VCI/split_evidence_sufficiency/test_dedup.csv

entry_index,variant,hgnc_gene,disease,mondo_id,assertion,mode_inheritance,expert_panel,pub_date,evidence_code,met_status,pmid,comments,summary,summary_comments,path
592,NM_000277.2(PAH):c.164T>C (p.Phe55Ser),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-06,PP4,met,PubMed:26666653,"Phe55Ser identified in 1 patient with classic PKU. A total of 364 hyperphenylalaninemic patients, including 42 siblings, were investigated. They represented mixed origin people from 20 French Centers for Inborn Errors of Metabolism. According to their blood Phenylalanine concentration at time of diagnosis, these patients were assigned to one of the three phenotype categories. classical phenylketonuria (cPKU, Phe > 1200 μmol/L).",Identified in 1 French patient with classic PKU. BH4 deficiency not assessed. PMID: 26666653,"Identified in 1 French patient with classic PKU. BH4 deficiency not assessed. PMID: 26666653 Phe55Ser identified in 1 patient with classic PKU. A total of 364 hyperphenylalaninemic patients, including 42 siblings, were investigated. They represented mixed origin people from 20 French Centers for Inborn Errors of Metabolism. According to their blood Phenylalanine concentration at time of diagnosis, these patients were assigned to one of the three phenotype categories. classical phenylketonuria (cPKU, Phe > 1200 μmol/L).",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
625,NM_000277.2(PAH):c.785T>G (p.Val262Gly),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-05,PP4,met,PubMed:26666653,"A total of 364 hyperphenylalaninemic patients, including 42 siblings, were investigated. According to their blood Phenylalanine concentration at time of diagnosis, these patients were assigned to one of the three phenotype categories. V262G was observed in 1 patient with classic PKU.",V262G observed in 1 patient with classic PKU. BH4 deficiencies not assessed. PMID: 26666653.,"V262G observed in 1 patient with classic PKU. BH4 deficiencies not assessed. PMID: 26666653. A total of 364 hyperphenylalaninemic patients, including 42 siblings, were investigated. According to their blood Phenylalanine concentration at time of diagnosis, these patients were assigned to one of the three phenotype categories. V262G was observed in 1 patient with classic PKU.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
665,NM_000277.2(PAH):c.127G>T (p.Glu43Ter),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-06,PP4,met,PubMed:26503515,Variant is reported in 2 patients from mainland China in a cohort study. BH4 deficiency not ruled out.,, Variant is reported in 2 patients from mainland China in a cohort study. BH4 deficiency not ruled out.,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
671,NM_000277.2(PAH):c.493G>C (p.Ala165Pro),PAH,phenylketonuria,MONDO:0009861,Uncertain Significance,Autosomal recessive inheritance,Phenylketonuria,2019-04-07,PP4,met,PubMed:26666653,"detected in 1 patient with mild PKU (mPKU, 600 < Phe < 1200 μmol/L). BH4 deficiency not assessed/stated.",detected in 1 patient with mild PKU (PMID: 26666653). BH4 deficiency not assessed/stated.,"detected in 1 patient with mild PKU (PMID: 26666653). BH4 deficiency not assessed/stated. detected in 1 patient with mild PKU (mPKU, 600 < Phe < 1200 μmol/L). BH4 deficiency not assessed/stated.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
687,NM_000277.2(PAH):c.196G>T (p.Glu66Ter),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-05-26,PP4,met,PubMed:26666653,"The c.196G>T (p.Glu66Ter) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120270); the collection method is stated as “literature only” and no further information is provided. With respect to the published literature, it has been previously reported in one proband with classic PKU (defined by the authors as plasma phenylalanine levels > 1200umol/L) (PMID: 26666653) (PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic allele (per ClinGen PAH working group classification, see ClinVar ID ) c. 1315+1G>A variant; however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence.",The c.196G>T (p.Glu66Ter) variant in PAH has been previously reported in one proband with classic PKU (plasma phenylalanine levels > 1200umol/L) (PMID: 26666653),"The c.196G>T (p.Glu66Ter) variant in PAH has been previously reported in one proband with classic PKU (plasma phenylalanine levels > 1200umol/L) (PMID: 26666653) The c.196G>T (p.Glu66Ter) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120270); the collection method is stated as “literature only” and no further information is provided. With respect to the published literature, it has been previously reported in one proband with classic PKU (defined by the authors as plasma phenylalanine levels > 1200umol/L) (PMID: 26666653) (PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic allele (per ClinGen PAH working group classification, see ClinVar ID ) c. 1315+1G>A variant; however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
688,NM_000277.2(PAH):c.504C>A (p.Tyr168Ter),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-05-26,PP4,met,PubMed:26666653,,The c.504C>A (p.Tyr168Ter) variant in PAH has been previously reported in one proband with mild hyperphenylalanemia (defined by the authors as plasma phenylalanine levels >180 umol/L and <600umol/L) (PMID: 26666653) (PP4).,The c.504C>A (p.Tyr168Ter) variant in PAH has been previously reported in one proband with mild hyperphenylalanemia (defined by the authors as plasma phenylalanine levels >180 umol/L and <600umol/L) (PMID: 26666653) (PP4). ,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
715,NM_000277.2(PAH):c.887A>G (p.Asp296Gly),PAH,phenylketonuria,MONDO:0009861,Uncertain Significance,Autosomal recessive inheritance,Phenylketonuria,2019-07-14,PP4,met,PubMed:26666653,reported in a proband with classic PKU (plasma phenylalanine 1326 umol/L); BH4 deficiency does not appear to have been formally excluded,reported in a proband with classic PKU (plasma phenylalanine 1326 umol/L); BH4 deficiency does not appear to have been formally excluded (PP4).,reported in a proband with classic PKU (plasma phenylalanine 1326 umol/L); BH4 deficiency does not appear to have been formally excluded (PP4). reported in a proband with classic PKU (plasma phenylalanine 1326 umol/L); BH4 deficiency does not appear to have been formally excluded,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
717,NM_000277.2(PAH):c.931_932delCT (p.Leu311Glyfs),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-07-14,PP4,met,PubMed:26666653,A compound heterozygous proband with the c.931_932del variant was described with a mild PKU phenotype and 600 <  Phe  < 1200 umol/L. Defects in BH4 cofactor metabolism were not excluded.,A compound heterozygous proband with the c.931_932del variant was described with a mild PKU phenotype and 600 <  Phe  < 1200 umol/L. Defects in BH4 cofactor metabolism were not excluded.,A compound heterozygous proband with the c.931_932del variant was described with a mild PKU phenotype and 600 <  Phe  < 1200 umol/L. Defects in BH4 cofactor metabolism were not excluded. A compound heterozygous proband with the c.931_932del variant was described with a mild PKU phenotype and 600 <  Phe  < 1200 umol/L. Defects in BH4 cofactor metabolism were not excluded.,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
746,NM_000277.2(PAH):c.1163T>C (p.Val388Ala),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-07-19,PP4,met,PubMed:26666653,"The c.1163T>C (p.Val388Ala) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120260); the collection method is stated as “literature only” and no further information is provided. With respect to the published literature, it has been previously reported in a French proband classified as having mild PKU (defined by the authors as plasma phenylalanine levels between 600-1200uL/L) (PMID: 26666653); formal testing to exclude BH4 deficiency was not noted (PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic (per ClinGen PAH working group classification, see ClinVar ID 92731) c.1208C>T (Ala403Val); however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence.","The c.1163T>C (p.Val388Ala) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120260); the collection method is stated as “literature only” and no further information is provided. With respect to the published literature, it has been previously reported in a French proband classified as having mild PKU (defined by the authors as plasma phenylalanine levels between 600-1200uL/L) (PMID: 26666653); formal testing to exclude BH4 deficiency was not noted (PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic (per ClinGen PAH working group classification, see ClinVar ID 92731) c.1208C>T (Ala403Val); however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence.","The c.1163T>C (p.Val388Ala) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120260); the collection method is stated as “literature only” and no further information is provided. With respect to the published literature, it has been previously reported in a French proband classified as having mild PKU (defined by the authors as plasma phenylalanine levels between 600-1200uL/L) (PMID: 26666653); formal testing to exclude BH4 deficiency was not noted (PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic (per ClinGen PAH working group classification, see ClinVar ID 92731) c.1208C>T (Ala403Val); however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence. The c.1163T>C (p.Val388Ala) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120260); the collection method is stated as “literature only” and no further information is provided. With respect to the published literature, it has been previously reported in a French proband classified as having mild PKU (defined by the authors as plasma phenylalanine levels between 600-1200uL/L) (PMID: 26666653); formal testing to exclude BH4 deficiency was not noted (PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic (per ClinGen PAH working group classification, see ClinVar ID 92731) c.1208C>T (Ala403Val); however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
843,NM_000277.2(PAH):c.547_548delGAinsTT (p.Glu183Leu),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-08-11,PP4,met,PubMed:26666653,A compound heterozygous proband with this variant was described with the classic PKU phenotype and PHE >1200umol/L. Defects in BH4 cofactor metabolism were not excluded.,A compound heterozygous proband with this variant was described with the classic PKU phenotype and PHE >1200umol/L. Defects in BH4 cofactor metabolism were not excluded.,A compound heterozygous proband with this variant was described with the classic PKU phenotype and PHE >1200umol/L. Defects in BH4 cofactor metabolism were not excluded. A compound heterozygous proband with this variant was described with the classic PKU phenotype and PHE >1200umol/L. Defects in BH4 cofactor metabolism were not excluded.,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
844,NM_000277.1(PAH):c.782G>C (p.Arg261Pro),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-08-11,PP4,met,PubMed:26666653,"Table1_p. [Ile65Thr]; [Arg261Pro]_pt has classic PKU and Total BH4 loading test not responding. ['According to their blood Phenylalanine concentration at time of diagnosis, these patients were assigned to one of the three phenotype categories: mild hyperphenylalaninemia (mHP, 180 < Phe < 600 μmol/L); mild phenylketonuria (mPKU, 600 < Phe < 1200 μmol/L) and classical phenylketonuria (cPKU, Phe > 1200 μmol/L).']",Detected in 5 patients with PKU (PMID: 26666653). BH4 deficiency not ruled out.,"Detected in 5 patients with PKU (PMID: 26666653). BH4 deficiency not ruled out. Table1_p. [Ile65Thr]; [Arg261Pro]_pt has classic PKU and Total BH4 loading test not responding. ['According to their blood Phenylalanine concentration at time of diagnosis, these patients were assigned to one of the three phenotype categories: mild hyperphenylalaninemia (mHP, 180 < Phe < 600 μmol/L); mild phenylketonuria (mPKU, 600 < Phe < 1200 μmol/L) and classical phenylketonuria (cPKU, Phe > 1200 μmol/L).']",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
858,NM_000277.2(PAH):c.155delT (p.Leu52Cysfs),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-08-16,PP4,met,PubMed:26666653,"This variant was reported in a patient with PKU who carried a second nonsense mutation in PAH (Arg261*), however BH4 deficiency was not ruled out.",," This variant was reported in a patient with PKU who carried a second nonsense mutation in PAH (Arg261*), however BH4 deficiency was not ruled out.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
954,NM_000277.2(PAH):c.169G>T (p.Glu57Ter),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-10-02,PP4,met,PubMed:26666653,"The c.169G>T (p.Glu57Ter) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120268); the collection method is stated as “literature only” and no further information is provided. With respect to the published literature, it has been previously reported in one proband with classic PKU (defined by the authors as plasma phenylalanine levels > 1200umol/L) (PMID: 26666653) (PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic allele (per ClinGen PAH working group classification, see ClinVar ID 636) c.194T>C (p.Ile65Thr); however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence.","The c.169G>T (p.Glu57Ter) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120268); the collection method is stated as “literature only” and no further information is provided. With respect to the published literature, it has been previously reported in one proband with classic PKU (defined by the authors as plasma phenylalanine levels > 1200umol/L) (PMID: 26666653) (PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic allele (per ClinGen PAH working group classification, see ClinVar ID 636) c.194T>C (p.Ile65Thr); however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence.","The c.169G>T (p.Glu57Ter) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120268); the collection method is stated as “literature only” and no further information is provided. With respect to the published literature, it has been previously reported in one proband with classic PKU (defined by the authors as plasma phenylalanine levels > 1200umol/L) (PMID: 26666653) (PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic allele (per ClinGen PAH working group classification, see ClinVar ID 636) c.194T>C (p.Ile65Thr); however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence. The c.169G>T (p.Glu57Ter) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120268); the collection method is stated as “literature only” and no further information is provided. With respect to the published literature, it has been previously reported in one proband with classic PKU (defined by the authors as plasma phenylalanine levels > 1200umol/L) (PMID: 26666653) (PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic allele (per ClinGen PAH working group classification, see ClinVar ID 636) c.194T>C (p.Ile65Thr); however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1010,NM_000277.2(PAH):c.913-8A>G,PAH,phenylketonuria,MONDO:0009861,Uncertain Significance,Autosomal recessive inheritance,Phenylketonuria,2019-11-08,PP4,met,PubMed:26666653,A compound heterozygous proband with the c.913-8A>G variant was described with the classic PKU phenotype and PHE >1200umol/L. Defects in BH4 cofactor metabolism were not excluded.,A compound heterozygous proband with the c.913-8A>G variant was described with the classic PKU phenotype and PHE >1200umol/L. Defects in BH4 cofactor metabolism were not excluded.,A compound heterozygous proband with the c.913-8A>G variant was described with the classic PKU phenotype and PHE >1200umol/L. Defects in BH4 cofactor metabolism were not excluded. A compound heterozygous proband with the c.913-8A>G variant was described with the classic PKU phenotype and PHE >1200umol/L. Defects in BH4 cofactor metabolism were not excluded.,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1495,NM_000277.2(PAH):c.682G>A (p.Glu228Lys),PAH,phenylketonuria,MONDO:0009861,Uncertain Significance,Autosomal recessive inheritance,Phenylketonuria,2020-06-26,PP4,met,PubMed:26666653,"A total of 364 hyperphenylalaninemic patients, including 42 siblings, were investigated. E228K was seen on 1 allele of a patient with classic PKU.",E228K seen in 1 patient with classic PKU. BH4 deficiency not assessed.,"E228K seen in 1 patient with classic PKU. BH4 deficiency not assessed. A total of 364 hyperphenylalaninemic patients, including 42 siblings, were investigated. E228K was seen on 1 allele of a patient with classic PKU.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1505,NM_000277.1(PAH):c.1180G>T (p.Asp394Tyr),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2020-07-10,PP4,met,PubMed:26666653,"364 hyperphenylalaninemic patients, including 42 siblings, were investigated. Asp394Tyr found in 2 patients.",Seen in 2 mild PKU patients. BH4 deficiency not ruled out.  PMID: 26666653,"Seen in 2 mild PKU patients. BH4 deficiency not ruled out.  PMID: 26666653 364 hyperphenylalaninemic patients, including 42 siblings, were investigated. Asp394Tyr found in 2 patients.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1695,NM_000277.3(PAH):c.648C>G (p.Tyr216Ter),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2020-10-30,PP4,met,PubMed:26666653,,At least one proband with this variant has been described (PMID: 26666653) with the classic PKU phenotype and PHE >1200umol/L. Exclusion of defects in BH4 cofactor metabolism was not reported.,At least one proband with this variant has been described (PMID: 26666653) with the classic PKU phenotype and PHE >1200umol/L. Exclusion of defects in BH4 cofactor metabolism was not reported. ,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
5921,NM_000277.1:c.510-19_667del,PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2023-12-30,PP4,met,PubMed:23842451,"Data were collected from 183 patients in six Dutch university medical centres. Blood Phe concentrations in dried blood spots were measured by the patients’ respective centre laboratory according to standard quantitative methods, with the same method per patient. c.510-21_665del was detected in one patient with Phe level 855 at baseline (T=0).",c.510-21_665del was detected in one patient with Phe level 855. BH4 deficiency not reported/assessed. PMID: 23842451,"c.510-21_665del was detected in one patient with Phe level 855. BH4 deficiency not reported/assessed. PMID: 23842451 Data were collected from 183 patients in six Dutch university medical centres. Blood Phe concentrations in dried blood spots were measured by the patients’ respective centre laboratory according to standard quantitative methods, with the same method per patient. c.510-21_665del was detected in one patient with Phe level 855 at baseline (T=0).",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1004,NM_000277.3(PAH):c.1315+4A>G,PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-11-06,PP4-Moderate,not_met,PubMed:26503515,"This variant was documented twice in patients from Southern China and once in a patient from Northern China with PAH deficiency (PMID: 26503515). It was not specified whether the 2 alleles in Southern China were from 2 compound heterozygous individuals or from one homozygous individual. This study included 796 PKU patients from mainland China diagnosed through neonatal screening or by clinical presentation. Phenylalanine plasma concentrations >120 µmol/L were reported for all subjects. Tetrahydrobiopterin (BH4) deficiency was excluded through a BH4 loading test, urinary pterin analysis, DHPR activity assay.",This variant was documented twice in patients from Southern China and once in a patient from Northern China with PAH deficiency (PMID: 26503515).,"This variant was documented twice in patients from Southern China and once in a patient from Northern China with PAH deficiency (PMID: 26503515). This variant was documented twice in patients from Southern China and once in a patient from Northern China with PAH deficiency (PMID: 26503515). It was not specified whether the 2 alleles in Southern China were from 2 compound heterozygous individuals or from one homozygous individual. This study included 796 PKU patients from mainland China diagnosed through neonatal screening or by clinical presentation. Phenylalanine plasma concentrations >120 µmol/L were reported for all subjects. Tetrahydrobiopterin (BH4) deficiency was excluded through a BH4 loading test, urinary pterin analysis, DHPR activity assay.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1006,NM_000277.3(PAH):c.1315+6T>A,PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-11-06,PP4-Moderate,not_met,PubMed:26503515,"This variant was documented three times in Southern Chinese patients and 5 times in Northern Chinese patients with PAH deficiency (PMID: 26503515). It was not specified whether patient genotypes were homozygous or compound heterozygous for the variant. Subjects in this study were diagnosed through neonatal screening program or by clinical presentation. Phenylalanine plasma concentrations >120 µmol/L were reported for all subjects. Tetrahydrobiopterin (BH4) deficiency was excluded through a BH4 loading test, urinary pterin analysis, DHPR activity assay.",This variant was documented three times in Southern Chinese patients and 5 times in Northern Chinese patients with PAH deficiency (PMID: 26503515).,"This variant was documented three times in Southern Chinese patients and 5 times in Northern Chinese patients with PAH deficiency (PMID: 26503515). This variant was documented three times in Southern Chinese patients and 5 times in Northern Chinese patients with PAH deficiency (PMID: 26503515). It was not specified whether patient genotypes were homozygous or compound heterozygous for the variant. Subjects in this study were diagnosed through neonatal screening program or by clinical presentation. Phenylalanine plasma concentrations >120 µmol/L were reported for all subjects. Tetrahydrobiopterin (BH4) deficiency was excluded through a BH4 loading test, urinary pterin analysis, DHPR activity assay.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1012,NM_000277.3(PAH):c.379G>A (p.Glu127Lys),PAH,phenylketonuria,MONDO:0009861,Uncertain Significance,Autosomal recessive inheritance,Phenylketonuria,2019-11-10,PP4-Moderate,not_met,PubMed:26503515,,"Detected on 1 allele in a PKU patient. dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading was assessed. PMID: 26503515","Detected on 1 allele in a PKU patient. dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading was assessed. PMID: 26503515 ",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1265,NM_000277.2(PAH):c.301G>A (p.Asp101Asn),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2020-04-10,PP4-Moderate,not_met,PubMed:26503515,"A total of 796 unrelated patients from 29 separate newborn screening centres of China were enrolled. Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected. p.D101N (c.301G>A) was detected in 1 patient.",p.D101N (c.301G>A) was detected in 3 patients with PKU. BH4 deficiency assessed. PMID: 26503515,"p.D101N (c.301G>A) was detected in 3 patients with PKU. BH4 deficiency assessed. PMID: 26503515 A total of 796 unrelated patients from 29 separate newborn screening centres of China were enrolled. Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected. p.D101N (c.301G>A) was detected in 1 patient.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1285,NM_000277.3(PAH):c.799C>T (p.Gln267Ter),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2020-05-09,PP4-Moderate,not_met,PubMed:26322415,,The variant c.799C>T (p.Gln267Ter) was reported in a Chinese patient with classic PKU (Phe levels >20 mg/dl). All patients in this study had a blood phenylalanine concentration >2 mg/dl. BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes. (PMID: 26322415),The variant c.799C>T (p.Gln267Ter) was reported in a Chinese patient with classic PKU (Phe levels >20 mg/dl). All patients in this study had a blood phenylalanine concentration >2 mg/dl. BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes. (PMID: 26322415) ,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1689,NM_000277.3(PAH):c.190del (p.His64fs),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2020-10-30,PP4-Moderate,not_met,PubMed:23271928,,"Patient 25 of PMID: 23271928 is a PKU patient, with blood phenylalanine concentrations > 20 mg/dL. Urinary pterin analysis and blood neopterin dihydropteridine reductase assays were used to exclude tetrahydrobiopterin deficiency.","Patient 25 of PMID: 23271928 is a PKU patient, with blood phenylalanine concentrations > 20 mg/dL. Urinary pterin analysis and blood neopterin dihydropteridine reductase assays were used to exclude tetrahydrobiopterin deficiency. ",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
