERPINC1 (HGNC:775),PP1,Supporting,Appropriate to use when there are 2-3 meioses across one or more families.,Disease-specific
-SERPINC1 (HGNC:775),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-SERPINC1 (HGNC:775),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-SERPINC1 (HGNC:775),PP3,Supporting,"Appropriate to use for missense variants that have a REVEL score of greater or equal to 0.6. For potential splicing variants, use of 2 independent 
-in silico
- splicing tools must predict a damaging impact.",Gene-specific
-SERPINC1 (HGNC:775),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-SERPINC1 (HGNC:775),PP4,Supporting,"Proband must have an antithrombin activity level of < 0.8 IU/mL (or below the lower limit of a laboratory’s assays reference range). confirmed on repeated independent samples. An abnormal crossed immunoelectrophoresis assay demonstrating decreased antithrombin function may be used in lieu of low activity levels, which is typically caused by type II variants.",Disease-specific
-SERPINC1 (HGNC:775),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SERPINC1 (HGNC:775),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-SERPINC1 (HGNC:775),BA1,Stand Alone,Appropriate to use for variants with a popmax MAF of greater than or equal to 0.002 in gnomAD.,"Disease-specific,Gene-specific"
-SERPINC1 (HGNC:775),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-SERPINC1 (HGNC:775),BS1,Strong,Appropriate to use for variants with a Popmax MAF of >0.0002 in gnomAD.,"Disease-specific,Gene-specific"
-SERPINC1 (HGNC:775),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-SERPINC1 (HGNC:775),BS2,Strong,This evidence code is available when the variant is identified in 2 or more heterozygotes or 1 or more homozygotes with normal antithrombin levels [> 0.8 IU/mL (or above the lower limit of a laboratory’s assays reference range)].,Disease-specific
-SERPINC1 (HGNC:775),BS2,Supporting,This evidence code is available when the variant is identified in 1 heterozygote with normal antithrombin levels [> 0.8 IU/mL (or above the lower limit of a laboratory’s assays reference range)].,Disease-specific
-SERPINC1 (HGNC:775),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-SERPINC1 (HGNC:775),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-SERPINC1 (HGNC:775),BS4,Strong,"Appropriate to use when the variant is found not to segregate in a minimum of four relatives with abnormal antithrombin activity levels [< 0.8 IU/mL (or below the lower limit of a laboratory’s assays reference range)] within the same family, 
-OR
- the variant does not segregate in 2 or more families. Non-segregation defined by having abnormal antithrombin activity levels without 
-SERPINC1
- variant of interest.",Disease-specific
-SERPINC1 (HGNC:775),BS4,Supporting,Appropriate to use when the variant is found not to segregate in a minimum of two relatives with abnormal antithrombin activity levels [< 0.8 IU/mL (or below the lower limit of a laboratory’s assays reference range)] within the same family.,Disease-specific
-SERPINC1 (HGNC:775),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-SERPINC1 (HGNC:775),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-SERPINC1 (HGNC:775),BP2,Supporting,"This rule can be applied when a 
-SERPINC1
- variant is 
-in cis
- with another pathogenic 
-SERPINC1
- variant. The pathogenic variant must be evaluated using ClinGen 
-SERPINC1
- specified rules. This rule cannot be applied to a variant 
-in trans
- with a pathogenic variant, as this scenario could reasonably occur and increase the risk of venous thrombosis.",Disease-specific
-SERPINC1 (HGNC:775),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-SERPINC1 (HGNC:775),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SERPINC1 (HGNC:775),BP4,Supporting,"Use this code for missense variants with a REVEL score of < 0.30 and no evidence of a potential splicing effect using VarSEAK and Splice AI prediction tools, or for non-canonical intronic variants with no evidence of a potential splicing effect using VarSEAK and Splice AI prediction tools.",Gene-specific
-SERPINC1 (HGNC:775),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-SERPINC1 (HGNC:775),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SERPINC1 (HGNC:775),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-SERPINC1 (HGNC:775),BP7,Supporting,"Use tools VarSEAK and Splice AI to rule out a predicted splicing effect. Evolutionary conservation is defined as a PhyloP < 0.1 
-OR
- the reference nucleotide is present in 3 mammals or 1 primate.",General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenThrombosisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSERPINC1Version1.1.0_version=1.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenThrombosisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSERPINC1Version1.1.0_version=1.1.0.csv
deleted file mode 100644
index cdcbb10b47c1190cd2d7ca47c827cd62c3cc5b92..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenThrombosisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSERPINC1Version1.1.0_version=1.1.0.csv
+++ /dev/null
@@ -1,157 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-SERPINC1 (HGNC:775),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-SERPINC1 (HGNC:775),PVS1,Very Strong,Use decision tree as per SVI WG with specified “regions critical to protein function”.,Gene-specific
-SERPINC1 (HGNC:775),PVS1,Strong,Use decision tree as per SVI WG with specified “regions critical to protein function”.,Gene-specific
-SERPINC1 (HGNC:775),PVS1,Moderate,Use decision tree as per SVI WG with specified “regions critical to protein function”.,Gene-specific
-SERPINC1 (HGNC:775),PVS1,Supporting,Use decision tree as per SVI WG with specified “regions critical to protein function”.,Gene-specific
-SERPINC1 (HGNC:775),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SERPINC1 (HGNC:775),PS1,Strong,"Use with no specification except comparison variant must be classified as pathogenic using 
-SERPINC1
- rule specifications from the Thrombosis VCEP.",Gene-specific
-SERPINC1 (HGNC:775),PS1,Moderate,"Use with no specification except comparison variant must be classified as likely pathogenic using 
-SERPINC1
- rule specifications from the Thrombosis VCEP.",Gene-specific
-SERPINC1 (HGNC:775),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-SERPINC1 (HGNC:775),PS2,Very Strong,Use proposed SVI point recommendations for “Phenotype highly specific for gene.” See de novo rule code guidance attached. Required 4 points.,Disease-specific
-SERPINC1 (HGNC:775),PS2,Strong,Use proposed SVI point recommendations for “Phenotype highly specific for gene.” See de novo rule code guidance attached. Required 2 points.,Disease-specific
-SERPINC1 (HGNC:775),PS2,Moderate,Use proposed SVI point recommendations for “Phenotype highly specific for gene.” See de novo rule code guidance attached. Required 1 point.,Disease-specific
-SERPINC1 (HGNC:775),PS2,Supporting,Use proposed SVI point recommendations for “Phenotype highly specific for gene.” See de novo rule code guidance attached. Required 0.5 point.,Disease-specific
-SERPINC1 (HGNC:775),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-SERPINC1 (HGNC:775),PS3,Supporting,"See attached spreadsheet for list of approved assays to use for this rule code. Below is a general description of assays that can be used:
-
-
- - 
-In vitro
- functional studies in COS-1, HEK293T, HEK-EBNA cells demonstrating abnormal activity levels:
-
-
-
-
-Antithrombin activity levels measured by FXa inhibition activity assay
-
-
-Antithrombin activity levels measured by thrombin inhibition activity assay
-
-
-
-
-OR
-
-
-- 
-In vitro
- functional studies in COS-1, HEK293T, HEK-EBNA cells demonstrating abnormal antigen levels:
-
-
-
-
-Antithrombin antigen levels measured by ELISA
-
-
-Immunofluorescence assay – intracellular retention and secretion defects
-
-
-
-
-
-
-
-
-OR
-
-
-- 
-In vivo
- studies demonstrating rescue of antithrombin levels would be considered, but no studies are       known to be available at this time.",Disease-specific
-SERPINC1 (HGNC:775),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-SERPINC1 (HGNC:775),PS4,Very Strong,Appropriate to use code when there 8 or more proband points that meet the defined antithrombin deficiency laboratory phenotype.,Disease-specific
-SERPINC1 (HGNC:775),PS4,Strong,Appropriate to use code when there 4-7 proband points that meet the defined antithrombin deficiency laboratory phenotype.,Disease-specific
-SERPINC1 (HGNC:775),PS4,Moderate,Appropriate to use code when there 2-3 proband points that meet the defined antithrombin deficiency laboratory phenotype.,Disease-specific
-SERPINC1 (HGNC:775),PS4,Supporting,Appropriate to use code when there is 1 proband point that meets the defined antithrombin deficiency laboratory phenotype.,Disease-specific
-SERPINC1 (HGNC:775),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-SERPINC1 (HGNC:775),PM1,Moderate,"This code is applicable for variants disrupting cystine residues involved in disulfide bridges (Cys40, Cys53, Cys127, Cys160, Cys279, Cys462)
-1
-, variants that would impact heparin binding site residues (Ile39, Arg56, Pro73, Arg79), variants involving reactive site residues (Ala414 and Ala416)
-2
-, and variants involving the N-glycosylation site (Asn224)
-3
-.",Gene-specific
-SERPINC1 (HGNC:775),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-SERPINC1 (HGNC:775),PM2,Supporting,Use code for variants with a popmax MAF of <0.00002 in gnomAD.,"Disease-specific,Gene-specific"
-SERPINC1 (HGNC:775),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-SERPINC1 (HGNC:775),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-SERPINC1 (HGNC:775),PM4,Moderate,No specification,None
-SERPINC1 (HGNC:775),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-SERPINC1 (HGNC:775),PM5,Moderate,"Use code when previously reported variant reaches a pathogenic classification using the 
-SERPINC1
- rule specifications from the Thrombosis VCEP.",General recommendation
-SERPINC1 (HGNC:775),PM5,Supporting,"Use code when previously reported variant reaches a likely pathogenic classification using the 
-SERPINC1
- rule specifications from the Thrombosis VCEP.",General recommendation
-SERPINC1 (HGNC:775),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-SERPINC1 (HGNC:775),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-SERPINC1 (HGNC:775),PP1,Strong,Appropriate to use there are 7 or more meioses across more than one family.,Disease-specific
-SERPINC1 (HGNC:775),PP1,Moderate,Appropriate to use there are 4-6 meioses across one or more families.,Disease-specific
-SERPINC1 (HGNC:775),PP1,Supporting,Appropriate to use when there are 2-3 meioses across one or more families.,Disease-specific
-SERPINC1 (HGNC:775),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-SERPINC1 (HGNC:775),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-SERPINC1 (HGNC:775),PP3,Supporting,"Appropriate to use for missense variants that have a REVEL score of greater or equal to 0.6. For potential splicing variants, SpliceAI must predict a damaging impact with a score greater or equal to 0.5.",Gene-specific
-SERPINC1 (HGNC:775),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-SERPINC1 (HGNC:775),PP4,Supporting,"Proband must have an antithrombin activity level of < 0.8 IU/mL (or below the lower limit of a laboratory’s assays reference range). confirmed on repeated independent samples. An abnormal crossed immunoelectrophoresis assay demonstrating decreased antithrombin function may be used in lieu of low activity levels, which is typically caused by type II variants.",Disease-specific
-SERPINC1 (HGNC:775),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SERPINC1 (HGNC:775),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-SERPINC1 (HGNC:775),BA1,Stand Alone,Appropriate to use for variants with a popmax MAF of greater than or equal to 0.002 in gnomAD.,"Disease-specific,Gene-specific"
-SERPINC1 (HGNC:775),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-SERPINC1 (HGNC:775),BS1,Strong,Appropriate to use for variants with a Popmax MAF of >0.0002 in gnomAD.,"Disease-specific,Gene-specific"
-SERPINC1 (HGNC:775),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-SERPINC1 (HGNC:775),BS2,Strong,This evidence code is available when the variant is identified in 2 or more heterozygotes or 1 or more homozygotes with normal antithrombin levels [> 0.8 IU/mL (or above the lower limit of a laboratory’s assays reference range)].,Disease-specific
-SERPINC1 (HGNC:775),BS2,Supporting,This evidence code is available when the variant is identified in 1 heterozygote with normal antithrombin levels [> 0.8 IU/mL (or above the lower limit of a laboratory’s assays reference range)].,Disease-specific
-SERPINC1 (HGNC:775),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-SERPINC1 (HGNC:775),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-SERPINC1 (HGNC:775),BS4,Strong,"Appropriate to use when the variant is found not to segregate in a minimum of four relatives with abnormal antithrombin activity levels [< 0.8 IU/mL (or below the lower limit of a laboratory’s assays reference range)] within the same family, 
-OR
- the variant does not segregate in 2 or more families. Non-segregation defined by having abnormal antithrombin activity levels without 
-SERPINC1
- variant of interest.",Disease-specific
-SERPINC1 (HGNC:775),BS4,Supporting,Appropriate to use when the variant is found not to segregate in a minimum of two relatives with abnormal antithrombin activity levels [< 0.8 IU/mL (or below the lower limit of a laboratory’s assays reference range)] within the same family.,Disease-specific
-SERPINC1 (HGNC:775),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-SERPINC1 (HGNC:775),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-SERPINC1 (HGNC:775),BP2,Supporting,"This rule can be applied when a 
-SERPINC1
- variant is 
-in cis
- with another pathogenic 
-SERPINC1
- variant. The pathogenic variant must be evaluated using ClinGen 
-SERPINC1
- specified rules. This rule cannot be applied to a variant 
-in trans
- with a pathogenic variant, as this scenario could reasonably occur and increase the risk of venous thrombosis.",Disease-specific
-SERPINC1 (HGNC:775),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-SERPINC1 (HGNC:775),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-SERPINC1 (HGNC:775),BP4,Supporting,"Use this code for missense variants with a REVEL score of < or equal to 0.30 and no evidence of a potential splicing effect using the Splice AI prediction tool (less than or equal to 0.1), or for non-canonical intronic variants with no evidence of a potential splicing effect using the Splice AI prediction tool.",Gene-specific
-SERPINC1 (HGNC:775),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,NA
-SERPINC1 (HGNC:775),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-SERPINC1 (HGNC:775),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-SERPINC1 (HGNC:775),BP7,Supporting,"Use Splice AI to rule out a predicted splicing effect (less than or equal to 0.1). Evolutionary conservation is defined as a PhyloP > 0.1 
-OR
- the reference nucleotide is present in 3 mammals or 1 primate.",General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenVHLExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforVHLVersion1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenVHLExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforVHLVersion1.0.0_version=1.0.0.csv
deleted file mode 100644
index 19b6fd032eb0e801a90d84a992dd51f71d3ec7b8..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenVHLExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforVHLVersion1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,249 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-VHL (HGNC:12687),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-VHL (HGNC:12687),PVS1,Very Strong,"LINK TO PVS1 DECISION TREE DOCUMENT:
- 
-https://drive.google.com/file/d/1mGfChgxbGVbzYn6Ggmb9rYvoGGah25ll/view?usp=sharing
-
-
-Do not apply PVS1 for truncations that occur prior to Codon 54 (including frameshift events that start and end prior to Codon 54 but the truncation extends beyond Codon 54.)