2303,NM_000277.2(PAH):c.1031G>A (p.Gly344Asp),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2021-06-11,PP4-Moderate,not_met,PubMed:26503515,"Seen in 2 individuals with PKU. Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected.","Seen in 2 individuals with PKU. Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected.  PMID: 26503515","Seen in 2 individuals with PKU. Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected.  PMID: 26503515 Seen in 2 individuals with PKU. Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
2641,NM_000277.1:c.1123C>G,PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2021-09-19,PP4-Moderate,not_met,PubMed:26503515,"Seen in 2 individuals with Classic PKU.  Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected.","Seen in 2 individuals with Classic PKU. Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected.  PMID: 26503515","Seen in 2 individuals with Classic PKU. Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected.  PMID: 26503515 Seen in 2 individuals with Classic PKU.  Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
2648,NM_000277.2(PAH):c.832A>G (p.Thr278Ala),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2021-09-24,PP4-Moderate,not_met,PubMed:26503515,"Seen in 4 individuals with PKU. Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected.","Seen in 4 individuals with PKU. Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected.  PMID: 26503515","Seen in 4 individuals with PKU. Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected.  PMID: 26503515 Seen in 4 individuals with PKU. Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
2716,NM_000277.1:c.668A>T,PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2021-10-10,PP4-Moderate,not_met,PubMed:26503515,796 PKU patients from mainland China diagnosed at birth either through a neonatal screening program or based on clinical presentation. N223I found on 2 alleles.,N223I found on 2 alleles of PKU patients. BH4 cofactor deficiency assessed. Upgraded per ClinGen PAHEP.  PMID: 30050108,N223I found on 2 alleles of PKU patients. BH4 cofactor deficiency assessed. Upgraded per ClinGen PAHEP.  PMID: 30050108 796 PKU patients from mainland China diagnosed at birth either through a neonatal screening program or based on clinical presentation. N223I found on 2 alleles.,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
3647,NM_001354304.2:c.920G>A,PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2022-06-12,PP4-Moderate,not_met,PubMed:26322415,BH4 defects excluded in all patients.  Single patient in this paper c.920G>A/C.331C>T (pathogenic) with mild PKU,BH4 defects excluded in all patients.  Single patient in this paper c.920G>A/C.331C>T (pathogenic) with mild PKU,BH4 defects excluded in all patients.  Single patient in this paper c.920G>A/C.331C>T (pathogenic) with mild PKU BH4 defects excluded in all patients.  Single patient in this paper c.920G>A/C.331C>T (pathogenic) with mild PKU,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
5673,NM_001354304.1:c.478C>T,PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2023-10-15,PP4-Moderate,not_met,PubMed:26322415,"165 PKU patients from China who had undergone a 24-h loading test with BH4 administration were recruited. All patients fulfilled the diagnostic criteria of PKU, with a blood phenylalanine concentration >2 mg/dl. BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes. Genotyping was performed by NGS. c.478C>T (p.Q160*) was detected on 1 allele in a patient with MHP (Phe levels<10 mg/dl).","Detected on 1 allele in a patient with Mild HP (Phe levels 2-10 mg/dl), BH4 deficiency was excluded.  PMID: 26322415","Detected on 1 allele in a patient with Mild HP (Phe levels 2-10 mg/dl), BH4 deficiency was excluded.  PMID: 26322415 165 PKU patients from China who had undergone a 24-h loading test with BH4 administration were recruited. All patients fulfilled the diagnostic criteria of PKU, with a blood phenylalanine concentration >2 mg/dl. BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes. Genotyping was performed by NGS. c.478C>T (p.Q160*) was detected on 1 allele in a patient with MHP (Phe levels<10 mg/dl).",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
5918,NM_000277.3(PAH):c.113_115TCT[1] (p.Phe39del),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2023-12-30,PP4-Moderate,not_met,PubMed:26503515,"This variant was documented twice in Northern Chinese and once in Southern Chinese PKU patients (PMID: 26503515). It was not specific whether the two alleles counted in Northern China were form a homozygous or compound heterozygous patient. Subjects in this study were diagnosed through neonatal screening program or by clinical presentation. Phenylalanine plasma concentrations >120 µmol/L were reported for all subjects. Tetrahydrobiopterin (BH4) deficiency was excluded through a BH4 loading test, urinary pterin analysis, DHPR activity assay.","This variant was documented twice in Northern Chinese patients and once in Southern Chinese patients with PAH deficiency (PMID: 26503515). Tetrahydrobiopterin (BH4) deficiency was excluded through a BH4 loading test, urinary pterin analysis, DHPR activity assay.","This variant was documented twice in Northern Chinese patients and once in Southern Chinese patients with PAH deficiency (PMID: 26503515). Tetrahydrobiopterin (BH4) deficiency was excluded through a BH4 loading test, urinary pterin analysis, DHPR activity assay. This variant was documented twice in Northern Chinese and once in Southern Chinese PKU patients (PMID: 26503515). It was not specific whether the two alleles counted in Northern China were form a homozygous or compound heterozygous patient. Subjects in this study were diagnosed through neonatal screening program or by clinical presentation. Phenylalanine plasma concentrations >120 µmol/L were reported for all subjects. Tetrahydrobiopterin (BH4) deficiency was excluded through a BH4 loading test, urinary pterin analysis, DHPR activity assay.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
5919,NM_000277.3:c.353-2A>T,PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2023-12-30,PP4-Moderate,not_met,PubMed:26322415,"c.353-2A>T identified in 1 patient with classic PKU. All patients fulfilled the diagnostic criteria of PKU, with a blood phenylalanine concentration >2 mg/dl. BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes.",c.353-2A>T identified in 1 patient with classic PKU. BH4 deficiency was excluded. PMID: 26322415,"c.353-2A>T identified in 1 patient with classic PKU. BH4 deficiency was excluded. PMID: 26322415 c.353-2A>T identified in 1 patient with classic PKU. All patients fulfilled the diagnostic criteria of PKU, with a blood phenylalanine concentration >2 mg/dl. BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
5929,NM_000277.1(PAH):c.964G>A (p.Ala322Thr),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2023-12-30,PP4-Moderate,not_met,PubMed:26322415,147 patients. A single patient with this variant c.964G>A (p.A322T) / c.331C>T (pR111X) (pathogenic) with mild hyperphenylalanemia (Phe <10mg/dL) Methods – All patients were picked up by NBS and BH4 defect was excluded in all patients with urine pterins and DHPR activity.,BH4 defect was excluded in all patients with urine pterins and DHPR activity.,BH4 defect was excluded in all patients with urine pterins and DHPR activity. 147 patients. A single patient with this variant c.964G>A (p.A322T) / c.331C>T (pR111X) (pathogenic) with mild hyperphenylalanemia (Phe <10mg/dL) Methods – All patients were picked up by NBS and BH4 defect was excluded in all patients with urine pterins and DHPR activity.,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
76,NM_000277.1(PAH):c.926C>T (p.Ala309Val),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-05,PM3,met,PubMed:26666653,"Genotype-phenotype association in French patients with PKU.  364 patients, 24hr BH4 loading test.","Single patient with classic PKU, c.842C>T (pathogenic in ClinVar) / c.926C>T","Single patient with classic PKU, c.842C>T (pathogenic in ClinVar) / c.926C>T Genotype-phenotype association in French patients with PKU.  364 patients, 24hr BH4 loading test.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
562,NM_000277.1:c.1285C>A,PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-06,PM3,met,PubMed:28982351,Patient 328 has genotype EX6-96A>G (VarID 590; P/LP)/p.Gln429Lys. Peripheral blood samples were collected from the patients and parents in each of the 643 core families.,Detected with EX6-96A>G (VarID 590; P/LP).,Detected with EX6-96A>G (VarID 590; P/LP). Patient 328 has genotype EX6-96A>G (VarID 590; P/LP)/p.Gln429Lys. Peripheral blood samples were collected from the patients and parents in each of the 643 core families.,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
592,NM_000277.2(PAH):c.164T>C (p.Phe55Ser),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-06,PM3,met,PubMed:26666653,Patient genotype: c. [164T>C]; [1066-11G>A].,"Detected with c.1066-11G>A, PMID: 26666653","Detected with c.1066-11G>A, PMID: 26666653 Patient genotype: c. [164T>C]; [1066-11G>A].",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
597,NM_000277.2(PAH):c.812A>G (p.His271Arg),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-06,PM3,met,PubMed:26666653,Patient genotype: [His271Arg]; [Arg408Trp].,"Detected with R408W,  PMID: 26666653","Detected with R408W,  PMID: 26666653 Patient genotype: [His271Arg]; [Arg408Trp].",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
625,NM_000277.2(PAH):c.785T>G (p.Val262Gly),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-05,PM3,met,PubMed:26666653,"c. [117C > G]; [785 T > G]/p. [Phe39Leu];[Val262Gly]. F39L, VarID 605, Pathogenic","V262G detected with F39L,  PMID: 26666653","V262G detected with F39L,  PMID: 26666653 c. [117C > G]; [785 T > G]/p. [Phe39Leu];[Val262Gly]. F39L, VarID 605, Pathogenic",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
671,NM_000277.2(PAH):c.493G>C (p.Ala165Pro),PAH,phenylketonuria,MONDO:0009861,Uncertain Significance,Autosomal recessive inheritance,Phenylketonuria,2019-04-07,PM3,not_met,PubMed:26666653,Patient genotype: c. [493G > C]; [1169A > G] p. [Ala165Pro]; [Glu390Gly] (P/LP by 10 submitters). Phasing not determined/reported.,"Detected with p.Glu390Gly (P/LP by 10 submitters), but phasing not determined/reported.","Detected with p.Glu390Gly (P/LP by 10 submitters), but phasing not determined/reported. Patient genotype: c. [493G > C]; [1169A > G] p. [Ala165Pro]; [Glu390Gly] (P/LP by 10 submitters). Phasing not determined/reported.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
674,NM_000277.2(PAH):c.521T>C (p.Ile174Thr),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-08,PM3,met,PubMed:23842451,"patient genotype: p.I174T/p.F299C (P/LP, 6 submitters)","detected with p.F299C (P/LP, 6 submitters) 23842451","detected with p.F299C (P/LP, 6 submitters) 23842451 patient genotype: p.I174T/p.F299C (P/LP, 6 submitters)",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
675,NM_000277.2(PAH):c.523C>T (p.Pro175Ser),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-08,PM3,met,PubMed:26322415,"Patient genotype: c.[523C>T ];[1238G>C], p.[P175S];[R413P]. All mutations identified in patients were confirmed by analyzing parental DNA. When mutation loci were detected in patients, the same locus of the parental sample was amplified by PCR and analyzed by Sanger automated sequencing.","detected in trans with p.R413P (P, 6 submitters)  PMID: 26322415","detected in trans with p.R413P (P, 6 submitters)  PMID: 26322415 Patient genotype: c.[523C>T ];[1238G>C], p.[P175S];[R413P]. All mutations identified in patients were confirmed by analyzing parental DNA. When mutation loci were detected in patients, the same locus of the parental sample was amplified by PCR and analyzed by Sanger automated sequencing.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
676,NM_000277.2(PAH):c.143T>C (p.Leu48Ser),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-08,PM3,met,PubMed:26322415,"Patient genotype: c.[143T>C];[739G>C], p.[L48S];[G247R] (LP, 2 submitters). All mutations identified in patients were confirmed by analyzing parental DNA. When mutation loci were detected in patients, the same locus of the parental sample was amplified by PCR and analyzed by Sanger automated sequencing.","detected in trans with p.G247R (LP, 2 submitters)  PMID: 26322415","detected in trans with p.G247R (LP, 2 submitters)  PMID: 26322415 Patient genotype: c.[143T>C];[739G>C], p.[L48S];[G247R] (LP, 2 submitters). All mutations identified in patients were confirmed by analyzing parental DNA. When mutation loci were detected in patients, the same locus of the parental sample was amplified by PCR and analyzed by Sanger automated sequencing.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1010,NM_000277.2(PAH):c.913-8A>G,PAH,phenylketonuria,MONDO:0009861,Uncertain Significance,Autosomal recessive inheritance,Phenylketonuria,2019-11-08,PM3,met,PubMed:26666653,"The c.913-8A>G intronic variant has been observed in trans with the previously assessed pathogenic variant c.1315+1G>A (ClinVar 576, Pathogenic).","The c.913-8A>G intronic variant has been observed in trans with the previously assessed pathogenic variant c.1315+1G>A (ClinVar 576, Pathogenic).","The c.913-8A>G intronic variant has been observed in trans with the previously assessed pathogenic variant c.1315+1G>A (ClinVar 576, Pathogenic). The c.913-8A>G intronic variant has been observed in trans with the previously assessed pathogenic variant c.1315+1G>A (ClinVar 576, Pathogenic).",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1505,NM_000277.1(PAH):c.1180G>T (p.Asp394Tyr),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2020-07-10,PM3,met,PubMed:26666653,"Asp394Tyr seen with 1066-3C > T in 1 PKU patient and Thr380Met (VarID 628, Pathogenic/Likely Pathogenic in ClinVar) in a 2nd patient.",Detected with T380M (P 11 submitters) and 1066-3C > T (P 3 submitters) parental analysis not performed,"Detected with T380M (P 11 submitters) and 1066-3C > T (P 3 submitters) parental analysis not performed Asp394Tyr seen with 1066-3C > T in 1 PKU patient and Thr380Met (VarID 628, Pathogenic/Likely Pathogenic in ClinVar) in a 2nd patient.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
5673,NM_001354304.1:c.478C>T,PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2023-10-15,PM3,met,PubMed:26322415,Patient genotype: p.R241C;Q160*. All mutations identified in patients were confirmed by analyzing parental DNA.,Detected in trans with p.R241C (pathogenic in ClinVar),Detected in trans with p.R241C (pathogenic in ClinVar) Patient genotype: p.R241C;Q160*. All mutations identified in patients were confirmed by analyzing parental DNA.,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
5919,NM_000277.3:c.353-2A>T,PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2023-12-30,PM3,met,PubMed:26322415,"c.[353-2A>T ];[331C>T ], p.[(?)];[R111*]. All mutations identified in patients were confirmed by analyzing parental DNA. When mutation loci were detected in patients, the same locus of the parental sample was amplified by PCR and analyzed by Sanger automated sequencing.",detected in trans with p.R111*  PMID: 26322415,"detected in trans with p.R111*  PMID: 26322415 c.[353-2A>T ];[331C>T ], p.[(?)];[R111*]. All mutations identified in patients were confirmed by analyzing parental DNA. When mutation loci were detected in patients, the same locus of the parental sample was amplified by PCR and analyzed by Sanger automated sequencing.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
688,NM_000277.2(PAH):c.504C>A (p.Tyr168Ter),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-05-26,PM3-Supporting,not_met,PubMed:26666653,"The proband was said to be heterozygous for the variant and also harbor the known pathogenic allele (per ClinGen PAH working group classification, see ClinVar ID 92751) c. 898G > T (p.Ala300Ser) variant; however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing.","Detected with c.898G>T (p.Ala300Ser), however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing.","Detected with c.898G>T (p.Ala300Ser), however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. The proband was said to be heterozygous for the variant and also harbor the known pathogenic allele (per ClinGen PAH working group classification, see ClinVar ID 92751) c. 898G > T (p.Ala300Ser) variant; however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
715,NM_000277.2(PAH):c.887A>G (p.Asp296Gly),PAH,phenylketonuria,MONDO:0009861,Uncertain Significance,Autosomal recessive inheritance,Phenylketonuria,2019-07-14,PM3-Supporting,not_met,PubMed:26666653,"detected with the pathogenic variant c.1222C > T (p.Arg408Trp). Although the paper said that parental samples were collected in the study, it did not explicitly state whether the phase of the variants was confirmed via parental testing.","detected with the pathogenic variant (per ClinGen PAH Working Group – see ClinVar variant ID 577) c.1222C > T (p.Arg408Trp). Although the paper said that parental samples were collected in the study, it did not explicitly state whether the phase of the variants was confirmed via parental testing. Thus, PM3 is downgraded to supporting.","detected with the pathogenic variant (per ClinGen PAH Working Group – see ClinVar variant ID 577) c.1222C > T (p.Arg408Trp). Although the paper said that parental samples were collected in the study, it did not explicitly state whether the phase of the variants was confirmed via parental testing. Thus, PM3 is downgraded to supporting. detected with the pathogenic variant c.1222C > T (p.Arg408Trp). Although the paper said that parental samples were collected in the study, it did not explicitly state whether the phase of the variants was confirmed via parental testing.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
717,NM_000277.2(PAH):c.931_932delCT (p.Leu311Glyfs),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-07-14,PM3-Supporting,not_met,PubMed:26666653,"The c.931_932del frameshift variant was observed in trans with the pathogenic variant Arg241Cys (ClinVar 102803, Pathogenic). Parental testing was not performed.",," The c.931_932del frameshift variant was observed in trans with the pathogenic variant Arg241Cys (ClinVar 102803, Pathogenic). Parental testing was not performed.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1287,NM_000277.3(PAH):c.707-1G>A,PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2020-05-09,PM3-Supporting,not_met,PubMed:28754886,,"The PAH variant c.707-1G>A (IVS6-1G>A) was detected in two Chinese patients with classic PKU (cPKU Phe more than 1200 μmol/L). These two patients were identified with another pathogenic variant in the PAH gene:
c.1285C>A (p.Gln429Lys) (ClinVar ID: 551555) Likely Pathogenic (1*0.25=0.25)
c.526C>T (p.Arg176Ter) (ClinVar ID: 102723) Pathogenic (PMID: 28754886) (1*0.5=0.5)","The PAH variant c.707-1G>A (IVS6-1G>A) was detected in two Chinese patients with classic PKU (cPKU Phe more than 1200 μmol/L). These two patients were identified with another pathogenic variant in the PAH gene:
c.1285C>A (p.Gln429Lys) (ClinVar ID: 551555) Likely Pathogenic (1*0.25=0.25)
c.526C>T (p.Arg176Ter) (ClinVar ID: 102723) Pathogenic (PMID: 28754886) (1*0.5=0.5) ",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1495,NM_000277.2(PAH):c.682G>A (p.Glu228Lys),PAH,phenylketonuria,MONDO:0009861,Uncertain Significance,Autosomal recessive inheritance,Phenylketonuria,2020-06-26,PM3-Supporting,not_met,PubMed:26666653,Seen in 1 patient with c.1066-11G>A (pathogenic in ClinVar),Seen with c.1066-11G>A (pathogenic in ClinVar) parental analysis not performed  PMID: 26666653,Seen with c.1066-11G>A (pathogenic in ClinVar) parental analysis not performed  PMID: 26666653 Seen in 1 patient with c.1066-11G>A (pathogenic in ClinVar),ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
5921,NM_000277.1:c.510-19_667del,PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2023-12-30,PM3-Supporting,not_met,PubMed:23842451,"Patient genotype: c.510-21_665del/G272* (VarID 596, Pathogenic)","Detected with G272*, Pathogenic in ClinVar. Parental confirmation not reported.","Detected with G272*, Pathogenic in ClinVar. Parental confirmation not reported. Patient genotype: c.510-21_665del/G272* (VarID 596, Pathogenic)",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1511,NM_000277.3(PAH):c.204A>T (p.Arg68Ser),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2020-07-24,PM3-Very Strong,not_met,PubMed:26666653,,"Detected in trans with several pathogenic variants including p.Ala300Ser, Asp415Asn , Arg158Gln, and c.1315+1G>A. Additionally, found homozygous (p.[Arg68Ser];[Arg68Ser] (n=2) )with mild HPA. Segregation analysis was done in PMID 27121329. Segregation analysis was also in PMID 22841515.","Detected in trans with several pathogenic variants including p.Ala300Ser, Asp415Asn , Arg158Gln, and c.1315+1G>A. Additionally, found homozygous (p.[Arg68Ser];[Arg68Ser] (n=2) )with mild HPA. Segregation analysis was done in PMID 27121329. Segregation analysis was also in PMID 22841515. ",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
5917,NM_000277.1(PAH):c.466G>C (p.Ala156Pro),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2023-12-30,PM3-Very Strong,not_met,PubMed:26322415,"PMID 26322415: listed p.[A156P];[H220P] in one patient with classic PKU (Phe levels >20mg/dl). All patients fulfilled the diagnostic criteria of PKU, with a blood phenylalanine concentration >2mg/dl. BH4 deficiency was excluded byanalysis of urinary pterins and dihydropteridine reductase activity in erythrocytes.","PMID 26322415: detected with p.[H220P] (not in ClinVar, LP by PAH VCEP) All mutations identified in patients were confirmed by analyzing parental DNA. When mutation loci were detected in patients, the same locus of the parental sample was amplified by PCR and analyzed by Sanger automated sequencing. Detected with c.611A>G (EX6-96A>G, P-6 submitters), parental analysis performed.  PMID: 26600521 	p.A156P/p.V5Sfs*33 (P-1), p.R158W (P-4)/p.A156P, p.R241C (P-8)/p.A156P (2 patients), p.R261Q (P-9)/p.A156P, p.A156P/p.R400T (P-1), p.A156P/p.T418P (P-1) The validation tests on parents were performed using Sanger sequencing.  PMID: 30050108 Detected with p.R408Q parental analysis not reported PMID: 25894915","PMID 26322415: detected with p.[H220P] (not in ClinVar, LP by PAH VCEP) All mutations identified in patients were confirmed by analyzing parental DNA. When mutation loci were detected in patients, the same locus of the parental sample was amplified by PCR and analyzed by Sanger automated sequencing. Detected with c.611A>G (EX6-96A>G, P-6 submitters), parental analysis performed.  PMID: 26600521 	p.A156P/p.V5Sfs*33 (P-1), p.R158W (P-4)/p.A156P, p.R241C (P-8)/p.A156P (2 patients), p.R261Q (P-9)/p.A156P, p.A156P/p.R400T (P-1), p.A156P/p.T418P (P-1) The validation tests on parents were performed using Sanger sequencing.  PMID: 30050108 Detected with p.R408Q parental analysis not reported PMID: 25894915 PMID 26322415: listed p.[A156P];[H220P] in one patient with classic PKU (Phe levels >20mg/dl). All patients fulfilled the diagnostic criteria of PKU, with a blood phenylalanine concentration >2mg/dl. BH4 deficiency was excluded byanalysis of urinary pterins and dihydropteridine reductase activity in erythrocytes.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
5929,NM_000277.1(PAH):c.964G>A (p.Ala322Thr),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2023-12-30,PM3-Very Strong,not_met,PubMed:26322415,"147 patients.  A single patient with this variant c.964G>A (p.A322T) / c.331C>T (pR111X) (pathogenic) with mild hyperphenylalanemia (Phe <10mg/dL)
Methods – All patients were picked up by NBS and BH4 defect was excluded in all patients with urine pterins and DHPR activity.","The variant has been previously noted in at least four PKU patients among whom BH4 deficiency was excluded, including in trans with Pathogenic or Likely Pathogenic alleles (PM3_VeryStrong (4 points); PP4_Moderate). The variant has been previously reported in a Chinese patient with mild hyperphenylalanemia in trans with the p.R111* variant (Pathogenic in ClinVar and by the ClinGen PAH VCEP); BH4 deficiency was excluded via analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PMID: 30050108; PMID: 26322415). It has been noted in a Spanish patient with mild hyperphenylalanemia in trans with the p.S349P variant (Pathogenic in ClinVar and by the ClinGen PAH VCEP); BH4 deficiency was excluded analyzing urinary pterin levels as well as by measuring the dihydropteridine reductase activity (PMID: 27121329). It was found in a Slovak patient with mild hyperphenylalanemia in trans with the p.A403V variant (Pathogenic in ClinVar and by the ClinGen PAH VCEP); BH4 deficiency was excluded (PMID: 23764561). It has been noted in a Chinese patient with PKU (plasma Phe >120 umol/L; no further specification) and BH4 deficiency excluded in trans with p.R176* (Pathogenic in ClinVar and by the ClinGen PAH VCEP) (PMID: 26600521).","The variant has been previously noted in at least four PKU patients among whom BH4 deficiency was excluded, including in trans with Pathogenic or Likely Pathogenic alleles (PM3_VeryStrong (4 points); PP4_Moderate). The variant has been previously reported in a Chinese patient with mild hyperphenylalanemia in trans with the p.R111* variant (Pathogenic in ClinVar and by the ClinGen PAH VCEP); BH4 deficiency was excluded via analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PMID: 30050108; PMID: 26322415). It has been noted in a Spanish patient with mild hyperphenylalanemia in trans with the p.S349P variant (Pathogenic in ClinVar and by the ClinGen PAH VCEP); BH4 deficiency was excluded analyzing urinary pterin levels as well as by measuring the dihydropteridine reductase activity (PMID: 27121329). It was found in a Slovak patient with mild hyperphenylalanemia in trans with the p.A403V variant (Pathogenic in ClinVar and by the ClinGen PAH VCEP); BH4 deficiency was excluded (PMID: 23764561). It has been noted in a Chinese patient with PKU (plasma Phe >120 umol/L; no further specification) and BH4 deficiency excluded in trans with p.R176* (Pathogenic in ClinVar and by the ClinGen PAH VCEP) (PMID: 26600521). 147 patients.  A single patient with this variant c.964G>A (p.A322T) / c.331C>T (pR111X) (pathogenic) with mild hyperphenylalanemia (Phe <10mg/dL)
Methods – All patients were picked up by NBS and BH4 defect was excluded in all patients with urine pterins and DHPR activity.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1610,NM_000277.3(PAH):c.1194A>G (p.Lys398=),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2020-09-12,PM3-Strong,not_met,PubMed:28982351,,Two compound heterozygotes have been reported (PMID: 28982351 and PMID: 25894915) with pathogenic variants R413P and R241C confirmed in trans.,Two compound heterozygotes have been reported (PMID: 28982351 and PMID: 25894915) with pathogenic variants R413P and R241C confirmed in trans. ,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
3151,NM_000277.2(PAH):c.699C>A (p.Phe233Leu),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2022-02-20,PM3-Strong,not_met,PubMed:24705691,"Patient 11 Genotype: c.699C>A, F233L (maternally inherited)/ p.S70del (paternally inherited)","Detected in trans with S70del (Pathogenic in ClinVar).  PMID: 24705691; p.Ala403Val (P), p.Arg243Gln (P) with p.Phe233Leu (c.699C>A). variable sites in patient genes were aligned with the corresponding sites from the respective parents.  PMID: 29316886 3.0 pts","Detected in trans with S70del (Pathogenic in ClinVar).  PMID: 24705691; p.Ala403Val (P), p.Arg243Gln (P) with p.Phe233Leu (c.699C>A). variable sites in patient genes were aligned with the corresponding sites from the respective parents.  PMID: 29316886 3.0 pts Patient 11 Genotype: c.699C>A, F233L (maternally inherited)/ p.S70del (paternally inherited)",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
670,NM_000277.2(PAH):c.493G>A (p.Ala165Thr),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-07,PP1,met,PubMed:26666653,c.493G>A]; [493G>A] genotype was observed in two cPKU siblings. The one tested between 3 and 10 years of age showed no decrease in Phe concentration (H0 384 μmol/L) while the one tested in the neonatal period showed a 36% decrease (H0 1680 μmol/L) but is not currently under BH4 treatment.,c.493G>A;493G>A genotype was observed in two cPKU siblings  PMID: 26666653,c.493G>A;493G>A genotype was observed in two cPKU siblings  PMID: 26666653 c.493G>A]; [493G>A] genotype was observed in two cPKU siblings. The one tested between 3 and 10 years of age showed no decrease in Phe concentration (H0 384 μmol/L) while the one tested in the neonatal period showed a 36% decrease (H0 1680 μmol/L) but is not currently under BH4 treatment.,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
7865,NM_000277.1:c.686A>G,PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2024-09-06,PS3-Supporting,not_met,PubMed:31208052,"The p.Asn167Tyr, p.Thr200Asn, p.Asp229Gly, p.Gly239Ala, p.Phe263Ser, p.Ala342Pro, and p.Ile406Met PAH variants were expressed in prokaryotic and eukaryotic expression systems and assayed in vitro to investigate their specific activity, oligomeric pattern, and the mutant PAH protein stability in the presence of sepiapterin, which is the BH4 precursor, as well as GroEL/ES bacterial chaperones. p.Asp229Gly had 0% residual activity as compared to WT PAH activity and was calculated as a mean of nine independent functional assays. Western blot analysis revealed decreased protein levels of each tested PAH mutant cultivated under both conditions compared to WT PAH. The overall results were calculated from three independent Western blot analyses performed from three independent PAH expressions in HepG2 cells.",p.Asp229Gly had 0% residual activity as compared to WT PAH activity and was calculated as a mean of nine independent functional assays. Western blot analysis revealed decreased protein levels of each tested PAH mutant cultivated under both conditions compared to WT PAH. The overall results were calculated from three independent Western blot analyses performed from three independent PAH expressions in HepG2 cells.  PMID: 31208052,"p.Asp229Gly had 0% residual activity as compared to WT PAH activity and was calculated as a mean of nine independent functional assays. Western blot analysis revealed decreased protein levels of each tested PAH mutant cultivated under both conditions compared to WT PAH. The overall results were calculated from three independent Western blot analyses performed from three independent PAH expressions in HepG2 cells.  PMID: 31208052 The p.Asn167Tyr, p.Thr200Asn, p.Asp229Gly, p.Gly239Ala, p.Phe263Ser, p.Ala342Pro, and p.Ile406Met PAH variants were expressed in prokaryotic and eukaryotic expression systems and assayed in vitro to investigate their specific activity, oligomeric pattern, and the mutant PAH protein stability in the presence of sepiapterin, which is the BH4 precursor, as well as GroEL/ES bacterial chaperones. p.Asp229Gly had 0% residual activity as compared to WT PAH activity and was calculated as a mean of nine independent functional assays. Western blot analysis revealed decreased protein levels of each tested PAH mutant cultivated under both conditions compared to WT PAH. The overall results were calculated from three independent Western blot analyses performed from three independent PAH expressions in HepG2 cells.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
143,NM_206933.2(USH2A):c.12295-?_14133+?del,USH2A,Usher syndrome,MONDO:0019501,Likely Pathogenic,Autosomal recessive inheritance,Hearing Loss,2023-10-05,PM3,met,PubMed:26969326,"1 proband compound het with c.2276G>T, p.Cys759Phe. Unsure of phase.","3 LMM probands:
1 homozygote with Usher (0.5 points)
1 cmp het (VUS phase unknown) with hearing loss and light sensitivity (teens, 0.25 points)
1 cmp het (p.Tyr3747X, phase unknown) with hearing loss (<5 years old, 0.5 points)","3 LMM probands:
1 homozygote with Usher (0.5 points)
1 cmp het (VUS phase unknown) with hearing loss and light sensitivity (teens, 0.25 points)
1 cmp het (p.Tyr3747X, phase unknown) with hearing loss (<5 years old, 0.5 points) 1 proband compound het with c.2276G>T, p.Cys759Phe. Unsure of phase.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
733,NM_005422.2(TECTA):c.2061C>G (p.Asn687Lys),TECTA,nonsyndromic genetic deafness,MONDO:0019497,Likely Benign,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PM3,not_met,PubMed:30675382,,The p.Asn687Lys variant was identified in the homozygous state in an individual with Asperger syndrome who is hypersensitive to sound.,The p.Asn687Lys variant was identified in the homozygous state in an individual with Asperger syndrome who is hypersensitive to sound. ,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
745,NM_004004.5(GJB2):c.109G>A (p.Val37Ile),GJB2,nonsyndromic genetic deafness,MONDO:0019497,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PM3,met,PubMed:31160754,>120 compound hets with the p.V37I variant,"Shen et al 2019 demonstrated in the combined analysis of at least 10 clinical sites that there were >120 compound heterozygotes with the p.Val37Ile variant. However, because the variant is also very frequent in the general population, the HL group decided to only apply this criteria at the usual strength of Moderate.","Shen et al 2019 demonstrated in the combined analysis of at least 10 clinical sites that there were >120 compound heterozygotes with the p.Val37Ile variant. However, because the variant is also very frequent in the general population, the HL group decided to only apply this criteria at the usual strength of Moderate. >120 compound hets with the p.V37I variant","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
639,NM_000441.1(SLC26A4):c.919-2A>G,SLC26A4,Pendred syndrome,MONDO:0010134,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,BP2,not_met,PubMed:23151025,Retrospective review of 1065 Chinese probands with moderate-to-profound bilateral sensorineural hearing loss found 53 homozygous and 80 heterozygous for the c.919-2A>G variant. 16 individuals were compound het. for the pathogenic p.H723R variant in SLC26A4.,, Retrospective review of 1065 Chinese probands with moderate-to-profound bilateral sensorineural hearing loss found 53 homozygous and 80 heterozygous for the c.919-2A>G variant. 16 individuals were compound het. for the pathogenic p.H723R variant in SLC26A4.,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
707,NM_004004.5(GJB2):c.101T>C (p.Met34Thr),GJB2,nonsyndromic genetic deafness,MONDO:0019497,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-06-28,BP2,not_met,PubMed:31160754,"This study showed that the p.Met34Thr variant occurred in 27 homozygous probands, 17 times in trans with the p.Val37Ile variant, 138 times in trans with a P/LP variant and 78 times in trans with a premature termination codon in GJB2. This more than maxes out the PM3_VS points.",," This study showed that the p.Met34Thr variant occurred in 27 homozygous probands, 17 times in trans with the p.Val37Ile variant, 138 times in trans with a P/LP variant and 78 times in trans with a premature termination codon in GJB2. This more than maxes out the PM3_VS points.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
732,NM_005422.2(TECTA):c.3097C>T (p.Arg1033Trp),TECTA,nonsyndromic genetic deafness,MONDO:0019497,Likely Benign,Autosomal dominant inheritance,Hearing Loss,2019-07-17,BP2,not_met,PubMed:26969326,"Patient 369 carries the p.Arg1033Trp variant in heterozygosity, as well as a heterozygous c.701A>G p.Gln234Arg TECTA variant. The p.Gln234Arg variant is present in 112/24924 (0.45%) African alleles in gnomad and has been classified as likely benign by the HL VCEP. This patient has sporadic, mild-moderate, symmetric, childhood onset hearing loss.",," Patient 369 carries the p.Arg1033Trp variant in heterozygosity, as well as a heterozygous c.701A>G p.Gln234Arg TECTA variant. The p.Gln234Arg variant is present in 112/24924 (0.45%) African alleles in gnomad and has been classified as likely benign by the HL VCEP. This patient has sporadic, mild-moderate, symmetric, childhood onset hearing loss.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
650,NM_000441.2(SLC26A4):c.706C>G (p.Leu236Val),SLC26A4,Pendred syndrome,MONDO:0010134,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2025-01-06,PM3-Very Strong,not_met,PubMed:25991456,"No other pathogenic variant identified in patient. Patient had bilateral SNHL w/ “atypical phenotype"""," This variant has been detected in 3 probands in trans with a pathogenic variant, in 5 probands in phase unknown with a pathogenic variant, and in the homozygous state in 3 probands, all of whom had hearing loss and/or inner ear malformations consistent with Pendred syndrome. The variant was also identified with a pathogenic splice site variant in 2 probands (Partners Laboratory for Molecular Medicine internal data ClinVar SCV000060159.5, ARUP internal data ClinVar SCV000605149.1, Chinese PLA General Hospital internal data, Molecular Otolaryngology and Renal Research Laboratories internal data, Revvity internal data ClinVar SCV002023538.3, GeneDx internal data ClinVar SCV001783711.3, Invitae internal data ClinVar SCV002234501.3). This variant was seen in two probands with no second variant identified whose phenotypes were consistent with Pendred syndrome (PMID: 34410491, 34515852), as well as in one proband with enlarged vestibular aqueduct who was compound heterozygous with a likely pathogenic variant in phase unknown (PMID: 36703223)."," This variant has been detected in 3 probands in trans with a pathogenic variant, in 5 probands in phase unknown with a pathogenic variant, and in the homozygous state in 3 probands, all of whom had hearing loss and/or inner ear malformations consistent with Pendred syndrome. The variant was also identified with a pathogenic splice site variant in 2 probands (Partners Laboratory for Molecular Medicine internal data ClinVar SCV000060159.5, ARUP internal data ClinVar SCV000605149.1, Chinese PLA General Hospital internal data, Molecular Otolaryngology and Renal Research Laboratories internal data, Revvity internal data ClinVar SCV002023538.3, GeneDx internal data ClinVar SCV001783711.3, Invitae internal data ClinVar SCV002234501.3). This variant was seen in two probands with no second variant identified whose phenotypes were consistent with Pendred syndrome (PMID: 34410491, 34515852), as well as in one proband with enlarged vestibular aqueduct who was compound heterozygous with a likely pathogenic variant in phase unknown (PMID: 36703223). No other pathogenic variant identified in patient. Patient had bilateral SNHL w/ “atypical phenotype""","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
707,NM_004004.5(GJB2):c.101T>C (p.Met34Thr),GJB2,nonsyndromic genetic deafness,MONDO:0019497,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-06-28,PM3-Very Strong,not_met,PubMed:31160754,"This study showed that the p.Met34Thr variant occurred in 27 homozygous probands, 17 times in trans with the p.Val37Ile variant, 138 times in trans with a P/LP variant and 78 times in trans with a premature termination codon in GJB2. This more than maxes out the PM3_VS points.","This study showed that the p.Met34Thr variant occurred in 27 homozygous probands, 17 times in trans with the p.Val37Ile variant, 138 times in trans with a P/LP variant and 78 times in trans with a premature termination codon in GJB2. This more than maxes out the PM3_VS points. PMID 31160754","This study showed that the p.Met34Thr variant occurred in 27 homozygous probands, 17 times in trans with the p.Val37Ile variant, 138 times in trans with a P/LP variant and 78 times in trans with a premature termination codon in GJB2. This more than maxes out the PM3_VS points. PMID 31160754 This study showed that the p.Met34Thr variant occurred in 27 homozygous probands, 17 times in trans with the p.Val37Ile variant, 138 times in trans with a P/LP variant and 78 times in trans with a premature termination codon in GJB2. This more than maxes out the PM3_VS points.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
649,NM_206933.2(USH2A):c.8559-2A>G,USH2A,Usher syndrome,MONDO:0019501,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,BS4,not_met,PubMed:19023448,"2 Usher affected families:

F4:  2 individuals having a p.R34fs frameshift variant in trans with the splice variant. There were 4 unaffected sibs (2 het for p.R34fs, 2 WT/WT).

F3: Variant was inherited in trans with a p.T3936P variant in USH2A in other family. This individual has an unaffected sib with only the p.T3936P variant and experienced HL onset at age 10 while other individuals had congenital HL.",," 2 Usher affected families:

F4:  2 individuals having a p.R34fs frameshift variant in trans with the splice variant. There were 4 unaffected sibs (2 het for p.R34fs, 2 WT/WT).

F3: Variant was inherited in trans with a p.T3936P variant in USH2A in other family. This individual has an unaffected sib with only the p.T3936P variant and experienced HL onset at age 10 while other individuals had congenital HL.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
745,NM_004004.5(GJB2):c.109G>A (p.Val37Ile),GJB2,nonsyndromic genetic deafness,MONDO:0019497,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,BS4,not_met,PubMed:31160754,,"Although homozygous or compound heterozygous observations have been identified in hearing individuals, it has been suggested that individuals with the p.Val37Ile variant lose hearing at ~1dB/year, suggesting an age-related penetrance. Therefore, BS4 is not met.","Although homozygous or compound heterozygous observations have been identified in hearing individuals, it has been suggested that individuals with the p.Val37Ile variant lose hearing at ~1dB/year, suggesting an age-related penetrance. Therefore, BS4 is not met. ","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
745,NM_004004.5(GJB2):c.109G>A (p.Val37Ile),GJB2,nonsyndromic genetic deafness,MONDO:0019497,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PS4,met,PubMed:31160754,This is the case-control paper from the HL VCEP that demonstrates significant enrichment of V37I in patients compared to controls.,A case-control comparison was done by the HL group that demonstrated that this variant is highly enriched in cases v controls. For homozygotes the OR is 20 and the p value is <0.0001,A case-control comparison was done by the HL group that demonstrated that this variant is highly enriched in cases v controls. For homozygotes the OR is 20 and the p value is <0.0001 This is the case-control paper from the HL VCEP that demonstrates significant enrichment of V37I in patients compared to controls.,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
968,NM_004004.5(GJB2):c.516G>C (p.Trp172Cys),GJB2,nonsyndromic genetic deafness,MONDO:0019497,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-10-17,PS4,met,PubMed:31195736,"220 Tuvinians (Southern Siberia, Russia) with hearing loss were tested for variants in GJB2. The p.Trp172Cys accounted for 62.9% of all mutant GJB2 alleles. It was present in 25 homozygous individuals, 7 compound heterozygous individuals (with c.-23+1G>A, and in 9 heterozygotes. This variant was not found to be biallelic in any of the 157 ethnically-matched controls, but it was observed in 6 carriers.","A 2x2 conttingency analysis of total variant alleles in cases v controls was performed. The variant is present in 66/440 case alleles and 6/314 control alleles. With a fisher exact test, the p value is <0.0001. which is highly significant.","A 2x2 conttingency analysis of total variant alleles in cases v controls was performed. The variant is present in 66/440 case alleles and 6/314 control alleles. With a fisher exact test, the p value is <0.0001. which is highly significant. 220 Tuvinians (Southern Siberia, Russia) with hearing loss were tested for variants in GJB2. The p.Trp172Cys accounted for 62.9% of all mutant GJB2 alleles. It was present in 25 homozygous individuals, 7 compound heterozygous individuals (with c.-23+1G>A, and in 9 heterozygotes. This variant was not found to be biallelic in any of the 157 ethnically-matched controls, but it was observed in 6 carriers.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
649,NM_206933.2(USH2A):c.8559-2A>G,USH2A,Usher syndrome,MONDO:0019501,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PP1-Strong,not_met,PubMed:19023448,"2 Usher affected families:

F4:  2 individuals having a p.R34fs frameshift variant in trans with the splice variant. There were 4 unaffected sibs (2 het for p.R34fs, 2 WT/WT).

F3: Variant was inherited in trans with a p.T3936P variant in USH2A in other family. This individual has an unaffected sib with only the p.T3936P variant and experienced HL onset at age 10 while other individuals had congenital HL.","Dai et al. 2008 is the only paper with genotyping data for family members. They have a total of 6 unaffected sibs across 2 families and 3 affected individuals with the variant between the two families. (Figure 1) This would actually be 1 affected segregation and 5 unaffected segregations, LOD = 0.75

The variant has been reported in two probands with Usher syndrome. In one family, the variant was identified in trans with a frameshift variant in two affected siblings, and four unaffected siblings were either heterozygous for a single variant or wild-type for both variants. In the second family, an unaffected sibling was heterozygous for a single variant (PP1_Strong, PMID: 19023448).","Dai et al. 2008 is the only paper with genotyping data for family members. They have a total of 6 unaffected sibs across 2 families and 3 affected individuals with the variant between the two families. (Figure 1) This would actually be 1 affected segregation and 5 unaffected segregations, LOD = 0.75

The variant has been reported in two probands with Usher syndrome. In one family, the variant was identified in trans with a frameshift variant in two affected siblings, and four unaffected siblings were either heterozygous for a single variant or wild-type for both variants. In the second family, an unaffected sibling was heterozygous for a single variant (PP1_Strong, PMID: 19023448). 2 Usher affected families:

F4:  2 individuals having a p.R34fs frameshift variant in trans with the splice variant. There were 4 unaffected sibs (2 het for p.R34fs, 2 WT/WT).

F3: Variant was inherited in trans with a p.T3936P variant in USH2A in other family. This individual has an unaffected sib with only the p.T3936P variant and experienced HL onset at age 10 while other individuals had congenital HL.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
643,NM_206933.2(USH2A):c.5581G>A (p.Gly1861Ser),USH2A,Usher syndrome,MONDO:0019501,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PP1,met,PubMed:26310143,This is a case report of a Chinese family with pseudo-dominant Usher syndrome. The proband is compound het for p.Gly1861Ser and p.C934W. There is also an affected brother who has this genotype.,The proband and 1 affected sib carry this variant.,The proband and 1 affected sib carry this variant. This is a case report of a Chinese family with pseudo-dominant Usher syndrome. The proband is compound het for p.Gly1861Ser and p.C934W. There is also an affected brother who has this genotype.,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
647,NM_206933.2(USH2A):c.4510dupA (p.Arg1504Lysfs),USH2A,Usher syndrome,MONDO:0019501,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PM3-Strong,not_met,PubMed:22135276,"Total: 3 Path variants in trans. The variant was detected in a proband from a UK study with Usher type 2 in trans with the p.Trp2744X variant. The variant was also identified in two more USH2A patients, one with a p.Cys419Phe which is a P/LP variant and another in a proband with the p.Glu767SerfsX21 variant. Patients were recruited through Moorfields Eye Hospital which was also the case of the patient described in Carss 2017, though that proband was not counted because the other allele was not identified.",There were 2 occasions where this variant was observed in trans with another LOF variant and another instance where the variant was identified in trans with the p.Cys419Phe variant which is Path/LP in ClinVar by 6 submitters.,"There were 2 occasions where this variant was observed in trans with another LOF variant and another instance where the variant was identified in trans with the p.Cys419Phe variant which is Path/LP in ClinVar by 6 submitters. Total: 3 Path variants in trans. The variant was detected in a proband from a UK study with Usher type 2 in trans with the p.Trp2744X variant. The variant was also identified in two more USH2A patients, one with a p.Cys419Phe which is a P/LP variant and another in a proband with the p.Glu767SerfsX21 variant. Patients were recruited through Moorfields Eye Hospital which was also the case of the patient described in Carss 2017, though that proband was not counted because the other allele was not identified.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
707,NM_004004.5(GJB2):c.101T>C (p.Met34Thr),GJB2,nonsyndromic genetic deafness,MONDO:0019497,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-06-28,BA1,not_met,PubMed:31160754,Showed this variant is statistically enriched in affected populations therefore BA1 should not be applied,"This variant was detected in 510/25108 European (Finnish) alleles in gnomAD. The calculated filtering allele frequency in European (non-Finnish) genomes is 0.01462 (1655/128490) with 18 homozygotes.

There are 28 homozygotes in gnomAD.

However, this variant is statistically enriched in affected populations as shown by Shen et al. 2019 and therefore BA1 should not be applied.","This variant was detected in 510/25108 European (Finnish) alleles in gnomAD. The calculated filtering allele frequency in European (non-Finnish) genomes is 0.01462 (1655/128490) with 18 homozygotes.

There are 28 homozygotes in gnomAD.