-
-
-Note1: Exon presence in biologically relevant transcripts:
- In some transcripts exon 2 of 
-VHL
- is skipped and expressed at low levels. The function of this transcript is not fully known. Exon 2 comprises almost the entirety of the nuclear export function region of the Beta domain and is critical for known VHL function. Exon 1 contains the only initiator codons in 
-VHL
-. Exon 3 contains the elongin binding function. 
-All exons should be considered as ""present in biologically relevant transcripts"" in the PVS1 decision tree.
-
-
-Note 2: The 10% PVS1 downgrade to Moderate cannot apply to VHL
- because of the small size.
-
-
-Nonsense Mediated Decay
- 
-5
- 
-4
-  
-NMD experimental evidence in 1st exon after codon 54 and to 5' region of 2nd exon (codon 138)
-.**
-
-
-Critical Domains:
-
-
-1st Beta (β) domain (63-154), especially Nuclear Export (114-155)
-
-
-Alpha (ɑ) domain (155-192), especially Elongin C binding (157 - 172)
-
-
-Second Beta domain (193-204)   
-
-
-Truncating variants after Met54 and predicted to undergo NMD (from AA55-AA136/c.408) or in the beta or alpha domains can receive PVS1, and those outside the second Beta domain (205-213) can receive PVS1_Moderate downgrade to account for minimal loss of VHL protein. Notably a frame shift deletion at 205 is pathogenic in ClinVar (ID 18971) as are stop loss extension variants in the last codons (see PM4).
-
-
-SPLICE: If any canonical exon is skipped, the variant receives PVS1.
- If a cryptic splice disrupts the reading frame, and is in a critical domain (AA63-AA204) or is predicted to undergo NMD (AA55-AA136) it receives PVS1. If it is outside a critical domain and predicted to undergo NMD (AA55-62), it receives PVS1_Strong (the second site outside of critical domains AA205-213 is not predicted to undergo NMD). If a cryptic splice does not alter the reading frame, and is in a critical domain (AA 63-204), it can receive PVS1_Strong, and if it is outside the critical domain (AA 205-213) or  in an NMD prediction (AA 55-62), it receives PVS1_Moderate. Note:  There is a cryptic exon (E1) in intron 1 
-7
- 
-6
-, and silent variants in exon 2 that are reported to cause skipping of exon 1. If there is functional evidence of exon skipping (RNA splice assay) then PVS1 can apply. Do not double count evidence. Ex. PVS1 should be used in place of PS3 functional evidence confirming splice alteration, but PS3 evidence code could still apply to other relevant assays confirming effect on HIF1/2a presence etc. 
-
-
-EXON DELETION:
- SVI PVS1 decision tree modified for whole exon deletions. There are only 3 exons in 
-VHL
- and each has an important functional domain. Any exon deletion of 
-VHL
- receives PVS1. 
-
-
-EXON DUPLICATION:
- Follow PVS1 decision tree. Note: few pathogenic exon duplications are reported in ClinVar.   (ID:417571, ID:584137). These have no literature cited. 
-
-
-INITIATION CODON:
- VHL Met 1 (in VHL p30) truncation or missense would not affect VHL p19, as VHL has a second start at codon 54 (VHL p19), it cannot be scored in the PVS1 decision tree. After that, no other viable alternative starts are known. Start loss at codon 54 would presumably result in an impact, as VHL p30 and p19 would be truncated prior to any known functional domains (PVS1). Ong 2007 has 1 family (2 subjects) with Met54X and reports cerebellar hemangioblastomas. There is no functional study in the paper for this variant. Olschwang et al 1998 VHL Type 2A, one subject with 161insT (FS result). There is no functional study in the paper. Missense at Met 54 (VHL p19 initiation codon) would presumably not result in as strong an impact as the full length VHL p30 would still be produced (PVS1 decision tree = N/A). ClinVar has M54T (ID:819688) and M54L (ID:843990). M54T is uncertain, with no other evidence provided. M54L references M54I which segregates in homozygous state with erythrocytosis in individuals of Moroccan descent 
-9
- 
-8
-, and those heterozygous for M54I did not present VHL phenotype 
-9
-.","Disease-specific,General recommendation"
-VHL (HGNC:12687),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-VHL (HGNC:12687),PS1,Strong,Applied only to variants with interpretation by the VHL VCEP or by a variant with pathogenicity established using VHL VCEP specifications.,General recommendation
-VHL (HGNC:12687),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-VHL (HGNC:12687),PS2,Very Strong,"A single proband cannot be very strong evidence, but multiple probands can be combined to reach very strong (4+ points).",Strength
-VHL (HGNC:12687),PS2,Strong,"Phenotype highly specific for the gene (Danish Criteria) (≥2 but less than 4 
-de novo
- points).",Strength
-VHL (HGNC:12687),PS2,Moderate,"Phenotype consistent but not highly specific. Ex. VHL spectrum cancer without family history or strong indication of VHL phenotype. (≥1 but less than 2 
-de novo
- points)","General recommendation,Strength"
-VHL (HGNC:12687),PS2,Supporting,"Phenotype consistent but not highly specific (≥0.5 but less than 1 
-de novo
- points) Ex. subject included in a VHL cohort, but specific information on tumor types is not provided.",Strength
-VHL (HGNC:12687),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-VHL (HGNC:12687),PS3,Supporting,"Acceptable assays that display functional effect in VHL are the following:  
-
-
-• HIF 1/2a degradation assays -- HIF1/2a is not degraded and/or 
-
-
-• VBC complex stability is affected and/or
-
-
-• Pathogenicity supported by abnormal ECM formation and impaired fibronectin binding 
-1
- , 
-2
- , 
-3
- , 
-17
-
-
-Multiple studies and publications confirm the role of VHL in HIF1/2a regulation and VBC complex stability for VHL Type 1, and 2A/B, as well as fibronectin binding/deposition and assays evaluating extra-cellular matrix composition. In-vitro assays should display total loss of HIF1/2a degradation (i.e. HIF1/2a presence) for VHL Type 1, and 2A/B.  VHL Type 2C should display presence of HIF1/2a (with VBC complex stability variably affected and fibronectin deposition/extra cellular matrix composition affected). These assays are typically performed in Renal Cell Carcinoma (RCC) cells lacking VHL, introducing normal pVHL as a control in addition to a variant-VHL, then comparing HIF1/2a levels to WT pVHL. Brnich et al proposed 10 controls to achieve PS3_Supporting and 11 for PS3_Moderate 
-10
-. We propose to 
-follow the workflow outlined in Brnich et al.
-  Type 2C VHL variants are typically missense variants in the alpha domain of VHL, and do not usually affect HIF1/2a. If HIF1/2a maintains presence and VHL Type 2C is suspected, assays evaluating fibronectin deposition or extracellular matrix assembly should be used. 
-
-
-SPLICING:
- 
-PS3:
- RNA transcripts carrying splicing mutation display splicing defects in patient cells. 
-PS3_Moderate
-: RNA transcripts carrying splicing mutation display splicing defects in in-vivo or in-vitro assays.   