However, this variant is statistically enriched in affected populations as shown by Shen et al. 2019 and therefore BA1 should not be applied. Showed this variant is statistically enriched in affected populations therefore BA1 should not be applied","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
707,NM_004004.5(GJB2):c.101T>C (p.Met34Thr),GJB2,nonsyndromic genetic deafness,MONDO:0019497,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-06-28,BS1,not_met,PubMed:31160754,Showed this variant is statistically enriched in affected populations therefore BA1 should not be applied,see BA1,see BA1 Showed this variant is statistically enriched in affected populations therefore BA1 should not be applied,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
707,NM_004004.5(GJB2):c.101T>C (p.Met34Thr),GJB2,nonsyndromic genetic deafness,MONDO:0019497,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-06-28,BS2,not_met,PubMed:31160754,"This study described two confirmed accounts of incomplete pentrance of the M34T variant. In two Ashkenazi Jewish compound heterozygotes, the M34T variant was seen in trans with the p.Leu90Pro in one case and the p.Leu56Argfs varint in another case. Both individuals were confirmed to be unaffected by audiological evaluation.","There have been at least 2 confirmed accounts of incomplete penetrance of the M34T variant. In two Ashkenazi Jewish compound heterozygotes, the M34T variant was seen in trans with the p.Leu90Pro in one case and the p.Leu56Argfs varint in another case. Both individuals were confirmed to be unaffected by audiological evaluation.
However, the homozygous genotype has been shown to be statistically enriched in patients with hearing loss relative to those in the general population. Therefore this code cannot be applied.","There have been at least 2 confirmed accounts of incomplete penetrance of the M34T variant. In two Ashkenazi Jewish compound heterozygotes, the M34T variant was seen in trans with the p.Leu90Pro in one case and the p.Leu56Argfs varint in another case. Both individuals were confirmed to be unaffected by audiological evaluation.
However, the homozygous genotype has been shown to be statistically enriched in patients with hearing loss relative to those in the general population. Therefore this code cannot be applied. This study described two confirmed accounts of incomplete pentrance of the M34T variant. In two Ashkenazi Jewish compound heterozygotes, the M34T variant was seen in trans with the p.Leu90Pro in one case and the p.Leu56Argfs varint in another case. Both individuals were confirmed to be unaffected by audiological evaluation.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
707,NM_004004.5(GJB2):c.101T>C (p.Met34Thr),GJB2,nonsyndromic genetic deafness,MONDO:0019497,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-06-28,PM2,not_met,PubMed:31160754,Showed this variant is statistically enriched in affected populations therefore BA1 should not be applied,See BA1,See BA1 Showed this variant is statistically enriched in affected populations therefore BA1 should not be applied,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
985,NM_206933.3(USH2A):c.12295-3T>A,USH2A,Usher syndrome,MONDO:0019501,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2023-02-06,PS3,not_met,PubMed:25649381,"RT-PCR analysis of patient with c.12295-3T>A mutation showed a shorter product corresponding to skipping of USH2A exon 63, creating a premature stop codon. The patient also had another variant in USH2A, c.12093C>A and direct sequencing showed the variants are on different alleles (in trans).",VCEP advised for evidence to be scored as PVS1 not PS3.,"VCEP advised for evidence to be scored as PVS1 not PS3. RT-PCR analysis of patient with c.12295-3T>A mutation showed a shorter product corresponding to skipping of USH2A exon 63, creating a premature stop codon. The patient also had another variant in USH2A, c.12093C>A and direct sequencing showed the variants are on different alleles (in trans).","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
985,NM_206933.3(USH2A):c.12295-3T>A,USH2A,Usher syndrome,MONDO:0019501,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2023-02-06,PP4,met,PubMed:22135276,Patient diagnosed with Usher syndrome type 2 and found to have variants in only USH2A.,, Patient diagnosed with Usher syndrome type 2 and found to have variants in only USH2A.,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
1023,NM_004700.4(KCNQ4):c.803_805CCT[1] (p.Ser269del),KCNQ4,nonsyndromic genetic deafness,MONDO:0019497,Pathogenic,Autosomal dominant inheritance,Hearing Loss,2023-10-05,PS3-Moderate,not_met,PubMed:34316018,"Variant used as the null control for patch-clamp studies. Compared to WT, significantly reduced whole-cell K+ currents. KCNQ openers did not rescue homomeric KCNQ4 mutant channels.",VCEP decided to upgrade from supporting to moderate level based on quality of evidence on call from 8.16.2023. ,"VCEP decided to upgrade from supporting to moderate level based on quality of evidence on call from 8.16.2023.  Variant used as the null control for patch-clamp studies. Compared to WT, significantly reduced whole-cell K+ currents. KCNQ openers did not rescue homomeric KCNQ4 mutant channels.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
2759,NM_006218.3(PIK3CA):c.2740G>A (p.Gly914Arg),PIK3CA,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Pathogenic,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-12,PM6,not_met,PubMed:22729224,"102/811 reads in LCL and 56/313 in saliva in individual LR11-070, 112/818 in blood and 103/171 saliva in individual LR06-341",," 102/811 reads in LCL and 56/313 in saliva in individual LR11-070, 112/818 in blood and 103/171 saliva in individual LR06-341",ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2761,NM_006218.4(PIK3CA):c.2176G>A (p.Glu726Lys),PIK3CA,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Pathogenic,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-12,PM6,not_met,PubMed:22729224,"LR08-261 (12% blood 41% buccal), LR06-333 (14% LCL and 15% saliva)",," LR08-261 (12% blood 41% buccal), LR06-333 (14% LCL and 15% saliva)",ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2767,NM_001386501.1:c.3127G>T,MTOR,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Uncertain Significance,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-11,PM6,not_met,PubMed:27830187,This variant was detected at an allele frequency of 2.41% in brain and 1.3% in blood,, This variant was detected at an allele frequency of 2.41% in brain and 1.3% in blood,ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2773,NM_004958.3:c.4468T>C,MTOR,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Likely Pathogenic,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-11,PM6,not_met,PubMed:27830187,de novo germline variant,, de novo germline variant,ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2778,NM_006218.4(PIK3CA):c.3140A>G (p.His1047Arg),PIK3CA,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Pathogenic,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-11,PM6,not_met,PubMed:29988677,"was identified in the affected tissue sample. In particular, position 3140 was analyzed in a total of 463 reads in both strands and the variant was identified in 43 of these reads, indicating a variant allele frequency of 9.3%",," was identified in the affected tissue sample. In particular, position 3140 was analyzed in a total of 463 reads in both strands and the variant was identified in 43 of these reads, indicating a variant allele frequency of 9.3%",ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2747,NM_005027.4(PIK3R2):c.1117G>A (p.Gly373Arg),PIK3R2,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Pathogenic,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-17,PS2-Moderate,not_met,PubMed:22729224,"13 MPPH (1 family w/ 3 affected sibs, parent was  inferred to have germline mosaicism)",," 13 MPPH (1 family w/ 3 affected sibs, parent was  inferred to have germline mosaicism)",ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2773,NM_004958.3:c.4468T>C,MTOR,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Likely Pathogenic,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-11,PS2-Moderate,not_met,PubMed:27830187,de novo germline variant,, de novo germline variant,ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2778,NM_006218.4(PIK3CA):c.3140A>G (p.His1047Arg),PIK3CA,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Pathogenic,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-11,PS2-Moderate,not_met,PubMed:29988677,"was identified in the affected tissue sample. In particular, position 3140 was analyzed in a total of 463 reads in both strands and the variant was identified in 43 of these reads, indicating a variant allele frequency of 9.3%",," was identified in the affected tissue sample. In particular, position 3140 was analyzed in a total of 463 reads in both strands and the variant was identified in 43 of these reads, indicating a variant allele frequency of 9.3%",ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2759,NM_006218.3(PIK3CA):c.2740G>A (p.Gly914Arg),PIK3CA,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Pathogenic,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-12,BS3,not_met,PubMed:22729224,increased PIP3 levels in cell lines derived from patient lines showed,, increased PIP3 levels in cell lines derived from patient lines showed,ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2761,NM_006218.4(PIK3CA):c.2176G>A (p.Glu726Lys),PIK3CA,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Pathogenic,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-12,BS3,not_met,PubMed:28566443,Patient cell lines show increased phos,, Patient cell lines show increased phos,ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2759,NM_006218.3(PIK3CA):c.2740G>A (p.Gly914Arg),PIK3CA,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Pathogenic,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-12,PS3,not_met,PubMed:22729224,increased PIP3 levels in cell lines derived from patient lines showed,, increased PIP3 levels in cell lines derived from patient lines showed,ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2761,NM_006218.4(PIK3CA):c.2176G>A (p.Glu726Lys),PIK3CA,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Pathogenic,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-12,PS3,not_met,PubMed:28566443,Patient cell lines show increased phos,, Patient cell lines show increased phos,ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2773,NM_004958.3:c.4468T>C,MTOR,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Likely Pathogenic,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-11,PS4,met,PubMed:27830187,macrocephaly and mild ID,, macrocephaly and mild ID,ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2759,NM_006218.3(PIK3CA):c.2740G>A (p.Gly914Arg),PIK3CA,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Pathogenic,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-12,PS2,met,PubMed:22729224,"102/811 reads in LCL and 56/313 in saliva in individual LR11-070, 112/818 in blood and 103/171 saliva in individual LR06-341",," 102/811 reads in LCL and 56/313 in saliva in individual LR11-070, 112/818 in blood and 103/171 saliva in individual LR06-341",ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2739,NM_005465.7(AKT3):c.49G>A (p.Glu17Lys),AKT3,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Pathogenic,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-12,PS3-Supporting,not_met,PubMed:18813315,"generated cell lines, increased AKT phosphorylation",," generated cell lines, increased AKT phosphorylation",ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2767,NM_001386501.1:c.3127G>T,MTOR,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Uncertain Significance,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-11,PS4-Supporting,not_met,PubMed:27830187,Neuroimaging appearance consistent with a malformation of cortical development (without neuropathology,, Neuroimaging appearance consistent with a malformation of cortical development (without neuropathology,ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2767,NM_001386501.1:c.3127G>T,MTOR,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Uncertain Significance,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-11,BP2,met,PubMed:27830187,This variant was identified in CIS with a known pathogenic variant c.4379T>C,, This variant was identified in CIS with a known pathogenic variant c.4379T>C,ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2767,NM_001386501.1:c.3127G>T,MTOR,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Uncertain Significance,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-11,PM3,not_met,PubMed:27830187,This variant was identified in CIS with a known pathogenic variant c.4379T>C,, This variant was identified in CIS with a known pathogenic variant c.4379T>C,ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
183,NM_000257.3(MYH7):c.2717A>G (p.Asp906Gly),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
184,NM_000257.3(MYH7):c.2681A>G (p.Glu894Gly),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
186,NM_000257.3(MYH7):c.2609G>A (p.Arg870His),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
189,NM_000257.3(MYH7):c.2513C>T (p.Pro838Leu),MYH7,restrictive cardiomyopathy,MONDO:0005201,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
190,NM_000257.3(MYH7):c.2360G>A (p.Arg787His),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Likely Benign,Autosomal dominant inheritance,Cardiomyopathy,2021-06-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
191,NM_000257.3(MYH7):c.2221G>T (p.Gly741Trp),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
192,NM_000257.3(MYH7):c.2221G>C (p.Gly741Arg),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
193,NM_000257.3(MYH7):c.2207T>C (p.Ile736Thr),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
194,NM_000257.3(MYH7):c.2167C>T (p.Arg723Cys),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
195,NM_000257.3(MYH7):c.2167C>G (p.Arg723Gly),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
244,NM_000257.3(MYH7):c.2156G>A (p.Arg719Gln),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
245,NM_000257.3(MYH7):c.2155C>T (p.Arg719Trp),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
247,NM_000257.3(MYH7):c.2146G>A (p.Gly716Arg),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
248,NM_000257.3(MYH7):c.1988G>A (p.Arg663His),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
249,NM_000257.3(MYH7):c.1750G>C (p.Gly584Arg),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
253,NM_000257.3(MYH7):c.1208G>A (p.Arg403Gln),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
255,NM_000257.3(MYH7):c.1358G>A (p.Arg453His),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Head domain (aa 181-937),Head domain (aa 181-937),Head domain (aa 181-937) Head domain (aa 181-937),ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
2709,NM_000257.4(MYH7):c.2602G>C (p.Ala868Pro),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Likely Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2021-10-01,PM1,met,PubMed:27532257,mutation hotspot in between amino acids 181-937 in MYH7,Missense variants between amino acids 181-937 PMID: 27532257,Missense variants between amino acids 181-937 PMID: 27532257 mutation hotspot in between amino acids 181-937 in MYH7,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
184,NM_000257.3(MYH7):c.2681A>G (p.Glu894Gly),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PS4,met,PubMed:27532257,7 probands with HCM identified,">20 HCM probands including SHaRe, ClinVar SCV000059463.5; ClinVar SCV000212641.2; ClinVar SCV000253683.5)",">20 HCM probands including SHaRe, ClinVar SCV000059463.5; ClinVar SCV000212641.2; ClinVar SCV000253683.5) 7 probands with HCM identified",ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
199,NM_000257.3(MYH7):c.2358G>T (p.Thr786=),MYH7,cardiomyopathy,MONDO:0004994,Benign,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,BA1,met,PubMed:29300372,BA1 applied,The filtering allele frequency of the c.2358G>T (p.Thr786=) variant in the MYH7 gene is 0.15% (33/16512) of South Asian chromosomes by the Exome Aggregation Consortium,The filtering allele frequency of the c.2358G>T (p.Thr786=) variant in the MYH7 gene is 0.15% (33/16512) of South Asian chromosomes by the Exome Aggregation Consortium BA1 applied,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
311,NM_002880.3(RAF1):c.775T>A (p.Ser259Thr),RAF1,RASopathy,MONDO:0021060,Pathogenic,Autosomal dominant inheritance,RASopathy,2020-04-13,PM1,met,PubMed:29493581,"Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581).",The variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581).,"The variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581).",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
312,NM_002880.3(RAF1):c.788T>G (p.Val263Gly),RAF1,RASopathy,MONDO:0021060,Pathogenic,Autosomal dominant inheritance,RASopathy,2020-07-01,PM1,met,PubMed:29493581,"Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581).",The variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581).,"The variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581).",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
322,NM_002834.4(PTPN11):c.781C>T (p.Leu261Phe),PTPN11,RASopathy,MONDO:0021060,Pathogenic,Autosomal dominant inheritance,RASopathy,2018-12-10,PM1,met,PubMed:29493581,"Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID 29493581).","Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID 29493581).","Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID 29493581).",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
328,NM_002834.4(PTPN11):c.794G>A (p.Arg265Gln),PTPN11,Noonan syndrome,MONDO:0018997,Pathogenic,Autosomal dominant inheritance,RASopathy,2018-12-10,PM1,met,PubMed:29493581,"Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID 29493581).","Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID 29493581).","Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTPN11 (PM1; PMID 29493581).",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
348,NM_005343.3(HRAS):c.175G>A (p.Ala59Thr),HRAS,RASopathy,MONDO:0009026,Likely Pathogenic,Autosomal dominant inheritance,RASopathy,2024-10-02,PM1,met,PubMed:29493581,"Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of HRAS (PM1; PMID 29493581).","The variant is in a location (amino acids 57 – 64), that has been defined by the ClinGen RASopathy Expert Panel to be a critical functional domain of HRAS (PM1)","The variant is in a location (amino acids 57 – 64), that has been defined by the ClinGen RASopathy Expert Panel to be a critical functional domain of HRAS (PM1) Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of HRAS (PM1; PMID 29493581).",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHRASVersion2.3.0_version=2.3.0.csv
377,NM_005633.3(SOS1):c.508A>G (p.Lys170Glu),SOS1,Noonan syndrome,MONDO:0018997,Pathogenic,Autosomal dominant inheritance,RASopathy,2018-12-10,PM1,met,PubMed:29493581,"Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of SOS1 (PM1; PMID 29493581)","Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of SOS1 (PM1; PMID 29493581)","Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of SOS1 (PM1; PMID 29493581) Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of SOS1 (PM1; PMID 29493581)",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
378,NM_002880.3(RAF1):c.770C>T (p.Ser257Leu),RAF1,Noonan syndrome,MONDO:0018997,Pathogenic,Autosomal dominant inheritance,RASopathy,2018-12-10,PM1,met,PubMed:29493581,the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot,"Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581).","Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581). the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
381,NM_002880.3(RAF1):c.1472C>T (p.Thr491Ile),RAF1,RASopathy,MONDO:0021060,Pathogenic,Autosomal dominant inheritance,RASopathy,2018-12-10,PM1,met,PubMed:29493581,"Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581).","Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581).","Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581).",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
728,NM_002834.4(PTPN11):c.1403C>T (p.Thr468Met),PTPN11,Noonan syndrome with multiple lentigines,MONDO:0007893,Pathogenic,Autosomal dominant inheritance,RASopathy,2019-07-15,PM1,met,PubMed:29493581,ClinGen RAS EP decided this AA is located in a hotspot,The variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTNP11  (PM1; PMID 29493581).,The variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of PTNP11  (PM1; PMID 29493581). ClinGen RAS EP decided this AA is located in a hotspot,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
1530,NM_005633.3(SOS1):c.1276C>A (p.Gln426Lys),SOS1,RASopathy,MONDO:0021060,Likely Pathogenic,Autosomal dominant inheritance,RASopathy,2020-07-27,PM1,met,PubMed:29493581,,The RASopathy EP has defined amino acids 420-500 of SOS1 to be a region supporting pathogenicity.,The RASopathy EP has defined amino acids 420-500 of SOS1 to be a region supporting pathogenicity. ,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
309,NM_007373.3(SHOC2):c.4A>G (p.Ser2Gly),SHOC2,Noonan syndrome-like disorder with loose anagen hair 1,MONDO:0054637,Pathogenic,Autosomal dominant inheritance,RASopathy,2018-12-10,PS3,met,PubMed:19684605,In vitro functional studies provide some evidence that the p.Ser2Gly variant may impact protein function (PS3; PMID: 19684605).,In vitro functional studies provide some evidence that the p.Ser2Gly variant may impact protein function (PS3; PMID: 19684605).,In vitro functional studies provide some evidence that the p.Ser2Gly variant may impact protein function (PS3; PMID: 19684605). In vitro functional studies provide some evidence that the p.Ser2Gly variant may impact protein function (PS3; PMID: 19684605).,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSHOC2Version2.3.0_version=2.3.0.csv
1197,NM_002834.4(PTPN11):c.184T>G (p.Tyr62Asp),PTPN11,RASopathy,MONDO:0021060,Pathogenic,Autosomal dominant inheritance,RASopathy,2020-02-18,PS3,met,PubMed:22711529,“Under basal conditions the NS-causing SHP2Asp62 that showed a 2.3-fold increase in substrate dephosphorylation”,, “Under basal conditions the NS-causing SHP2Asp62 that showed a 2.3-fold increase in substrate dephosphorylation”,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