-Functional Assay Documentation
- : 
-https://drive.google.com/file/d/1w8P8zs1fHUolaAYmBL1jw-vcjsX3N_yh/view?usp=sharing","Disease-specific,Strength"
-VHL (HGNC:12687),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-VHL (HGNC:12687),PS4,Very Strong,"16+ points the PS4 cut-off and Proband Scoring Tables from a mix of any of the following phenotypes: specific, consistent and nonspecific.","Disease-specific,Strength"
-VHL (HGNC:12687),PS4,Strong,"5-15 points the PS4 cut-off and Proband Scoring Tables from a mix of any of the following phenotypes: specific, consistent and nonspecific.","Disease-specific,Strength"
-VHL (HGNC:12687),PS4,Moderate,"2 – 4 points the PS4 cut-off and Proband Scoring Tables from a mix of any of the following phenotypes: specific, consistent and nonspecific.","Disease-specific,Strength"
-VHL (HGNC:12687),PS4,Supporting,"1 point the PS4 cut-off and Proband Scoring Tables from a mix of any of the following phenotypes: specific, consistent and nonspecific.","Disease-specific,Strength"
-VHL (HGNC:12687),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-VHL (HGNC:12687),PM1,Moderate,Putative missense variants that are known germline hotspots AND/OR in key functional domains AND/OR somatic variants that have ≥10 instances for the same AA in cancerhotspots.org. See the table of Germline and Somatic Hotspots.,Disease-specific
-VHL (HGNC:12687),PM1,Supporting,"Putative missense variants seen in somatic databases, having <10 instances for the same AA in cancerhotspots.org. See the table of Germline and Somatic Hotspots.",Strength
-VHL (HGNC:12687),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-VHL (HGNC:12687),PM2,Supporting,"PM2_Supporting can be applied for variants either absent from gnomAD or with <= 0.00000156 (0.000156%) GroupMax Filtering Allele Frequency in gnomAD (based on gnomAD v4 release). If no GroupMax Filtering Allele Frequency is calculated (ex. due to a single variant present), PM2_Supporting may also be applied.","Disease-specific,Strength"
-VHL (HGNC:12687),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-VHL (HGNC:12687),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-VHL (HGNC:12687),PM4,Moderate,"In-frame insertion / deletions in the B and alpha domains and stop-loss variants adding significant additional amino acids to VHL 
-15
- cites multiple pathogenic cases and experimental evidence of stop loss extensions in VHL that are associated with Type 2A VHL disease).  The functional domains are: Beta (β) domain (AA 63 - 155, Nuclear Export), Alpha (ɑ) domain (AA 156-192, Elongin C binding), and Second Beta (β) domain (AA 193-204). 
-
-
-PM4 does not apply to in-frame indels prior to codon 54 that do not alter the Met54 VHL p19 codon and beyond.",Disease-specific
-VHL (HGNC:12687),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-VHL (HGNC:12687),PM5,Moderate,"Pathogenicity of prior variant is established by interpretation of the VHL VCEP or variants with pathogenicity established using VHL VCEP specifications. The Grantham distance should be used to compare variants. The variant under consideration must be equal or a larger distance than the classified pathogenic variant (Grantham, 1974, Table 2 
-16
- ). Splice metapredictors should be used to ensure the variant is not predicted to have an effect on splicing.",General recommendation
-VHL (HGNC:12687),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-VHL (HGNC:12687),PM6,Moderate,"See PS2 evidence code for scoring and phenotypes. Assumed 
-de novo
- receives half the points as compared to maternity and paternity confirmed 
-de novo
-. If paternity and maternity are not confirmed, score as the PM6 code. PM6 can receive “VeryStrong” strength. For example, if there are >4 de novo probands with Danish Criteria and none have paternity confirmed, this can receive PM6_VeryStrong. Note: the VCI as of Nov 2022 does not allow PM6_VeryStrong. Instead apply the PS2 evidence code and increase the strength to “VeryStrong” with a note that paternity and/or maternity is not confirmed.","Disease-specific,General recommendation"
-VHL (HGNC:12687),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-VHL (HGNC:12687),PP1,Strong,>7 meioses across >=2 families,Strength
-VHL (HGNC:12687),PP1,Moderate,5 – 6 meioses across ≥1 family.,Strength
-VHL (HGNC:12687),PP1,Supporting,3 – 4 meioses across ≥1 family.,General recommendation
-VHL (HGNC:12687),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-VHL (HGNC:12687),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-VHL (HGNC:12687),PP3,Supporting,"For missense variants, use REVEL score >=0.664. 
-
-
-For splice variants, concordance of Splice AI (>0.5) and VarSeak (class 4 or class 5).",Disease-specific
-VHL (HGNC:12687),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-VHL (HGNC:12687),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-VHL (HGNC:12687),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-VHL (HGNC:12687),BA1,Stand Alone,Use a BA1 cut off of >=0.000156 (0.0156%) GroupMax Filtering Allele Frequency in gnomAD (based on gnomAD v4 release).,Disease-specific
-VHL (HGNC:12687),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-VHL (HGNC:12687),BS1,Strong,Use BS1 cut off of  >=0.0000156 (0.00156%) GroupMax Filtering Allele Frequency in gnomAD (based on gnomAD v4).,Disease-specific
-VHL (HGNC:12687),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-VHL (HGNC:12687),BS2,Strong,"VHL is not highly penetrant 
-at an early age.
- BS2 can be applied if: There are at least 3 individuals, all >=65yo, unaffected, harboring the same variant, 
-with full phenotyping and screening
- for the absence of VHL-related cancers.",Disease-specific
-VHL (HGNC:12687),BS2,Supporting,"VHL is not highly penetrant 
-at an early age.
- BS2_Supporting can be applied if: At least 3 individuals, all >=65yo, unaffected, harboring the same variant, 
-lacking full phenotyping and screening
-, with no noted VHL-related cancers",Disease-specific
-VHL (HGNC:12687),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-VHL (HGNC:12687),BS3,Supporting,"• HIF 1/2a assay replicates WT function and/or
-
-
-• VBC complex stability is not affected and/or 
-
-
-• ECM formation/fibronectin binding is unaffected 
-
-
-This rule can be used and weighted as appropriate for functional tests of variants prior to codon 54 (which show the VHL19 product is not impacted). Evidence of benign effect for VHL Type 1 and 2A/B can be seen when HIF1/2a displays degradation (i.e. replicates WT function), and/or the VHL Elongin C, Elongin B, Cullin2 RBX1 (VCB-CR) E3 ubiquitin ligase complex stability is not affected and/or ECM formation/fibronectin binding is unaffected. Note: VHL Type 2C variants typically do not affect HIF1/2a; absence of HIF1/2a alone when testing a suspected VHL Type 2C variant should not be used for BS3. Functional studies of fibronectin and ECM formation are needed for VHL Type 2C. Follow modified SVI guidance for functional assays, general controls and benign controls. For splicing variants (and intronic/synonymous), RNA assays must demonstrate no impact on splicing.",Disease-specific
-VHL (HGNC:12687),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-VHL (HGNC:12687),BS4,Strong,Lack of segregation is seen in affected members of ≥2 families,General recommendation
-VHL (HGNC:12687),BS4,Supporting,Lack of segregation is seen in 1 family.,General recommendation
-VHL (HGNC:12687),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-VHL (HGNC:12687),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-VHL (HGNC:12687),BP2,Strong,"i) -variant observed in trans with a known pathogenic variant (phase confirmed), in the absence of congenital polycythemia (clinical manifestations or molecular)
-
-
-ii) -OR observed in the homozygous state in an individual without personal &/or family history of Von Hippel-Lindau disease or congenital polycythemia
-
-
-iii) -OR observed 
-in cis
- or with unknown phase with three or more different pathogenic 
-VHL
- variants",Disease-specific
-VHL (HGNC:12687),BP2,Supporting,"-variant is observed 
-in cis
- (or phase is unknown) w/ a pathogenic 
-VHL
- variant",Disease-specific
-VHL (HGNC:12687),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-VHL (HGNC:12687),BP3,Supporting,"BP3 can be applied to the 8x GXEEX AA repeat motif in the 5’ end of VHL p30 (AA14-AA48). Otherwise, the rest of the coding regions in VHL do not contain repeats (and none contain LINE/SINE, low complexity or other repeat types as identified by RepeatMasker) and BP3 is not applicable.",Disease-specific
-VHL (HGNC:12687),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-VHL (HGNC:12687),BP4,Supporting,"Due to the lack of benign variants, and the drop in classification accuracy for benign VHL variants, missense predictors should not be used to assign the BP4 evidence code. 