1580,NM_005633.3(SOS1):c.1656G>C (p.Arg552Ser),SOS1,RASopathy,MONDO:0021060,Pathogenic,Autosomal dominant inheritance,RASopathy,2019-06-28,PS3,met,PubMed:27304678,Transfected wild-type and mutant SOS1 constructs into HEK293T cells and measured the effect on basal levels of phosphorylated ERK1/2. Found that the p.R552S variant significantly increased p-ERK signaling relative to WT (p = 0.0039). This meets criteria for PS3.,variant increased p-ERK signaling (PMID 27304678),variant increased p-ERK signaling (PMID 27304678) Transfected wild-type and mutant SOS1 constructs into HEK293T cells and measured the effect on basal levels of phosphorylated ERK1/2. Found that the p.R552S variant significantly increased p-ERK signaling relative to WT (p = 0.0039). This meets criteria for PS3.,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
726,NM_005633.3(SOS1):c.512T>C (p.Val171Ala),SOS1,RASopathy,MONDO:0021060,Likely Pathogenic,Autosomal dominant inheritance,RASopathy,2019-07-15,PS4-Supporting,not_met,PubMed:29402968,"Variant was identified in a patient with a possible familial RASopathy, see supplemental table.",Has also been identified in 1 patient w/possible familial RASopathy in Leung et al. 2018 PMID:29402968,"Has also been identified in 1 patient w/possible familial RASopathy in Leung et al. 2018 PMID:29402968 Variant was identified in a patient with a possible familial RASopathy, see supplemental table.",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
960,NM_005633.3(SOS1):c.2673+14T>C,SOS1,RASopathy,MONDO:0021060,Benign,Autosomal dominant inheritance,RASopathy,2019-10-02,BP5,met,PubMed:21387466,"Identified as a disease-unrelated SOS1 sequence variant in a patient. The RASopathy phenotype was not specified for the individual, but patients in the study had NS, CFCS, and CHDs.","2 patients from LMM internal data had pathogenic variants in other genes (SHOC2:c.4A>G, classified as Path by RAS VCEP; PTPN11:c.179G>C, classified as Path by 5 submitters and well-studied in lit). Also observed by Lepri et al.","2 patients from LMM internal data had pathogenic variants in other genes (SHOC2:c.4A>G, classified as Path by RAS VCEP; PTPN11:c.179G>C, classified as Path by 5 submitters and well-studied in lit). Also observed by Lepri et al. Identified as a disease-unrelated SOS1 sequence variant in a patient. The RASopathy phenotype was not specified for the individual, but patients in the study had NS, CFCS, and CHDs.",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
1028,NM_002834.4(PTPN11):c.392A>G (p.Lys131Arg),PTPN11,RASopathy,MONDO:0021060,Likely Benign,Autosomal dominant inheritance,RASopathy,2019-12-03,BS2,not_met,PubMed:24728327,Variant identified in study of 158 genes causally implicated in carcinogenesis using WGS from an ancestrally diverse cohort of 681 healthy individuals. No phenotypic data available.,Variant observed in a proband inherited from asymptomatic father. 3 well phenotyped individuals required to apply BS2.,Variant observed in a proband inherited from asymptomatic father. 3 well phenotyped individuals required to apply BS2. Variant identified in study of 158 genes causally implicated in carcinogenesis using WGS from an ancestrally diverse cohort of 681 healthy individuals. No phenotypic data available.,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
1482,NM_002834.5(PTPN11):c.209A>G (p.Lys70Arg),PTPN11,RASopathy,MONDO:0021060,Pathogenic,Autosomal dominant inheritance,RASopathy,2020-06-25,PM6,met,PubMed:29084544,,, ,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
8336,NM_006912.6(RIT1):c.268A>G (p.Met90Val),RIT1,RASopathy,MONDO:0021060,Pathogenic,Autosomal dominant inheritance,RASopathy,2024-10-02,PS3-Supporting,not_met,PubMed:29734338,HEK293 analysis indicated elevated and prolonged ERK1/2 phosphorylation in the mutant compared to the wild-type. ,ERK1/2 phosphorylation assays in HEK293T cells showed elevated and prolonged ERK1/2 phosphorylation indicating that this variant impacts protein function (PMID:29734338)(PS3_Supporting). ,ERK1/2 phosphorylation assays in HEK293T cells showed elevated and prolonged ERK1/2 phosphorylation indicating that this variant impacts protein function (PMID:29734338)(PS3_Supporting).  HEK293 analysis indicated elevated and prolonged ERK1/2 phosphorylation in the mutant compared to the wild-type. ,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRIT1Version2.3.0_version=2.3.0.csv
917,NM_004360.4(CDH1):c.707C>A (p.Ser236Ter),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Pathogenic,Autosomal dominant inheritance,CDH1,2023-08-04,PS4,not_met,PubMed:26681312,One proband diagnosed with Gastric-NOS,"One proband with gastric cancer dx 30s, but no information on whether they meet HDGC criteria (PMID: 26681312). Same proband submitted to ClinVar (SCV000210901.9).","One proband with gastric cancer dx 30s, but no information on whether they meet HDGC criteria (PMID: 26681312). Same proband submitted to ClinVar (SCV000210901.9). One proband diagnosed with Gastric-NOS",ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
923,NM_004360.4(CDH1):c.2594G>A (p.Trp865Ter),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Uncertain Significance,Autosomal dominant inheritance,CDH1,2023-08-04,PS4,not_met,PubMed:29798843,Does not meet the criteria for HDGC.,"Reported in the literature (Ambry Genetics lab), but the family does not meet the criteria for HGDC (van der Post et al, J Med Genet (2015) 52(6):361-74).
SCV000700321.2 (one case but does not meet the HDGC criteria) and Counsyl - SCV000785524.2.","Reported in the literature (Ambry Genetics lab), but the family does not meet the criteria for HGDC (van der Post et al, J Med Genet (2015) 52(6):361-74).
SCV000700321.2 (one case but does not meet the HDGC criteria) and Counsyl - SCV000785524.2. Does not meet the criteria for HDGC.",ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
932,NM_004360.4(CDH1):c.2549_2550delCC (p.Ser850Phefs),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Uncertain Significance,Autosomal dominant inheritance,CDH1,2023-08-04,PS4,not_met,PubMed:29798843,"Family does not meet HDGC clinical criteria. Proband with bilateral/contralateral DCIS and IDC/ILC <50, and adenomatous polyps. Same case that has been submitted to ClinVar (SCV000185568.5).",No reported cases that meet HDGC clinical criteria.,"No reported cases that meet HDGC clinical criteria. Family does not meet HDGC clinical criteria. Proband with bilateral/contralateral DCIS and IDC/ILC <50, and adenomatous polyps. Same case that has been submitted to ClinVar (SCV000185568.5).",ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
935,NM_004360.4(CDH1):c.1711+1G>A,CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Likely Pathogenic,Autosomal dominant inheritance,CDH1,2023-08-04,PS4,not_met,PubMed:28152038,Hereditary cancer-predisposing syndrome proband with no other information. Also submitted to ClinVar - SCV000580706.,Proband with no further information (PMID: 28152038). SCV000817795.1 - One family meet HDGC clinical criteria.,Proband with no further information (PMID: 28152038). SCV000817795.1 - One family meet HDGC clinical criteria. Hereditary cancer-predisposing syndrome proband with no other information. Also submitted to ClinVar - SCV000580706.,ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
939,NM_004360.5(CDH1):c.1416C>T (p.Thr472=),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Likely Benign,Autosomal dominant inheritance,CDH1,2023-08-17,PS4,not_met,PubMed:24204729,"Index case with a DGC, age of diagnosis not reported. The family does not meet HDGC clinical criteria.",No reported families that meet HDGC clinical criteria.,"No reported families that meet HDGC clinical criteria. Index case with a DGC, age of diagnosis not reported. The family does not meet HDGC clinical criteria.",ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
1555,NM_004360.4(CDH1):c.2440-2A>G,CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Likely Pathogenic,Autosomal dominant inheritance,CDH1,2023-08-30,PS4,not_met,PubMed:29798843,"Identified in one individual with lobular breast cancer in her 40s and no family history (does not meet the criteria for HDGC, van der Post et al, J Med Genet (2015) 52(6):361-74)",Ambry Genetics - SCV000700319.2; PMID: 29798843 - Identified in one individual with lobular breast cancer in her 40s and no family history. Both probands do not meet the criteria for HDGC.,"Ambry Genetics - SCV000700319.2; PMID: 29798843 - Identified in one individual with lobular breast cancer in her 40s and no family history. Both probands do not meet the criteria for HDGC. Identified in one individual with lobular breast cancer in her 40s and no family history (does not meet the criteria for HDGC, van der Post et al, J Med Genet (2015) 52(6):361-74)",ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
523,NM_004360.4(CDH1):c.670C>T (p.Arg224Cys),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Likely Benign,Autosomal dominant inheritance,CDH1,2023-08-17,BS3,not_met,PubMed:27582386,Found variant weakly activates E-cadherin induced cell adhesion.,Two functional studies suggest little or no impact on cell adhesion.,Two functional studies suggest little or no impact on cell adhesion. Found variant weakly activates E-cadherin induced cell adhesion.,ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
1428,NM_004360.5(CDH1):c.1008+2T>C,CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Likely Pathogenic,Autosomal dominant inheritance,CDH1,2023-08-24,BS3,not_met,PubMed:31642931,"The CDH1 c.1008G>T variant, affecting the last nucleotide in exon 7, has been shown to result in abnormal splicing.","To our knowledge, in vitro splicing analysis for this variant has not been reported.","To our knowledge, in vitro splicing analysis for this variant has not been reported. The CDH1 c.1008G>T variant, affecting the last nucleotide in exon 7, has been shown to result in abnormal splicing.",ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
1637,NM_004360.5(CDH1):c.387+5G>A,CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Benign,Autosomal dominant inheritance,CDH1,2023-08-10,BS3,met,PubMed:31642931,RNA studies demonstrate no abnormal splicing,RNA studies demonstrate no abnormal splicing (SCV000186607.5).,RNA studies demonstrate no abnormal splicing (SCV000186607.5). RNA studies demonstrate no abnormal splicing,ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
2862,NM_004360.5(CDH1):c.808T>G (p.Ser270Ala),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Benign,Autosomal dominant inheritance,CDH1,2023-08-17,BS3,not_met,PubMed:27582386,"Exhibits strong adhesion, although a bit lower than WT, but cannot be activated by stimuli. ",," Exhibits strong adhesion, although a bit lower than WT, but cannot be activated by stimuli. ",ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
523,NM_004360.4(CDH1):c.670C>T (p.Arg224Cys),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Likely Benign,Autosomal dominant inheritance,CDH1,2023-08-17,PS3,not_met,PubMed:27582386,Found variant weakly activates E-cadherin induced cell adhesion.,Two functional studies suggest little or no impact on cell adhesion.,Two functional studies suggest little or no impact on cell adhesion. Found variant weakly activates E-cadherin induced cell adhesion.,ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
1428,NM_004360.5(CDH1):c.1008+2T>C,CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Likely Pathogenic,Autosomal dominant inheritance,CDH1,2023-08-24,PS3,not_met,PubMed:31642931,"The CDH1 c.1008G>T variant, affecting the last nucleotide in exon 7, has been shown to result in abnormal splicing.","To our knowledge, in vitro splicing analysis for this variant has not been reported. The CDH1 c.1008G>T variant, affecting the last nucleotide in exon 7, has been shown to result in abnormal splicing (PMID: 31642931).","To our knowledge, in vitro splicing analysis for this variant has not been reported. The CDH1 c.1008G>T variant, affecting the last nucleotide in exon 7, has been shown to result in abnormal splicing (PMID: 31642931). The CDH1 c.1008G>T variant, affecting the last nucleotide in exon 7, has been shown to result in abnormal splicing.",ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
2085,NM_004360.5(CDH1):c.1057G>A (p.Glu353Lys),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Likely Pathogenic,Autosomal dominant inheritance,CDH1,2023-08-24,PS3,met,PubMed:32133419,"RNA studies demonstrate abnormal splicing, r.1055_1137del (out-of-frame). ",PMID: 32133419 - RNA studies demonstrate abnormal splicing in the set of samples tested (Ambry internal data) - CDH1 r.1055_1137del (out-of-frame).,"PMID: 32133419 - RNA studies demonstrate abnormal splicing in the set of samples tested (Ambry internal data) - CDH1 r.1055_1137del (out-of-frame). RNA studies demonstrate abnormal splicing, r.1055_1137del (out-of-frame). ",ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
2862,NM_004360.5(CDH1):c.808T>G (p.Ser270Ala),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Benign,Autosomal dominant inheritance,CDH1,2023-08-17,PS3,not_met,PubMed:27582386,"Exhibits strong adhesion, although a bit lower than WT, but cannot be activated by stimuli. ","PMID: 27582386 - Exhibits strong adhesion, although a bit lower than WT, but cannot be activated by stimuli. ","PMID: 27582386 - Exhibits strong adhesion, although a bit lower than WT, but cannot be activated by stimuli.  Exhibits strong adhesion, although a bit lower than WT, but cannot be activated by stimuli. ",ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
898,NM_004360.4(CDH1):c.220C>T (p.Arg74Ter),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Pathogenic,Autosomal dominant inheritance,CDH1,2023-08-29,PS4-Supporting,not_met,PubMed:25123297,"Found in one individual (76 yo) with gastric adenocarcinoma with suspected family history of gastric cancer (mother, brother), but NOT germline.","Found in one individual (76 yo) with gastric adenocarcinoma with suspected family history of gastric cancer (mother, brother), but NOT germline.
SCV000288456.3 - one proband meet IGCLC HDGC criteria.
- one proband does not meet IGCLC HDGC criteria.
SCV000661607.2 - 3 cases do not meet HDGC criteria with unknown pathology.","Found in one individual (76 yo) with gastric adenocarcinoma with suspected family history of gastric cancer (mother, brother), but NOT germline.
SCV000288456.3 - one proband meet IGCLC HDGC criteria.
- one proband does not meet IGCLC HDGC criteria.
SCV000661607.2 - 3 cases do not meet HDGC criteria with unknown pathology. Found in one individual (76 yo) with gastric adenocarcinoma with suspected family history of gastric cancer (mother, brother), but NOT germline.",ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
557,NM_000314.6(PTEN):c.79+7A>G,PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Likely Benign,Autosomal dominant inheritance,PTEN,2023-10-19,BS3,met,PubMed:28677221,"Variant reported to not demonstrate splicing impact, but results not shown.","Intronic variant with RNA, mini-gene, or other splicing assay demonstrating no splicing impact. (Chen HJ et al. 2017 PMID: 28677221 showed c.79+7A>G had no demonstrated splicing impact)","Intronic variant with RNA, mini-gene, or other splicing assay demonstrating no splicing impact. (Chen HJ et al. 2017 PMID: 28677221 showed c.79+7A>G had no demonstrated splicing impact) Variant reported to not demonstrate splicing impact, but results not shown.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
764,NM_000314.6(PTEN):c.210-7_210-3del5,PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Benign,Autosomal dominant inheritance,PTEN,2019-07-23,BS3,met,PubMed:28677221,No splicing effect by mRNA testing (pt lymphoblast-derived cell lines were used).,Chen 2017,Chen 2017 No splicing effect by mRNA testing (pt lymphoblast-derived cell lines were used).,ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
1473,NM_000314.7(PTEN):c.210-39A>G,PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Benign,Autosomal dominant inheritance,PTEN,2020-06-18,BS3,met,PubMed:28677221,"Authors characterized PTEN mRNA processing, analyzed PTEN expression, and downstream readouts of P-AKT and P-ERK1/2. RNA for our variant showed no change.",RNA for our variant showed no change (PMID 28677221).,"RNA for our variant showed no change (PMID 28677221). Authors characterized PTEN mRNA processing, analyzed PTEN expression, and downstream readouts of P-AKT and P-ERK1/2. RNA for our variant showed no change.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
1539,NM_001304717.5(PTEN):c.730-2_731del,PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2019-12-04,BS3,not_met,PubMed:28677221,Nomenclature c.210-4_c.210-1delTTAG: variant resulted in exon 4 skipping in pt cells.,, Nomenclature c.210-4_c.210-1delTTAG: variant resulted in exon 4 skipping in pt cells.,ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
753,NM_000314.8(PTEN):c.1061C>T (p.Pro354Leu),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Uncertain Significance,Autosomal dominant inheritance,PTEN,2023-10-16,PS4,not_met,PubMed:21869887,1 patient with glioblastoma. No further details provided. Unable to calculate CC score.,"GeneDx internal data: 1 SSA dx 30s. Fam hx colon, ov, panc cancers. CC score = 0.","GeneDx internal data: 1 SSA dx 30s. Fam hx colon, ov, panc cancers. CC score = 0. 1 patient with glioblastoma. No further details provided. Unable to calculate CC score.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
756,NM_000314.6(PTEN):c.841C>G (p.Pro281Ala),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Uncertain Significance,Autosomal dominant inheritance,PTEN,2023-10-18,PS4,not_met,PubMed:29945567,Variant identified in a pt with pancreatic cancer; no other info provided.,"1 internal case from Charis Eng's lab: female age 49, consented age 47
CC Score: 1; OFC: 53.25 cm; Normal Head Size; Thyroid Nodule; Fibrocystic Breast Disease; Uterine Fibroids; Family: none; Other genotypes: none. Does not meet criteria for PS4, PS4_moderate, or PS4_supporting.","1 internal case from Charis Eng's lab: female age 49, consented age 47
CC Score: 1; OFC: 53.25 cm; Normal Head Size; Thyroid Nodule; Fibrocystic Breast Disease; Uterine Fibroids; Family: none; Other genotypes: none. Does not meet criteria for PS4, PS4_moderate, or PS4_supporting. Variant identified in a pt with pancreatic cancer; no other info provided.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
758,NM_000314.6(PTEN):c.-975G>C,PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Likely Benign,Autosomal dominant inheritance,PTEN,2019-07-23,PS3,not_met,PubMed:22171747,,Heikkinen et al (2011) analyzed the affects of promoter variants in PTEN and breast cancer progression and survival.  The presence of this variant is associated with poor survival in breast cancer patients. MPerpich entry.,Heikkinen et al (2011) analyzed the affects of promoter variants in PTEN and breast cancer progression and survival.  The presence of this variant is associated with poor survival in breast cancer patients. MPerpich entry. ,ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
1038,NM_000314.7(PTEN):c.254-30dup,PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Benign,Autosomal dominant inheritance,PTEN,2019-12-04,PS3,not_met,PubMed:28677221,Variant referred to as c.254-38dupT in paper. Authors characterized PTEN mRNA processing and analyzed PTEN expression. RNA analysis of c.254-38dupT showed no change.,, Variant referred to as c.254-38dupT in paper. Authors characterized PTEN mRNA processing and analyzed PTEN expression. RNA analysis of c.254-38dupT showed no change.,ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
98,NM_000314.6(PTEN):c.50_51delAA (p.Gln17Argfs),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2018-12-10,PS4-Supporting,not_met,PubMed:20223021,Proband(s) with phenotype specificity score of 1-1.5,, Proband(s) with phenotype specificity score of 1-1.5,ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
748,NM_000314.6(PTEN):c.740T>C (p.Leu247Ser),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Likely Pathogenic,Autosomal dominant inheritance,PTEN,2023-10-19,PP4,not_met,PubMed:28086757,Patient #5 proband specificity score is 5.,Patient #5 described in paper by Negishi et al is a 4.9mo female who has an OFC of 4.3 SD and developmental delay.  Proband specificity score is 5 so PP4 can be applied. - JM agree but added to PS4 instead of PP4.,Patient #5 described in paper by Negishi et al is a 4.9mo female who has an OFC of 4.3 SD and developmental delay.  Proband specificity score is 5 so PP4 can be applied. - JM agree but added to PS4 instead of PP4. Patient #5 proband specificity score is 5.,ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
759,NM_000314.6(PTEN):c.320A>T (p.Asp107Val),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2019-07-23,PS2,not_met,PubMed:25418537,,, ,ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
759,NM_000314.6(PTEN):c.320A>T (p.Asp107Val),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2019-07-23,PM6,met,PubMed:25418537,,"Variant occurred de novo in a child in the autism simplex cohort; methods appear to have been targeted to known candidate genes, not exome-based, but paper notes ""paternity firmly established"" via other variant info. May review with team to see whether would wish to apply PM6 or PS2. KS: Agrees and suggests applying PM6.","Variant occurred de novo in a child in the autism simplex cohort; methods appear to have been targeted to known candidate genes, not exome-based, but paper notes ""paternity firmly established"" via other variant info. May review with team to see whether would wish to apply PM6 or PS2. KS: Agrees and suggests applying PM6. ",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
4263,NC_012920.1:m.3291T>C,MT-TL1,mitochondrial disease,MONDO:0044970,Likely Pathogenic,Mitochondrial inheritance,Mitochondrial Diseases,2022-10-13,PS3-Supporting,not_met,PubMed:23273904,"Single fiber testing showed greater abundance of mutant genomes in COX-deficient (89.1± 9.9%, n=18), than in COX-positive fibers (51.1±27.1%, n=17; P < 0.001; PS3_supporting, PMID: 23273904).","Single fiber testing showed greater abundance of mutant genomes in COX-deficient (89.1± 9.9%, n=18), than in COX-positive fibers (51.1±27.1%, n=17; P < 0.001; PS3_supporting, PMID: 23273904).
","Single fiber testing showed greater abundance of mutant genomes in COX-deficient (89.1± 9.9%, n=18), than in COX-positive fibers (51.1±27.1%, n=17; P < 0.001; PS3_supporting, PMID: 23273904).