-
-
-BP4 can be applied to assess lack of splicing impact, with concordance of Splice AI (≤0.1) and VarSeak (Class 1 or Class 2).",Disease-specific
-VHL (HGNC:12687),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-VHL (HGNC:12687),BP5,Supporting,"BP5 can be applied for two or more co-occurrences with pathogenic variants in a different gene that fully explained the patient's phenotype, but specific circumstances would need to be met in order for a case to be considered for inclusion. First, the variant in the other gene must be considered highly penetrant, with both the individual's age, tumour type and gender taken into consideration. Additionally, the patient's personal and family history (including up to 2nd degree relatives) should not overlap with features seen in VHL and VHL tumour histologies. As an example, an individual with a personal and family history of pheochromocytoma who harbored a 
-VHL
- variant in addition to a pathogenic SDHB variant BP5 would not apply, because pheochromocytoma is a known risk in VHL and the 
-VHL
- variant might have contributed to this individual's pheochromocytoma cancer risk. However, an individual with a personal and family history of chromophobic RCC who was positive for a 
-VHL
- variant as well as a pathogenic FLCN variant would be considered for BP5 application, as non-clear cell RCC is not associated with VHL disease.",Disease-specific
-VHL (HGNC:12687),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-VHL (HGNC:12687),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-VHL (HGNC:12687),BP7,Supporting,"To evaluate splice prediction, use the BP4 code. If BP4 is met for lack of splice effect, BP7 can be applied to silent or intronic variants where the PhyloP score is ≤0.2.",General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenVHLExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforVHLVersion1.1.0_version=1.1.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenVHLExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforVHLVersion1.1.0_version=1.1.0.csv
deleted file mode 100644
index 19b6fd032eb0e801a90d84a992dd51f71d3ec7b8..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenVHLExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforVHLVersion1.1.0_version=1.1.0.csv
+++ /dev/null
@@ -1,249 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-VHL (HGNC:12687),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",
-VHL (HGNC:12687),PVS1,Very Strong,"LINK TO PVS1 DECISION TREE DOCUMENT:
- 
-https://drive.google.com/file/d/1mGfChgxbGVbzYn6Ggmb9rYvoGGah25ll/view?usp=sharing
-
-
-Do not apply PVS1 for truncations that occur prior to Codon 54 (including frameshift events that start and end prior to Codon 54 but the truncation extends beyond Codon 54.)
-
-
-Note1: Exon presence in biologically relevant transcripts:
- In some transcripts exon 2 of 
-VHL
- is skipped and expressed at low levels. The function of this transcript is not fully known. Exon 2 comprises almost the entirety of the nuclear export function region of the Beta domain and is critical for known VHL function. Exon 1 contains the only initiator codons in 
-VHL
-. Exon 3 contains the elongin binding function. 
-All exons should be considered as ""present in biologically relevant transcripts"" in the PVS1 decision tree.
-
-
-Note 2: The 10% PVS1 downgrade to Moderate cannot apply to VHL
- because of the small size.
-
-
-Nonsense Mediated Decay
- 
-5
- 
-4
-  
-NMD experimental evidence in 1st exon after codon 54 and to 5' region of 2nd exon (codon 138)
-.**
-
-
-Critical Domains:
-
-
-1st Beta (β) domain (63-154), especially Nuclear Export (114-155)
-
-
-Alpha (ɑ) domain (155-192), especially Elongin C binding (157 - 172)
-
-
-Second Beta domain (193-204)   
-
-
-Truncating variants after Met54 and predicted to undergo NMD (from AA55-AA136/c.408) or in the beta or alpha domains can receive PVS1, and those outside the second Beta domain (205-213) can receive PVS1_Moderate downgrade to account for minimal loss of VHL protein. Notably a frame shift deletion at 205 is pathogenic in ClinVar (ID 18971) as are stop loss extension variants in the last codons (see PM4).
-
-
-SPLICE: If any canonical exon is skipped, the variant receives PVS1.
- If a cryptic splice disrupts the reading frame, and is in a critical domain (AA63-AA204) or is predicted to undergo NMD (AA55-AA136) it receives PVS1. If it is outside a critical domain and predicted to undergo NMD (AA55-62), it receives PVS1_Strong (the second site outside of critical domains AA205-213 is not predicted to undergo NMD). If a cryptic splice does not alter the reading frame, and is in a critical domain (AA 63-204), it can receive PVS1_Strong, and if it is outside the critical domain (AA 205-213) or  in an NMD prediction (AA 55-62), it receives PVS1_Moderate. Note:  There is a cryptic exon (E1) in intron 1 
-7
- 
-6
-, and silent variants in exon 2 that are reported to cause skipping of exon 1. If there is functional evidence of exon skipping (RNA splice assay) then PVS1 can apply. Do not double count evidence. Ex. PVS1 should be used in place of PS3 functional evidence confirming splice alteration, but PS3 evidence code could still apply to other relevant assays confirming effect on HIF1/2a presence etc. 
-
-
-EXON DELETION:
- SVI PVS1 decision tree modified for whole exon deletions. There are only 3 exons in 
-VHL
- and each has an important functional domain. Any exon deletion of 
-VHL
- receives PVS1. 
-
-
-EXON DUPLICATION:
- Follow PVS1 decision tree. Note: few pathogenic exon duplications are reported in ClinVar.   (ID:417571, ID:584137). These have no literature cited. 
-
-
-INITIATION CODON:
- VHL Met 1 (in VHL p30) truncation or missense would not affect VHL p19, as VHL has a second start at codon 54 (VHL p19), it cannot be scored in the PVS1 decision tree. After that, no other viable alternative starts are known. Start loss at codon 54 would presumably result in an impact, as VHL p30 and p19 would be truncated prior to any known functional domains (PVS1). Ong 2007 has 1 family (2 subjects) with Met54X and reports cerebellar hemangioblastomas. There is no functional study in the paper for this variant. Olschwang et al 1998 VHL Type 2A, one subject with 161insT (FS result). There is no functional study in the paper. Missense at Met 54 (VHL p19 initiation codon) would presumably not result in as strong an impact as the full length VHL p30 would still be produced (PVS1 decision tree = N/A). ClinVar has M54T (ID:819688) and M54L (ID:843990). M54T is uncertain, with no other evidence provided. M54L references M54I which segregates in homozygous state with erythrocytosis in individuals of Moroccan descent 
-9
- 
-8
-, and those heterozygous for M54I did not present VHL phenotype 
-9
-.","Disease-specific,General recommendation"
-VHL (HGNC:12687),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-VHL (HGNC:12687),PS1,Strong,Applied only to variants with interpretation by the VHL VCEP or by a variant with pathogenicity established using VHL VCEP specifications.,General recommendation
-VHL (HGNC:12687),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-VHL (HGNC:12687),PS2,Very Strong,"A single proband cannot be very strong evidence, but multiple probands can be combined to reach very strong (4+ points).",Strength
-VHL (HGNC:12687),PS2,Strong,"Phenotype highly specific for the gene (Danish Criteria) (≥2 but less than 4 
-de novo
- points).",Strength
-VHL (HGNC:12687),PS2,Moderate,"Phenotype consistent but not highly specific. Ex. VHL spectrum cancer without family history or strong indication of VHL phenotype. (≥1 but less than 2 
-de novo
- points)","General recommendation,Strength"
-VHL (HGNC:12687),PS2,Supporting,"Phenotype consistent but not highly specific (≥0.5 but less than 1 
-de novo
- points) Ex. subject included in a VHL cohort, but specific information on tumor types is not provided.",Strength
-VHL (HGNC:12687),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-VHL (HGNC:12687),PS3,Supporting,"Acceptable assays that display functional effect in VHL are the following:  
-
-
-• HIF 1/2a degradation assays -- HIF1/2a is not degraded and/or 
-
-
-• VBC complex stability is affected and/or
-
-
-• Pathogenicity supported by abnormal ECM formation and impaired fibronectin binding 
-1
- , 
-2
- , 
-3
- , 
-17
-
-
-Multiple studies and publications confirm the role of VHL in HIF1/2a regulation and VBC complex stability for VHL Type 1, and 2A/B, as well as fibronectin binding/deposition and assays evaluating extra-cellular matrix composition. In-vitro assays should display total loss of HIF1/2a degradation (i.e. HIF1/2a presence) for VHL Type 1, and 2A/B.  VHL Type 2C should display presence of HIF1/2a (with VBC complex stability variably affected and fibronectin deposition/extra cellular matrix composition affected). These assays are typically performed in Renal Cell Carcinoma (RCC) cells lacking VHL, introducing normal pVHL as a control in addition to a variant-VHL, then comparing HIF1/2a levels to WT pVHL. Brnich et al proposed 10 controls to achieve PS3_Supporting and 11 for PS3_Moderate 
-10
-. We propose to 
-follow the workflow outlined in Brnich et al.
-  Type 2C VHL variants are typically missense variants in the alpha domain of VHL, and do not usually affect HIF1/2a. If HIF1/2a maintains presence and VHL Type 2C is suspected, assays evaluating fibronectin deposition or extracellular matrix assembly should be used. 
-
-
-SPLICING:
- 
-PS3:
- RNA transcripts carrying splicing mutation display splicing defects in patient cells. 
-PS3_Moderate
-: RNA transcripts carrying splicing mutation display splicing defects in in-vivo or in-vitro assays.   
-Functional Assay Documentation
- : 
-https://drive.google.com/file/d/1w8P8zs1fHUolaAYmBL1jw-vcjsX3N_yh/view?usp=sharing","Disease-specific,Strength"
-VHL (HGNC:12687),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",
-VHL (HGNC:12687),PS4,Very Strong,"16+ points the PS4 cut-off and Proband Scoring Tables from a mix of any of the following phenotypes: specific, consistent and nonspecific.","Disease-specific,Strength"
-VHL (HGNC:12687),PS4,Strong,"5-15 points the PS4 cut-off and Proband Scoring Tables from a mix of any of the following phenotypes: specific, consistent and nonspecific.","Disease-specific,Strength"
-VHL (HGNC:12687),PS4,Moderate,"2 – 4 points the PS4 cut-off and Proband Scoring Tables from a mix of any of the following phenotypes: specific, consistent and nonspecific.","Disease-specific,Strength"
-VHL (HGNC:12687),PS4,Supporting,"1 point the PS4 cut-off and Proband Scoring Tables from a mix of any of the following phenotypes: specific, consistent and nonspecific.","Disease-specific,Strength"
-VHL (HGNC:12687),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,
-VHL (HGNC:12687),PM1,Moderate,Putative missense variants that are known germline hotspots AND/OR in key functional domains AND/OR somatic variants that have ≥10 instances for the same AA in cancerhotspots.org. See the table of Germline and Somatic Hotspots.,Disease-specific
-VHL (HGNC:12687),PM1,Supporting,"Putative missense variants seen in somatic databases, having <10 instances for the same AA in cancerhotspots.org. See the table of Germline and Somatic Hotspots.",Strength
-VHL (HGNC:12687),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-VHL (HGNC:12687),PM2,Supporting,"PM2_Supporting can be applied for variants either absent from gnomAD or with <= 0.00000156 (0.000156%) GroupMax Filtering Allele Frequency in gnomAD (based on gnomAD v4 release). If no GroupMax Filtering Allele Frequency is calculated (ex. due to a single variant present), PM2_Supporting may also be applied.","Disease-specific,Strength"
-VHL (HGNC:12687),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",NA
-VHL (HGNC:12687),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-VHL (HGNC:12687),PM4,Moderate,"In-frame insertion / deletions in the B and alpha domains and stop-loss variants adding significant additional amino acids to VHL 
-15
- cites multiple pathogenic cases and experimental evidence of stop loss extensions in VHL that are associated with Type 2A VHL disease).  The functional domains are: Beta (β) domain (AA 63 - 155, Nuclear Export), Alpha (ɑ) domain (AA 156-192, Elongin C binding), and Second Beta (β) domain (AA 193-204). 
-
-
-PM4 does not apply to in-frame indels prior to codon 54 that do not alter the Met54 VHL p19 codon and beyond.",Disease-specific
-VHL (HGNC:12687),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-VHL (HGNC:12687),PM5,Moderate,"Pathogenicity of prior variant is established by interpretation of the VHL VCEP or variants with pathogenicity established using VHL VCEP specifications. The Grantham distance should be used to compare variants. The variant under consideration must be equal or a larger distance than the classified pathogenic variant (Grantham, 1974, Table 2 
-16
- ). Splice metapredictors should be used to ensure the variant is not predicted to have an effect on splicing.",General recommendation
-VHL (HGNC:12687),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",
-VHL (HGNC:12687),PM6,Moderate,"See PS2 evidence code for scoring and phenotypes. Assumed 
-de novo
- receives half the points as compared to maternity and paternity confirmed 
-de novo
-. If paternity and maternity are not confirmed, score as the PM6 code. PM6 can receive “VeryStrong” strength. For example, if there are >4 de novo probands with Danish Criteria and none have paternity confirmed, this can receive PM6_VeryStrong. Note: the VCI as of Nov 2022 does not allow PM6_VeryStrong. Instead apply the PS2 evidence code and increase the strength to “VeryStrong” with a note that paternity and/or maternity is not confirmed.","Disease-specific,General recommendation"
-VHL (HGNC:12687),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-VHL (HGNC:12687),PP1,Strong,>7 meioses across >=2 families,Strength
-VHL (HGNC:12687),PP1,Moderate,5 – 6 meioses across ≥1 family.,Strength
-VHL (HGNC:12687),PP1,Supporting,3 – 4 meioses across ≥1 family.,General recommendation
-VHL (HGNC:12687),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-VHL (HGNC:12687),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-VHL (HGNC:12687),PP3,Supporting,"For missense variants, use REVEL score >=0.664. 
-
-
-For splice variants, concordance of Splice AI (>0.5) and VarSeak (class 4 or class 5).",Disease-specific
-VHL (HGNC:12687),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,NA
-VHL (HGNC:12687),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-VHL (HGNC:12687),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-VHL (HGNC:12687),BA1,Stand Alone,Use a BA1 cut off of >=0.000156 (0.0156%) GroupMax Filtering Allele Frequency in gnomAD (based on gnomAD v4 release).,Disease-specific
-VHL (HGNC:12687),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-VHL (HGNC:12687),BS1,Strong,Use BS1 cut off of  >=0.0000156 (0.00156%) GroupMax Filtering Allele Frequency in gnomAD (based on gnomAD v4).,Disease-specific
-VHL (HGNC:12687),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",
-VHL (HGNC:12687),BS2,Strong,"VHL is not highly penetrant 
-at an early age.