 Single fiber testing showed greater abundance of mutant genomes in COX-deficient (89.1± 9.9%, n=18), than in COX-positive fibers (51.1±27.1%, n=17; P < 0.001; PS3_supporting, PMID: 23273904).",ClinGenMitochondrialDiseaseNuclearandMitochondrialExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_mtDNA_version=1.0.0.csv
4870,NC_012920.1:m.5690A>G,MT-TN,mitochondrial disease,MONDO:0044970,Likely Pathogenic,Mitochondrial inheritance,Mitochondrial Diseases,2023-03-31,PS3-Supporting,not_met,PubMed:23696415,Single fiber study demonstrated that the COX defect segregated dramatically with the mutation-bearing fibers.,"Single fiber testing showed higher levels of the variant in COX-deficient fibers (86.8 ± 18.3%) than in COX-positive fibers (27.9 ± 31.3%, p<0.0001, PMID: 23696415; PS3_supporting).","Single fiber testing showed higher levels of the variant in COX-deficient fibers (86.8 ± 18.3%) than in COX-positive fibers (27.9 ± 31.3%, p<0.0001, PMID: 23696415; PS3_supporting). Single fiber study demonstrated that the COX defect segregated dramatically with the mutation-bearing fibers.",ClinGenMitochondrialDiseaseNuclearandMitochondrialExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_mtDNA_version=1.0.0.csv
5109,m.7497G>A,MT-TS1,mitochondrial disease,MONDO:0044970,Likely Pathogenic,Mitochondrial inheritance,Mitochondrial Diseases,2023-05-19,PS3-Supporting,not_met,PubMed:16199753,"Cybrid studies showed a correlation between higher heteroplasmy level and lower complex I and IV activity (PS3_supporting, PMID: 16199753).  ","Cybrid studies showed a correlation between higher heteroplasmy level and lower complex I and IV activity (PS3_supporting, PMID: 16199753).  ","Cybrid studies showed a correlation between higher heteroplasmy level and lower complex I and IV activity (PS3_supporting, PMID: 16199753).   Cybrid studies showed a correlation between higher heteroplasmy level and lower complex I and IV activity (PS3_supporting, PMID: 16199753).  ",ClinGenMitochondrialDiseaseNuclearandMitochondrialExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_mtDNA_version=1.0.0.csv
6600,NC_012920.1(MT-ND6):m.14513_14514del,MT-ND6,mitochondrial disease,MONDO:0044970,Likely Pathogenic,Mitochondrial inheritance,Mitochondrial Diseases,2024-03-15,PS3-Supporting,not_met,PubMed:32158465,Single fiber testing showed that heteroplasmy levels in COX-positive ragged-red fibers was 90.9 ± 0.74% (n=21) and in COX-positive non-ragged-red fibers was 31.7 ± 9.6% (n=17; p < 0.0001; PS3_supporting; PMID: 32158465).,Single fiber testing showed that heteroplasmy levels in COX-positive ragged-red fibers was 90.9 ± 0.74% (n=21) and in COX-positive non-ragged-red fibers was 31.7 ± 9.6% (n=17; p < 0.0001; PS3_supporting; PMID: 32158465). ,Single fiber testing showed that heteroplasmy levels in COX-positive ragged-red fibers was 90.9 ± 0.74% (n=21) and in COX-positive non-ragged-red fibers was 31.7 ± 9.6% (n=17; p < 0.0001; PS3_supporting; PMID: 32158465).  Single fiber testing showed that heteroplasmy levels in COX-positive ragged-red fibers was 90.9 ± 0.74% (n=21) and in COX-positive non-ragged-red fibers was 31.7 ± 9.6% (n=17; p < 0.0001; PS3_supporting; PMID: 32158465).,ClinGenMitochondrialDiseaseNuclearandMitochondrialExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_mtDNA_version=1.0.0.csv
7456,NC_012920.1:m.8340G>A,,mitochondrial disease,MONDO:0044970,Likely Pathogenic,Mitochondrial inheritance,Mitochondrial Diseases,2024-07-23,PS3-Supporting,not_met,PubMed:28729369,"Muscle histology and histochemistry revealed numerous COX-deficient, ragged-red fibers. Quadruple immunofluorescence demonstrated loss of both complex I (NDUFBA) and complex IV (COX-1) subunits, confirming a multiple mitochondrial respiratory chain disorder. Single-fiber PCR analysis of the m.8340G>A variant showed clear segregation with a biochemical defect in individual COX-deficient muscle fibers.","Single fiber testing showed higher levels of the variant in COX-deficient fibers (93.1% ± 0.26%, N=17) than in COX-positive fibers (29.5% ± 8.97, N=16), p<0.0001 (PS3_supporting, PMID: 28729369). ","Single fiber testing showed higher levels of the variant in COX-deficient fibers (93.1% ± 0.26%, N=17) than in COX-positive fibers (29.5% ± 8.97, N=16), p<0.0001 (PS3_supporting, PMID: 28729369).  Muscle histology and histochemistry revealed numerous COX-deficient, ragged-red fibers. Quadruple immunofluorescence demonstrated loss of both complex I (NDUFBA) and complex IV (COX-1) subunits, confirming a multiple mitochondrial respiratory chain disorder. Single-fiber PCR analysis of the m.8340G>A variant showed clear segregation with a biochemical defect in individual COX-deficient muscle fibers.",ClinGenMitochondrialDiseaseNuclearandMitochondrialExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_mtDNA_version=1.0.0.csv
7655,NC_012920.1:m.14597A>G,,mitochondrial disease,MONDO:0044970,Likely Pathogenic,Mitochondrial inheritance,Mitochondrial Diseases,2024-08-12,PS3-Supporting,not_met,PubMed:34045482,"Analysis of three cybrid fibroblast cell lines demonstrated significantly reduced complex I activity, respiration rate, & ATP content.
","Cybrid studies support the functional impact of this variant (PS3_supporting; PMIDs: 34045482) as significantly reduced complex I activity, respiration rate, and ATP content in three cybrid fibroblast cell lines were demonstrated.","Cybrid studies support the functional impact of this variant (PS3_supporting; PMIDs: 34045482) as significantly reduced complex I activity, respiration rate, and ATP content in three cybrid fibroblast cell lines were demonstrated. Analysis of three cybrid fibroblast cell lines demonstrated significantly reduced complex I activity, respiration rate, & ATP content.
",ClinGenMitochondrialDiseaseNuclearandMitochondrialExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_mtDNA_version=1.0.0.csv
4852,m.14487T>C,MT-ND6,mitochondrial disease,MONDO:0044970,Pathogenic,Mitochondrial inheritance,Mitochondrial Diseases,2023-03-29,PS3-Moderate,not_met,PubMed:35715829,"Complex I-deficient fibroblasts were transiently co-cultured with bone marrow-derived MSCs. Co-culturing of complex I-deficient fibroblasts with MSC mitochondria lowered cellular ROS levels [and]  significantly improved mitochondrial respiration, indicating a mitigation of the oxidative phosphorylation defect.","Cybrid studies have shown independent functional consequences (PS3_moderate) including almost undetectable rotenone-dependent oxygen consumption (PMID 14520668), an overproduction of reactive oxygen species (ROS, PMID 16337195), and decreased complex I activity corresponding with heteroplasmy levels as well as decreased levels of fully assembled complex I (PMID 14595656). ","Cybrid studies have shown independent functional consequences (PS3_moderate) including almost undetectable rotenone-dependent oxygen consumption (PMID 14520668), an overproduction of reactive oxygen species (ROS, PMID 16337195), and decreased complex I activity corresponding with heteroplasmy levels as well as decreased levels of fully assembled complex I (PMID 14595656).  Complex I-deficient fibroblasts were transiently co-cultured with bone marrow-derived MSCs. Co-culturing of complex I-deficient fibroblasts with MSC mitochondria lowered cellular ROS levels [and]  significantly improved mitochondrial respiration, indicating a mitigation of the oxidative phosphorylation defect.",ClinGenMitochondrialDiseaseNuclearandMitochondrialExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_mtDNA_version=1.0.0.csv
6724,m.4160T>C,MT-ND1,mitochondrial disease,MONDO:0044970,Uncertain Significance,Mitochondrial inheritance,Mitochondrial Diseases,2024-04-02,PS3,not_met,PubMed:35699829,"Western blotting showed that the levels of mtDNA-encoded polypeptides (ND1, ND4, ND5, and ATP6) in mutant cybrid cells were significantly reduced, demonstrating that mitochondrial translation was 
impaired. The analysis of cellular bioenergetic activities indicated that the mitochondrial complex I- and II-associated respiration chains were remarkably deficient.","Cybrid studies supported the functional impact of this variant. However given these patients also harbored the m.14484 T>C, p.M64V therefore it will not be counted (PMID: 35699829).","Cybrid studies supported the functional impact of this variant. However given these patients also harbored the m.14484 T>C, p.M64V therefore it will not be counted (PMID: 35699829). Western blotting showed that the levels of mtDNA-encoded polypeptides (ND1, ND4, ND5, and ATP6) in mutant cybrid cells were significantly reduced, demonstrating that mitochondrial translation was 
impaired. The analysis of cellular bioenergetic activities indicated that the mitochondrial complex I- and II-associated respiration chains were remarkably deficient.",ClinGenMitochondrialDiseaseNuclearandMitochondrialExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_mtDNA_version=1.0.0.csv
1323,NM_000152.4(GAA):c.2662G>T (p.Glu888Ter),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-05-27,PP4,met,PubMed:25526786,,"At least 6 patients have been reported with have been reported with this variant and GAA activity <10% normal in lymphocytes, leukocytes, or muscle samples, or <30% normal activity in cultured fibroblasts, or in the affected range in a GAA activity assay (PMIDs 16531044, 17723315, 18458862, 21232767, 25526786). This meets the specifications for PP4.","At least 6 patients have been reported with have been reported with this variant and GAA activity <10% normal in lymphocytes, leukocytes, or muscle samples, or <30% normal activity in cultured fibroblasts, or in the affected range in a GAA activity assay (PMIDs 16531044, 17723315, 18458862, 21232767, 25526786). This meets the specifications for PP4. ",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1703,NM_000152.4(GAA):c.241C>T (p.Gln81Ter),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-11-11,PP4,met,PubMed:25526786,,"Three siblings with this variant have residual GAA activity in lymphocytes <10% of the normal mean (PMID 25526786). Note that in some other studies, c.2238G>C (p.Trp746Cys) has been found in cis with the pseudodeficiency variant, p.Gly576Ser. This pseudodeficiency variant was not reported in this study and hence PP4 is met.","Three siblings with this variant have residual GAA activity in lymphocytes <10% of the normal mean (PMID 25526786). Note that in some other studies, c.2238G>C (p.Trp746Cys) has been found in cis with the pseudodeficiency variant, p.Gly576Ser. This pseudodeficiency variant was not reported in this study and hence PP4 is met. ",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1737,NM_000152.5(GAA):c.2214G>A (p.Trp738Ter),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-11-12,PP4,met,PubMed:22676651,,Twins have been reported with this variant and GAA activity in dried blood spots in the affected range in a clinically validated assay (PMID 26575883) and another patient has GAA activity in the affected range in lymphocytes (PMID 22676651). This meets the specifications for PP4.,Twins have been reported with this variant and GAA activity in dried blood spots in the affected range in a clinically validated assay (PMID 26575883) and another patient has GAA activity in the affected range in lymphocytes (PMID 22676651). This meets the specifications for PP4. ,ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1347,NM_000152.5(GAA):c.1352C>G (p.Pro451Arg),GAA,glycogen storage disease II,MONDO:0009290,Likely Benign,Autosomal recessive inheritance,Lysosomal Diseases,2023-05-26,PM3,not_met,PubMed:29149851,"Patient 21, with limb girdle muscular dystrophy, is compound heterozygous for c.1352C>G (p.Pro451Arg) and an intronic variant, c.1438-7_1438-5delTGT. The phase of the variants is unknown. No GAA activity is provided for the patient. The authors stated that this combination of variants was not thought to be causative of the patient’s phenotype.","A patient with limb-girdle muscle weakness has been reported to be compound heterozygous for  c.1352C>G (p.Pro451Arg) and an intronic variant, c.1438-7_1438-5delTGT (PMID 29149851). The phase of the variants is unknown and no GAA activity was provided for the patient. The authors stated that this combination of variants was not thought to be causative of the patient’s phenotype. Therefore, this criterion is not met.","A patient with limb-girdle muscle weakness has been reported to be compound heterozygous for  c.1352C>G (p.Pro451Arg) and an intronic variant, c.1438-7_1438-5delTGT (PMID 29149851). The phase of the variants is unknown and no GAA activity was provided for the patient. The authors stated that this combination of variants was not thought to be causative of the patient’s phenotype. Therefore, this criterion is not met. Patient 21, with limb girdle muscular dystrophy, is compound heterozygous for c.1352C>G (p.Pro451Arg) and an intronic variant, c.1438-7_1438-5delTGT. The phase of the variants is unknown. No GAA activity is provided for the patient. The authors stated that this combination of variants was not thought to be causative of the patient’s phenotype.",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1720,NM_000152.5(GAA):c.755dup (p.Pro253fs),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-11-11,PM3,not_met,PubMed:29124014,,One patient meeting the ClinGen LSD VCEP's specifications for PP4 has been reported (PMID 29124014). This patient is compound heterozygous for the variant and c.569G>A (p.Arg190His). The phase is unknown. This is intrans data will be used in the assessment of p.Arg190His and is therefore not included here in order to avoid a circular argument.,One patient meeting the ClinGen LSD VCEP's specifications for PP4 has been reported (PMID 29124014). This patient is compound heterozygous for the variant and c.569G>A (p.Arg190His). The phase is unknown. This is intrans data will be used in the assessment of p.Arg190His and is therefore not included here in order to avoid a circular argument. ,ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1719,NM_000152.5(GAA):c.525_526del (p.Asn177fs),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-11-11,PM3-Supporting,not_met,PubMed:23825616,,"One individual with Pompe disease and meeting the ClinGen LSD VCEP’s specifications for PP4 has been reported in the literature (PMID 22252923, 23825616). This patient is homozygous for the variant, meeting PM3_Supporting. Two other individuals with the variant have been reported. One is homozygous (PMID 25455803; different than the individual reported in PMID 25455803 based on the age at diagnosis) another individual who is compound heterozygous for the variant and c.-32-13T>G (PMID 31392188). However, these patients were not included because the residual activity was not provided, and therefore PP4 cannot be assessed, and PM3 was not applied.","One individual with Pompe disease and meeting the ClinGen LSD VCEP’s specifications for PP4 has been reported in the literature (PMID 22252923, 23825616). This patient is homozygous for the variant, meeting PM3_Supporting. Two other individuals with the variant have been reported. One is homozygous (PMID 25455803; different than the individual reported in PMID 25455803 based on the age at diagnosis) another individual who is compound heterozygous for the variant and c.-32-13T>G (PMID 31392188). However, these patients were not included because the residual activity was not provided, and therefore PP4 cannot be assessed, and PM3 was not applied. ",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
3162,NM_000261.2:c.731G>T,MYOC,primary open angle glaucoma,MONDO:0007665,Uncertain Significance,Autosomal dominant inheritance,Glaucoma,2022-07-11,BS3,not_met,PubMed:27092720,"The G244V protein is secreted.
This study does not meet the OddsPath threshold for  BS3_Supporting (< 0.48).","The study reporting functional evidence (PMID: 27092720) demonstrated that the Gly244Val protein had similar secretion levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (< 0.48) for BS3_Supporting to be applied.","The study reporting functional evidence (PMID: 27092720) demonstrated that the Gly244Val protein had similar secretion levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (< 0.48) for BS3_Supporting to be applied. The G244V protein is secreted.
This study does not meet the OddsPath threshold for  BS3_Supporting (< 0.48).",ClinGenGlaucomaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYOCVersion2.0.0_version=2.0.0.csv
3208,NM_000261.2:c.898G>A,MYOC,primary open angle glaucoma,MONDO:0007665,Uncertain Significance,Autosomal dominant inheritance,Glaucoma,2022-07-11,BS3,not_met,PubMed:27092720,"The E300K protein is not secreted.
This study does not meet the OddsPath threshold for PS3_Supporting (> 2.1).  ","Although the OddsPath threshold for PS3_Supporting was not met, this variant may impact protein function (see PS3 comment).","Although the OddsPath threshold for PS3_Supporting was not met, this variant may impact protein function (see PS3 comment). The E300K protein is not secreted.
This study does not meet the OddsPath threshold for PS3_Supporting (> 2.1).  ",ClinGenGlaucomaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYOCVersion2.0.0_version=2.0.0.csv
4479,NM_000261.2:c.1037G>C,MYOC,primary open angle glaucoma,MONDO:0007665,Uncertain Significance,Autosomal dominant inheritance,Glaucoma,2022-12-14,BS3,not_met,PubMed:17615537,"The study reporting functional evidence (PMID: 17615537) demonstrated that the Arg346Thr
protein had reduced solubility levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (> 2.1) for PS3_Supporting to be applied.    ","No functional evidence has been found for this variant.
","No functional evidence has been found for this variant.
 The study reporting functional evidence (PMID: 17615537) demonstrated that the Arg346Thr
protein had reduced solubility levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (> 2.1) for PS3_Supporting to be applied.    ",ClinGenGlaucomaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYOCVersion2.0.0_version=2.0.0.csv
3162,NM_000261.2:c.731G>T,MYOC,primary open angle glaucoma,MONDO:0007665,Uncertain Significance,Autosomal dominant inheritance,Glaucoma,2022-07-11,PS3,not_met,PubMed:27092720,"The G244V protein is secreted.
This study does not meet the OddsPath threshold for  BS3_Supporting (< 0.48).","Although the OddsPath threshold for BS3_Supporting was not met, no functional evidence indicating that this variant impacts protein function has been found.
","Although the OddsPath threshold for BS3_Supporting was not met, no functional evidence indicating that this variant impacts protein function has been found.
 The G244V protein is secreted.
This study does not meet the OddsPath threshold for  BS3_Supporting (< 0.48).",ClinGenGlaucomaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYOCVersion2.0.0_version=2.0.0.csv
3208,NM_000261.2:c.898G>A,MYOC,primary open angle glaucoma,MONDO:0007665,Uncertain Significance,Autosomal dominant inheritance,Glaucoma,2022-07-11,PS3,not_met,PubMed:27092720,"The E300K protein is not secreted.
This study does not meet the OddsPath threshold for PS3_Supporting (> 2.1).  ","The study reporting functional evidence (PMID: 27092720) demonstrated that the Glu300Lys protein had reduced secretion levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (> 2.1) for PS3_Supporting to be applied. ","The study reporting functional evidence (PMID: 27092720) demonstrated that the Glu300Lys protein had reduced secretion levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (> 2.1) for PS3_Supporting to be applied.  The E300K protein is not secreted.
This study does not meet the OddsPath threshold for PS3_Supporting (> 2.1).  ",ClinGenGlaucomaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYOCVersion2.0.0_version=2.0.0.csv
4479,NM_000261.2:c.1037G>C,MYOC,primary open angle glaucoma,MONDO:0007665,Uncertain Significance,Autosomal dominant inheritance,Glaucoma,2022-12-14,PS3,not_met,PubMed:17615537,"The study reporting functional evidence (PMID: 17615537) demonstrated that the Arg346Thr
protein had reduced solubility levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (> 2.1) for PS3_Supporting to be applied.    ","The study reporting functional evidence (PMID: 17615537) demonstrated that the Arg346Thr
protein had reduced solubility levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (> 2.1) for PS3_Supporting to be applied.    
","The study reporting functional evidence (PMID: 17615537) demonstrated that the Arg346Thr
protein had reduced solubility levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (> 2.1) for PS3_Supporting to be applied.    
 The study reporting functional evidence (PMID: 17615537) demonstrated that the Arg346Thr
protein had reduced solubility levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (> 2.1) for PS3_Supporting to be applied.    ",ClinGenGlaucomaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYOCVersion2.0.0_version=2.0.0.csv
3859,NM_001754.5(RUNX1):c.496C>T (p.Arg166Ter),RUNX1,hereditary thrombocytopenia and hematologic cancer predisposition syndrome,MONDO:0011071,Pathogenic,Autosomal dominant inheritance,Myeloid Malignancy,2022-07-05,PS3,not_met,PubMed:33692461,"R139* shows Transactivation assays demonstrating altered transactivation (<20% of wt, and/or reduced to levels similar to well-established pathogenic variants such as R201Q or R166Q) in luciferase assay",: Transactivation assays demonstrating enhanced transactivation (>115% of wt) (PS3_Supporting; PMID: 33692461) Cannot be applied because meet PVS1,": Transactivation assays demonstrating enhanced transactivation (>115% of wt) (PS3_Supporting; PMID: 33692461) Cannot be applied because meet PVS1 R139* shows Transactivation assays demonstrating altered transactivation (<20% of wt, and/or reduced to levels similar to well-established pathogenic variants such as R201Q or R166Q) in luciferase assay",ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