- BS2 can be applied if: There are at least 3 individuals, all >=65yo, unaffected, harboring the same variant, 
-with full phenotyping and screening
- for the absence of VHL-related cancers.",Disease-specific
-VHL (HGNC:12687),BS2,Supporting,"VHL is not highly penetrant 
-at an early age.
- BS2_Supporting can be applied if: At least 3 individuals, all >=65yo, unaffected, harboring the same variant, 
-lacking full phenotyping and screening
-, with no noted VHL-related cancers",Disease-specific
-VHL (HGNC:12687),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,
-VHL (HGNC:12687),BS3,Supporting,"• HIF 1/2a assay replicates WT function and/or
-
-
-• VBC complex stability is not affected and/or 
-
-
-• ECM formation/fibronectin binding is unaffected 
-
-
-This rule can be used and weighted as appropriate for functional tests of variants prior to codon 54 (which show the VHL19 product is not impacted). Evidence of benign effect for VHL Type 1 and 2A/B can be seen when HIF1/2a displays degradation (i.e. replicates WT function), and/or the VHL Elongin C, Elongin B, Cullin2 RBX1 (VCB-CR) E3 ubiquitin ligase complex stability is not affected and/or ECM formation/fibronectin binding is unaffected. Note: VHL Type 2C variants typically do not affect HIF1/2a; absence of HIF1/2a alone when testing a suspected VHL Type 2C variant should not be used for BS3. Functional studies of fibronectin and ECM formation are needed for VHL Type 2C. Follow modified SVI guidance for functional assays, general controls and benign controls. For splicing variants (and intronic/synonymous), RNA assays must demonstrate no impact on splicing.",Disease-specific
-VHL (HGNC:12687),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-VHL (HGNC:12687),BS4,Strong,Lack of segregation is seen in affected members of ≥2 families,General recommendation
-VHL (HGNC:12687),BS4,Supporting,Lack of segregation is seen in 1 family.,General recommendation
-VHL (HGNC:12687),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-VHL (HGNC:12687),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,
-VHL (HGNC:12687),BP2,Strong,"i) -variant observed in trans with a known pathogenic variant (phase confirmed), in the absence of congenital polycythemia (clinical manifestations or molecular)
-
-
-ii) -OR observed in the homozygous state in an individual without personal &/or family history of Von Hippel-Lindau disease or congenital polycythemia
-
-
-iii) -OR observed 
-in cis
- or with unknown phase with three or more different pathogenic 
-VHL
- variants",Disease-specific
-VHL (HGNC:12687),BP2,Supporting,"-variant is observed 
-in cis
- (or phase is unknown) w/ a pathogenic 
-VHL
- variant",Disease-specific
-VHL (HGNC:12687),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,
-VHL (HGNC:12687),BP3,Supporting,"BP3 can be applied to the 8x GXEEX AA repeat motif in the 5’ end of VHL p30 (AA14-AA48). Otherwise, the rest of the coding regions in VHL do not contain repeats (and none contain LINE/SINE, low complexity or other repeat types as identified by RepeatMasker) and BP3 is not applicable.",Disease-specific
-VHL (HGNC:12687),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-VHL (HGNC:12687),BP4,Supporting,"Due to the lack of benign variants, and the drop in classification accuracy for benign VHL variants, missense predictors should not be used to assign the BP4 evidence code. 
-
-
-BP4 can be applied to assess lack of splicing impact, with concordance of Splice AI (≤0.1) and VarSeak (Class 1 or Class 2).",Disease-specific
-VHL (HGNC:12687),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-VHL (HGNC:12687),BP5,Supporting,"BP5 can be applied for two or more co-occurrences with pathogenic variants in a different gene that fully explained the patient's phenotype, but specific circumstances would need to be met in order for a case to be considered for inclusion. First, the variant in the other gene must be considered highly penetrant, with both the individual's age, tumour type and gender taken into consideration. Additionally, the patient's personal and family history (including up to 2nd degree relatives) should not overlap with features seen in VHL and VHL tumour histologies. As an example, an individual with a personal and family history of pheochromocytoma who harbored a 
-VHL
- variant in addition to a pathogenic SDHB variant BP5 would not apply, because pheochromocytoma is a known risk in VHL and the 
-VHL
- variant might have contributed to this individual's pheochromocytoma cancer risk. However, an individual with a personal and family history of chromophobic RCC who was positive for a 
-VHL
- variant as well as a pathogenic FLCN variant would be considered for BP5 application, as non-clear cell RCC is not associated with VHL disease.",Disease-specific
-VHL (HGNC:12687),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-VHL (HGNC:12687),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-VHL (HGNC:12687),BP7,Supporting,"To evaluate splice prediction, use the BP4 code. If BP4 is met for lack of splice effect, BP7 can be applied to silent or intronic variants where the PhyloP score is ≤0.2.",General recommendation
diff --git a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenvonWillebrandDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforVWFVersion1.0.0_version=1.0.0.csv b/VCI/parsing_csr_criteria/version_csv_individual/ClinGenvonWillebrandDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforVWFVersion1.0.0_version=1.0.0.csv
deleted file mode 100644
index 5e668c7ebcfac1ab2db08b75d246c1e31917a926..0000000000000000000000000000000000000000
--- a/VCI/parsing_csr_criteria/version_csv_individual/ClinGenvonWillebrandDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforVWFVersion1.0.0_version=1.0.0.csv
+++ /dev/null
@@ -1,112 +0,0 @@
-Gene,Code,Strength,Description,Modification Type
-VWF (HGNC:12726),PVS1,Original ACMG Summary,"Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
-Caveats:
- • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7).
- • Use caution interpreting LOF variants at the extreme 3’ end of a gene.
- • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact.
- • Use caution in the presence of multiple transcripts.",NA
-VWF (HGNC:12726),PS1,Original ACMG Summary,"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
-Example: Val->Leu caused by either G>C or G>T in the same codon.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-VWF (HGNC:12726),PS1,Strong,Use with no specification except comparison variant must be classified as pathogenic using rules from the VWD VCEP.,Gene-specific
-VWF (HGNC:12726),PS1,Moderate,Use with no specification except comparison variant must be classified as likely pathogenic using rules from the VWD VCEP.,Gene-specific
-VWF (HGNC:12726),PS2,Original ACMG Summary,"De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
-Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.",
-VWF (HGNC:12726),PS2,Very Strong,"Use proposed SVI point recommendations for 
-“Phenotype consistent with gene but not highly specific”
- if the proband meets 
-PP4 criteria
-.  Use 
-“Phenotype highly specific for gene”
- phenotype consistency if the proband meets 
-PP4_Moderate criteria
-. See Table 1 attached. Required 4 points.",Disease-specific
-VWF (HGNC:12726),PS2,Strong,"Use proposed SVI point recommendations for 
-“Phenotype consistent with gene but not highly specific”
- if the proband meets 
-PP4 criteria
-.  Use 
-“Phenotype highly specific for gene”
- phenotype consistency if the proband meets 
-PP4_Moderate criteria
-. See Table 1 attached. Required 2 points.",Disease-specific
-VWF (HGNC:12726),PS2,Moderate,"Use proposed SVI point recommendations for 
-“Phenotype consistent with gene but not highly specific”
- if the proband meets 
-PP4 criteria
-.  Use 
-“Phenotype highly specific for gene”
- phenotype consistency if the proband meets 
-PP4_Moderate criteria
-. See Table 1 attached. Required 1 point.",Disease-specific
-VWF (HGNC:12726),PS2,Supporting,"Use proposed SVI point recommendations for 
-“Phenotype consistent with gene but not highly specific”
- if the proband meets 
-PP4 criteria
-. If the proband meets PP4_Moderate criteria, use a moderate or higher evidence weight (see above). See Table 1 attached. Required 0.5 point.",Disease-specific
-VWF (HGNC:12726),PS3,Original ACMG Summary,"Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
-Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.",
-VWF (HGNC:12726),PS3,Strong,"Either (1) in a transgenic animal model, must demonstrate minimal to no function. (2) a Factor VIII binding assay using recombinant vWF resulting in decreased binding compared to WT.
-
-
-See attached spreadsheet for examples of approved assay instances to use for this rule code. There are no universal thresholds for these assays; however, the relevant results should be described as clinically significant if assays were performed in a clinical laboratory or statistically significant if pertaining to research findings.",Disease-specific
-VWF (HGNC:12726),PS4,Original ACMG Summary,"The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
-Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance.
-Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.",NA
-VWF (HGNC:12726),PM1,Original ACMG Summary,Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.,NA
-VWF (HGNC:12726),PM2,Original ACMG Summary,"Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
-Caveat: Population data for indels may be poorly called by next generation sequencing.",
-VWF (HGNC:12726),PM2,Supporting,Use code for variants with a popmax MAF of <0.005 in gnomAD.,"Disease-specific,Gene-specific"
-VWF (HGNC:12726),PM3,Original ACMG Summary,"For recessive disorders, detected in trans with a pathogenic variant
-Note: This requires testing of parents (or offspring) to determine phase.",
-VWF (HGNC:12726),PM3,Very Strong,Use SVI recommended point system for this code for probands with a VWD type 2N diagnosis. Total of 4 points required.,Disease-specific
-VWF (HGNC:12726),PM3,Strong,Use SVI recommended point system for this code for probands with a VWD type 2N diagnosis. Total of 2 points required.,Disease-specific
-VWF (HGNC:12726),PM3,Moderate,Use SVI recommended point system for this code for probands with a VWD type 2N diagnosis. Total of 1 point required.,Disease-specific
-VWF (HGNC:12726),PM3,Supporting,Use SVI recommended point system for this code for probands with a VWD type 2N diagnosis. Total of 0.5 points required.,Disease-specific
-VWF (HGNC:12726),PM4,Original ACMG Summary,Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.,
-VWF (HGNC:12726),PM4,Moderate,Use with no specification.,None
-VWF (HGNC:12726),PM5,Original ACMG Summary,"Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
-Example: Arg156His is pathogenic; now you observe Arg156Cys.
-Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.",
-VWF (HGNC:12726),PM5,Moderate,"Use code when previously reported variant reaches a pathogenic classification using the VWD Type 2 rule specifications. Previously reported variant can be associated with a different type of VWD.
-
-
-Code may also be applied when two previously reported variants reach a likely pathogenic classification using the VWD Type 2 rule specifications. Previously reported variants can be associated with a different type of VWD.","Disease-specific,General recommendation"
-VWF (HGNC:12726),PM5,Supporting,Use code when previously reported variant reaches a likely pathogenic classification using the VWD Type 2 rule specifications. Previously reported variant can be associated with a different type of VWD.,"Disease-specific,General recommendation"
-VWF (HGNC:12726),PM6,Original ACMG Summary,"Assumed de novo, but without confirmation of paternity and maternity.",NA
-VWF (HGNC:12726),PP1,Original ACMG Summary,"Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
-Note: May be used as stronger evidence with increasing segregation data.",
-VWF (HGNC:12726),PP1,Strong,Appropriate to use when a proband has three affected family members.,Disease-specific
-VWF (HGNC:12726),PP1,Moderate,Appropriate to use when a proband has two affected family members.,Disease-specific
-VWF (HGNC:12726),PP1,Supporting,Appropriate to use when a proband has one affected family member.,Disease-specific
-VWF (HGNC:12726),PP2,Original ACMG Summary,Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.,NA
-VWF (HGNC:12726),PP3,Original ACMG Summary,"Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant.",
-VWF (HGNC:12726),PP3,Supporting,Appropriate to use for missense variants that have a REVEL score of greater or equal to 0.644 OR a SpliceAI score suggestive of a splicing defect (greater or equal to 0.5).,Gene-specific
-VWF (HGNC:12726),PP4,Original ACMG Summary,Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.,
-VWF (HGNC:12726),PP4,Moderate,"The patient must have a clinical phenotype of excessive mucocutaneous bleeding and required laboratory values to use the PP4 rule code, including a low factor VIII activity level and evidence of decreased VWF:FVIII binding.
-
-
-Additional consistent information should be noted but is not required, including either normal or low VWF:Ag, normal high molecular weight multimers, and sequencing with duplication/deletion analysis of the F8 gene.",Disease-specific
-VWF (HGNC:12726),PP5,Original ACMG Summary,"Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-VWF (HGNC:12726),BA1,Original ACMG Summary,"Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.",
-VWF (HGNC:12726),BA1,Stand Alone,Appropriate to use for variants with a Popmax MAF of >0.1 in gnomAD.,"Disease-specific,Gene-specific"
-VWF (HGNC:12726),BS1,Original ACMG Summary,Allele frequency is greater than expected for disorder.,
-VWF (HGNC:12726),BS1,Strong,Appropriate to use for variants with a Popmax MAF of >0.01 in gnomAD.,"Disease-specific,Gene-specific"
-VWF (HGNC:12726),BS2,Original ACMG Summary,"Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.",NA
-VWF (HGNC:12726),BS3,Original ACMG Summary,Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.,NA
-VWF (HGNC:12726),BS4,Original ACMG Summary,"Lack of segregation in affected members of a family.
-Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.",
-VWF (HGNC:12726),BS4,Strong,"Appropriate to use when two or more relatives have the phenotype consistent with VWD type 2 without harboring the variant identified in other affected family members. Additionally, there is not another established cause of type 2 VWD (e.g. - there are not multiple type 2 VWD diagnoses) segregating in the family.",Disease-specific
-VWF (HGNC:12726),BS4,Supporting,"Appropriate to use when only one relative has the phenotype consistent with VWD type 2 without harboring the variant identified in other affected family members. Additionally, there is not another established cause of type 2 VWD (e.g. - there are not multiple type 2 VWD diagnoses) segregating in the family.",Disease-specific
-VWF (HGNC:12726),BP1,Original ACMG Summary,Missense variant in a gene for which primarily truncating variants are known to cause disease.,NA
-VWF (HGNC:12726),BP2,Original ACMG Summary,Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.,NA
-VWF (HGNC:12726),BP3,Original ACMG Summary,In frame-deletions/insertions in a repetitive region without a known function.,NA
-VWF (HGNC:12726),BP4,Original ACMG Summary,"Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
-Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant.",
-VWF (HGNC:12726),BP4,Supporting,Use for missense variants that have a REVEL score of less than or equal to 0.290 AND SpliceAI cutoff of <0.1. Use SpliceAI cutoff of <0.1 for other variant types.,Gene-specific
-VWF (HGNC:12726),BP5,Original ACMG Summary,Variant found in a case with an alternate molecular basis for disease.,
-VWF (HGNC:12726),BP5,Supporting,A second variant in VWF may be considered an alternate molecular basis for disease when that variant is LP/P (as evaluated by the VWD VCEP) and fully explains the phenotype of the patient's reported VWD subtype.,None
-VWF (HGNC:12726),BP6,Original ACMG Summary,"Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.",NA
-VWF (HGNC:12726),BP7,Original ACMG Summary,A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.,
-VWF (HGNC:12726),BP7,Supporting,Use SpliceAI for splicing predictor with a cutoff score of 0.,Disease-specific