3859,NM_001754.5(RUNX1):c.496C>T (p.Arg166Ter),RUNX1,hereditary thrombocytopenia and hematologic cancer predisposition syndrome,MONDO:0011071,Pathogenic,Autosomal dominant inheritance,Myeloid Malignancy,2022-07-05,BS3,not_met,PubMed:33692461,"R139* shows Transactivation assays demonstrating altered transactivation (<20% of wt, and/or reduced to levels similar to well-established pathogenic variants such as R201Q or R166Q) in luciferase assay",: Transactivation assays demonstrating enhanced transactivation (>115% of wt) (PS3_Supporting; PMID: 33692461) Cannot be applied because meets PVS1,": Transactivation assays demonstrating enhanced transactivation (>115% of wt) (PS3_Supporting; PMID: 33692461) Cannot be applied because meets PVS1 R139* shows Transactivation assays demonstrating altered transactivation (<20% of wt, and/or reduced to levels similar to well-established pathogenic variants such as R201Q or R166Q) in luciferase assay",ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
800,NM_001754.5(RUNX1):c.442_449del (p.Thr148fs),RUNX1,hereditary thrombocytopenia and hematologic cancer predisposition syndrome,MONDO:0011071,Pathogenic,Autosomal dominant inheritance,Myeloid Malignancy,2024-03-26,PS4-Supporting,not_met,PubMed:27112265,One family with FPD/AML.,One family with FPD/AML.,One family with FPD/AML. One family with FPD/AML.,ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
800,NM_001754.5(RUNX1):c.442_449del (p.Thr148fs),RUNX1,hereditary thrombocytopenia and hematologic cancer predisposition syndrome,MONDO:0011071,Pathogenic,Autosomal dominant inheritance,Myeloid Malignancy,2024-03-26,PP1,not_met,PubMed:27112265,One meiosis,One meiosis,One meiosis One meiosis,ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
800,NM_001754.5(RUNX1):c.442_449del (p.Thr148fs),RUNX1,hereditary thrombocytopenia and hematologic cancer predisposition syndrome,MONDO:0011071,Pathogenic,Autosomal dominant inheritance,Myeloid Malignancy,2024-03-26,BS4,not_met,PubMed:27112265,One meiosis,, One meiosis,ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
5936,NM_000162.5(GCK):c.449T>A (p.Phe150Tyr),GCK,monogenic diabetes,MONDO:0015967,Pathogenic,Semidominant inheritance,Monogenic Diabetes,2024-01-06,PS3-Moderate,not_met,PubMed:22761713,QC parameters met; RAI = 0.014 +/- 0.003,"MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.014, which is below the MDEP cutoff (<0.5) (PMID: 22761713).","MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.014, which is below the MDEP cutoff (<0.5) (PMID: 22761713). QC parameters met; RAI = 0.014 +/- 0.003",ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGCKVersion2.0.0_version=2.0.0.csv
3434,NM_001306179.2:c.763G>A,HNF1A,monogenic diabetes,MONDO:0015967,Uncertain Significance,Autosomal dominant inheritance,Monogenic Diabetes,2022-07-12,BS3-Supporting,not_met,PubMed:27229139,Functional studies demonstrated the p.255 protein has DNA binding above 75% of wild type (PMID: 27229139).,Functional studies demonstrated the p.Gly255Ser protein has DNA binding above 75% of wild type (PMID: 27229139).,Functional studies demonstrated the p.Gly255Ser protein has DNA binding above 75% of wild type (PMID: 27229139). Functional studies demonstrated the p.255 protein has DNA binding above 75% of wild type (PMID: 27229139).,ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF1AVersion2.1.0_version=2.1.0.csv
3619,NM_000545.8(HNF1A):c.185A>G (p.Asn62Ser),HNF1A,monogenic diabetes,MONDO:0015967,Benign,Autosomal dominant inheritance,Monogenic Diabetes,2022-06-03,BS3,not_met,PubMed:27899486,Figure 2 showed and table 1 summarized that N62S HNF1A has 65% transcriptional activity of wild type HNF1A. Figure 3 showed and table 1 summarized that N62S HNF1A has 70% of nuclear location of wild type HNF1A. (HZ 11/4/18),Najimi et al. reported that N62S HNF1A has 65% transcriptional activity and 70% of nuclear localization of wild type HNF1A.,Najimi et al. reported that N62S HNF1A has 65% transcriptional activity and 70% of nuclear localization of wild type HNF1A. Figure 2 showed and table 1 summarized that N62S HNF1A has 65% transcriptional activity of wild type HNF1A. Figure 3 showed and table 1 summarized that N62S HNF1A has 70% of nuclear location of wild type HNF1A. (HZ 11/4/18),ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF1AVersion2.1.0_version=2.1.0.csv
5545,NM_000545.8(HNF1A):c.66C>G (p.Ser22Arg),HNF1A,monogenic diabetes,MONDO:0015967,Uncertain Significance,Autosomal dominant inheritance,Monogenic Diabetes,2025-01-22,PS3-Supporting,not_met,PubMed:37798422, TA activity 36%; DNA binding 49%. (Supplementary Figure 6),"Functional studies demonstrated the p.Ser22Arg protein has transactivation below 40% of wildtype, indicating that this variant impacts protein function (PS3_Supporting; PMID: 37798422).","Functional studies demonstrated the p.Ser22Arg protein has transactivation below 40% of wildtype, indicating that this variant impacts protein function (PS3_Supporting; PMID: 37798422).  TA activity 36%; DNA binding 49%. (Supplementary Figure 6)",ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF1AVersion2.1.0_version=2.1.0.csv
7053,NM_000545.8(HNF1A):c.347C>T (p.Ala116Val),HNF1A,monogenic diabetes,MONDO:0015967,Pathogenic,Autosomal dominant inheritance,Monogenic Diabetes,2024-06-09,PS3,not_met,PubMed:32910913,"yielded transactivation values of 40% and ∼60% in HeLa and ∼50 and ∼100% in INS-1 assays, respectively","While studies exploring the effect of this variant on protein function have been performed, these studies do not meet the criteria set forth by the MDEP for the application of PS3 or BS3 as the transactitivation values were not consistently within or outside the cutoffs for PS3_Moderate or BS3_Supporting (PMID: 32910913). ","While studies exploring the effect of this variant on protein function have been performed, these studies do not meet the criteria set forth by the MDEP for the application of PS3 or BS3 as the transactitivation values were not consistently within or outside the cutoffs for PS3_Moderate or BS3_Supporting (PMID: 32910913).  yielded transactivation values of 40% and ∼60% in HeLa and ∼50 and ∼100% in INS-1 assays, respectively",ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF1AVersion2.1.0_version=2.1.0.csv
5072,NM_000527.5(LDLR):c.1003G>T (p.Gly335Cys),LDLR,"hypercholesterolemia, familial",MONDO:0007750,Likely Pathogenic,Semidominant inheritance,Familial Hypercholesterolemia,2023-05-01,PS3-Moderate,not_met,PubMed:34970301,"Heterologous cells (HEK293), Western blot and Dil-LDL (just uptake) assays - results: less mature LDLR detected, 43% uptake.","Level 2 FS: Hu et al. 2021 (PMID: 34970301): Heterologous cells (HEK293), Western blot and Dil-LDL (just uptake) assays - results: less mature LDLR detected, 43% uptake.
---- part of the LDLR cycle (uptake) is less than 70% activity of wild-type, so PS3_Moderate is met","Level 2 FS: Hu et al. 2021 (PMID: 34970301): Heterologous cells (HEK293), Western blot and Dil-LDL (just uptake) assays - results: less mature LDLR detected, 43% uptake.
---- part of the LDLR cycle (uptake) is less than 70% activity of wild-type, so PS3_Moderate is met Heterologous cells (HEK293), Western blot and Dil-LDL (just uptake) assays - results: less mature LDLR detected, 43% uptake.",ClinGenFamilialHypercholesterolemiaExpertPanelSpecificationstotheACMGAMPVariantClassificationGuidelinesVersion1.2_version=1.2.0.csv
8146,NM_000527.5(LDLR):c.1444G>C (p.Asp482His),LDLR,"hypercholesterolemia, familial",MONDO:0007750,Likely Pathogenic,Semidominant inheritance,Familial Hypercholesterolemia,2024-09-25,PS3-Moderate,not_met,PubMed:31587492,"Level 2 assay- HeLa cells and HEK-293T cells. In immunoblots of the mutants D482H, only the precursor form was observed (~120 kDa) and the mature receptor form was absent.","Level 2 assays PMID 31587492- HEK-293T cells. In immunoblots of the mutants, only the precursor form was observed (~120 kDa) and the mature receptor form was absent. So, PS3_Moderate was met.","Level 2 assays PMID 31587492- HEK-293T cells. In immunoblots of the mutants, only the precursor form was observed (~120 kDa) and the mature receptor form was absent. So, PS3_Moderate was met. Level 2 assay- HeLa cells and HEK-293T cells. In immunoblots of the mutants D482H, only the precursor form was observed (~120 kDa) and the mature receptor form was absent.",ClinGenFamilialHypercholesterolemiaExpertPanelSpecificationstotheACMGAMPVariantClassificationGuidelinesVersion1.2_version=1.2.0.csv
2358,NM_000527.5(LDLR):c.2575G>A (p.Val859Met),LDLR,"hypercholesterolemia, familial",MONDO:0007750,Likely Benign,Semidominant inheritance,Familial Hypercholesterolemia,2021-06-24,BS3,met,PubMed:25386756,"Expression >90%, uptake 90%, degradation of 125I-LDL 90%","PMID: 25386756 - Level 1 assay - Expression >90%, uptake 90%, degradation of 125I-LDL 90%.","PMID: 25386756 - Level 1 assay - Expression >90%, uptake 90%, degradation of 125I-LDL 90%. Expression >90%, uptake 90%, degradation of 125I-LDL 90%",ClinGenFamilialHypercholesterolemiaExpertPanelSpecificationstotheACMGAMPVariantClassificationGuidelinesVersion1.2_version=1.2.0.csv
8149,NM_000527.5(LDLR):c.1739C>T (p.Ser580Phe),LDLR,"hypercholesterolemia, familial",MONDO:0007750,Likely Pathogenic,Semidominant inheritance,Familial Hypercholesterolemia,2024-09-25,PS3-Supporting,not_met,PubMed:35474963,"het monocytes and lymphocytes used; 25-50% LDL uptake and LDLR surface expression (Fig 1G, 2A, 2B, SF1J)","Level 3 assay: PMID  35474963: Heterozygous patients monocytes and lymphocytes - results - 25-50% low-density lipoprotein particle uptake and LDLR surface expression. 
---- Overall LDLR expression and activity is below 85% of wild-type activity. So, PS3_Supporting is met.","Level 3 assay: PMID  35474963: Heterozygous patients monocytes and lymphocytes - results - 25-50% low-density lipoprotein particle uptake and LDLR surface expression. 
---- Overall LDLR expression and activity is below 85% of wild-type activity. So, PS3_Supporting is met. het monocytes and lymphocytes used; 25-50% LDL uptake and LDLR surface expression (Fig 1G, 2A, 2B, SF1J)",ClinGenFamilialHypercholesterolemiaExpertPanelSpecificationstotheACMGAMPVariantClassificationGuidelinesVersion1.2_version=1.2.0.csv
9523,NM_000180.4(GUCY2D):c.1762C>T (p.Arg588Trp),GUCY2D,GUCY2D-related recessive retinopathy,MONDO:0100453,Pathogenic,Autosomal recessive inheritance,Leber Congenital Amaurosis/early onset Retinal Dystrophy,2025-01-30,PS3-Supporting,not_met,PubMed:36274938,"The variant exhibited <1.5% of wt activity when stimulated with GCAP1, GCAP2, or GCAP3. which is lower than the ClinGen LCA / eoRD VCEP PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function . In addition, variant protein failed to co-localize with GCAP1 when co-expressed in HEK293 cells (PS3_Supporting).","The variant exhibited <1.5% of wt activity when stimulated with GCAP1, GCAP2, or GCAP3. which is lower than the ClinGen LCA / eoRD VCEP PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function . In addition, variant protein failed to co-localize with GCAP1 when co-expressed in HEK293 cells (PS3_Supporting, PMID: 36274938).","The variant exhibited <1.5% of wt activity when stimulated with GCAP1, GCAP2, or GCAP3. which is lower than the ClinGen LCA / eoRD VCEP PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function . In addition, variant protein failed to co-localize with GCAP1 when co-expressed in HEK293 cells (PS3_Supporting, PMID: 36274938). The variant exhibited <1.5% of wt activity when stimulated with GCAP1, GCAP2, or GCAP3. which is lower than the ClinGen LCA / eoRD VCEP PS3_Supporting threshold of <10% activity, indicating that it triggers a severe defect in protein function . In addition, variant protein failed to co-localize with GCAP1 when co-expressed in HEK293 cells (PS3_Supporting).",ClinGenLeberCongenitalAmaurosisearlyonsetRetinalDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGUCY2DVersion1.0.0_version=1.0.0.csv
9547,NM_000180.4(GUCY2D):c.3271C>T (p.Arg1091Ter),GUCY2D,GUCY2D-related recessive retinopathy,MONDO:0100453,Pathogenic,Autosomal recessive inheritance,Leber Congenital Amaurosis/early onset Retinal Dystrophy,2025-01-30,BS3,not_met,PubMed:27881908,"AAV-packaged WT or mutant GUCY2D expression constructs under a human rhodopsin kinase promoter were delivered by subretinal injenction into Gucy2e−/−Gucy2f−/− knockout mouse retinas. Electroretinography (Figure 2), guanylyl cyclase activity assays (Figure 3A), anti-GUCY2D immunoblotting (Figure 3B) and transcript quantification (Figure 3C), and anti-GUCY2D immunofluorescence (Figure 4) showed successful rescue by the variant.","The variant showed successsful rescue of rod and cone function when delivered by subretinal injection into Gucy2e−/−Gucy2f−/− knockout mouse retinas, however, this model was not considered sufficient evidence of non-pathogenicity in humans so was not applicable for BS3 (PMID: 27881908).","The variant showed successsful rescue of rod and cone function when delivered by subretinal injection into Gucy2e−/−Gucy2f−/− knockout mouse retinas, however, this model was not considered sufficient evidence of non-pathogenicity in humans so was not applicable for BS3 (PMID: 27881908). AAV-packaged WT or mutant GUCY2D expression constructs under a human rhodopsin kinase promoter were delivered by subretinal injenction into Gucy2e−/−Gucy2f−/− knockout mouse retinas. Electroretinography (Figure 2), guanylyl cyclase activity assays (Figure 3A), anti-GUCY2D immunoblotting (Figure 3B) and transcript quantification (Figure 3C), and anti-GUCY2D immunofluorescence (Figure 4) showed successful rescue by the variant.",ClinGenLeberCongenitalAmaurosisearlyonsetRetinalDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGUCY2DVersion1.0.0_version=1.0.0.csv
9547,NM_000180.4(GUCY2D):c.3271C>T (p.Arg1091Ter),GUCY2D,GUCY2D-related recessive retinopathy,MONDO:0100453,Pathogenic,Autosomal recessive inheritance,Leber Congenital Amaurosis/early onset Retinal Dystrophy,2025-01-30,PS3,not_met,PubMed:27881908,"AAV-packaged WT or mutant GUCY2D expression constructs under a human rhodopsin kinase promoter were delivered by subretinal injenction into Gucy2e−/−Gucy2f−/− knockout mouse retinas. Electroretinography (Figure 2), guanylyl cyclase activity assays (Figure 3A), anti-GUCY2D immunoblotting (Figure 3B) and transcript quantification (Figure 3C), and anti-GUCY2D immunofluorescence (Figure 4) showed successful rescue by the variant.",Activity is reduced to 25% but is not less than LCA/eoRD cutoff of <10% activity (PMID: 23035049),"Activity is reduced to 25% but is not less than LCA/eoRD cutoff of <10% activity (PMID: 23035049) AAV-packaged WT or mutant GUCY2D expression constructs under a human rhodopsin kinase promoter were delivered by subretinal injenction into Gucy2e−/−Gucy2f−/− knockout mouse retinas. Electroretinography (Figure 2), guanylyl cyclase activity assays (Figure 3A), anti-GUCY2D immunoblotting (Figure 3B) and transcript quantification (Figure 3C), and anti-GUCY2D immunofluorescence (Figure 4) showed successful rescue by the variant.",ClinGenLeberCongenitalAmaurosisearlyonsetRetinalDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGUCY2DVersion1.0.0_version=1.0.0.csv
9551,NM_000180.4(GUCY2D):c.1724C>T (p.Pro575Leu),GUCY2D,GUCY2D-related recessive retinopathy,MONDO:0100453,Benign,Autosomal recessive inheritance,Leber Congenital Amaurosis/early onset Retinal Dystrophy,2025-01-30,BS3-Supporting,not_met,PubMed:24616660,"The variant exhibited ~75% enzymatic activity in a guanylate cyclase assay relative to the wild-type control, which is higher than the ClinGen LCA / eoRD BS3_Supporting threshold of ≥50% activity, indicating that it largely preserves normal protein function (PMID: 24616660, BS3_Supporting). On the other hand, the variant protein shows enhanced sensitivity to calcium as an inhibitor of stimulation by GCAP1 and GCAP2 (Figure 4), however, controls are not present, and this is a mechanism relevant to the dominant rather than the recessive mode of inheritance.","The variant exhibited ~75% enzymatic activity in a guanylate cyclase assay relative to the wild-type control, which is higher than the ClinGen LCA / eoRD BS3_Supporting threshold of ≥50% activity, indicating that it largely preserves normal protein function (PMID: 24616660, BS3_Supporting). On the other hand, the variant protein shows enhanced sensitivity to calcium as an inhibitor of stimulation by GCAP1 and GCAP2 (Figure 4), however, controls are not present, and this is a mechanism relevant to the dominant rather than the recessive mode of inheritance.","The variant exhibited ~75% enzymatic activity in a guanylate cyclase assay relative to the wild-type control, which is higher than the ClinGen LCA / eoRD BS3_Supporting threshold of ≥50% activity, indicating that it largely preserves normal protein function (PMID: 24616660, BS3_Supporting). On the other hand, the variant protein shows enhanced sensitivity to calcium as an inhibitor of stimulation by GCAP1 and GCAP2 (Figure 4), however, controls are not present, and this is a mechanism relevant to the dominant rather than the recessive mode of inheritance. The variant exhibited ~75% enzymatic activity in a guanylate cyclase assay relative to the wild-type control, which is higher than the ClinGen LCA / eoRD BS3_Supporting threshold of ≥50% activity, indicating that it largely preserves normal protein function (PMID: 24616660, BS3_Supporting). On the other hand, the variant protein shows enhanced sensitivity to calcium as an inhibitor of stimulation by GCAP1 and GCAP2 (Figure 4), however, controls are not present, and this is a mechanism relevant to the dominant rather than the recessive mode of inheritance.",ClinGenLeberCongenitalAmaurosisearlyonsetRetinalDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGUCY2DVersion1.0.0_version=1.0.0.csv
9559,NM_000180.4(GUCY2D):c.1371C>T (p.Cys457=),GUCY2D,GUCY2D-related recessive retinopathy,MONDO:0100453,Benign,Autosomal recessive inheritance,Leber Congenital Amaurosis/early onset Retinal Dystrophy,2025-01-30,BA1,met,PubMed:18682808,"Seong, et al, 2008, tested 20 Korean patients diagnosed with LCA and 170 control patients. GUCY2D cys457= is listed as a polymorphic variant and had an allele frequency of 0.75 in 170 controls tested.","This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.1129, with 5137 alleles/44460 total alleles and 134 homozygotes in the East Asian population, which is higher than the ClinGen LCA/eoRD VCEP BA1 threshold of >0.008. (BA1).","This variant is present in gnomAD v.4.1.0 at a GrpMax allele frequency of 0.1129, with 5137 alleles/44460 total alleles and 134 homozygotes in the East Asian population, which is higher than the ClinGen LCA/eoRD VCEP BA1 threshold of >0.008. (BA1). Seong, et al, 2008, tested 20 Korean patients diagnosed with LCA and 170 control patients. GUCY2D cys457= is listed as a polymorphic variant and had an allele frequency of 0.75 in 170 controls tested.",ClinGenLeberCongenitalAmaurosisearlyonsetRetinalDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGUCY2DVersion1.0.0_version=1.0.0.csv
8400,NM_000251.3(MSH2):c.1012G>A (p.Gly338Arg),MSH2,Lynch syndrome,MONDO:0005835,Pathogenic,Autosomal dominant inheritance,InSiGHT Hereditary Colorectal Cancer/Polyposis,2024-10-11,PS3,met,PubMed:32849802,Functional odds: 158.581 (CIMRA Functional Odds for Pathogenicity >18.7)  Data_Sheet_1,Functional odds: 158.581 (CIMRA Functional Odds for Pathogenicity >18.7),Functional odds: 158.581 (CIMRA Functional Odds for Pathogenicity >18.7) Functional odds: 158.581 (CIMRA Functional Odds for Pathogenicity >18.7)  Data_Sheet_1,ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMSH2Version1.0.0_version=1.0.0.csv
8408,NM_000179.3(MSH6):c.3482CTG[1] (p.Ala1162del),MSH6,Lynch syndrome,MONDO:0005835,Likely Pathogenic,Autosomal dominant inheritance,InSiGHT Hereditary Colorectal Cancer/Polyposis,2024-10-11,PS3,met,PubMed:31965077,CIMRA has shown a relative repair compared to wild type (WT) = 7.0% (corresponds to odds of ~43),CIMRA has shown a relative repair compared to wild type (WT) = 7.0% (corresponds to odds of ~43),CIMRA has shown a relative repair compared to wild type (WT) = 7.0% (corresponds to odds of ~43) CIMRA has shown a relative repair compared to wild type (WT) = 7.0% (corresponds to odds of ~43),ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMSH6Version1.0.0_version=1.0.0.csv
8410,NM_000179.3(MSH6):c.1296T>G (p.Phe432Leu),MSH6,Lynch syndrome,MONDO:0005835,Likely Pathogenic,Autosomal dominant inheritance,InSiGHT Hereditary Colorectal Cancer/Polyposis,2024-10-11,PS3,met,PubMed:31965077,Supplementary material. Table S5: p.F432L CIMRA functional odds: 45.743 ,Functional odds: 45.743 (CIMRA Functional Odds for Pathogenicity >18.7),Functional odds: 45.743 (CIMRA Functional Odds for Pathogenicity >18.7) Supplementary material. Table S5: p.F432L CIMRA functional odds: 45.743 ,ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMSH6Version1.0.0_version=1.0.0.csv
8386,NM_000249.4(MLH1):c.649C>T (p.Arg217Cys),MLH1,Lynch syndrome 1,MONDO:0007356,Benign,Autosomal dominant inheritance,InSiGHT Hereditary Colorectal Cancer/Polyposis,2024-10-11,BS3,met,PubMed:32849802,CIMRA Functional Odds for Pathogenicity is  0.01 (Data_Sheet_1),CIMRA Functional Odds for Pathogenicity is  0.01 which is below the VCEP threshold of ≤ 0.052,CIMRA Functional Odds for Pathogenicity is  0.01 which is below the VCEP threshold of ≤ 0.052 CIMRA Functional Odds for Pathogenicity is  0.01 (Data_Sheet_1),ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMLH1Version1.0.0_version=1.0.0.csv
1587,NM_000546.6(TP53):c.329G>A (p.Arg110His),TP53,Li-Fraumeni syndrome,MONDO:0018875,Likely Benign,Autosomal dominant inheritance,TP53,2025-01-16,BS3-Supporting,not_met,PubMed:33051313,Report a deleterious effect of this variant using a functional assay from patient blood sample.,"In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation, and retained growth suppression activity indicating that this variant does not impact protein function
(BS3_Supporting; PMIDs: 12826609, 29979965, 30224644).","In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation, and retained growth suppression activity indicating that this variant does not impact protein function
(BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). Report a deleterious effect of this variant using a functional assay from patient blood sample.",ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
1589,NM_000546.5(TP53):c.877G>T (p.Gly293Trp),TP53,Li-Fraumeni syndrome,MONDO:0018875,Likely Benign,Autosomal dominant inheritance,TP53,2025-01-16,PM2-Supporting,not_met,PubMed:26367797,"Variant identified as an incidental finding in 1 of 3610 individual exomes sequenced as part of an initiative to identify genetic contribution to complex, quantitative traits in healthy individuals.  No age, cancer history, or health history is provided.","This variant has an allele frequency of 0.00003305 (39/1180036 alleles) in the European (Non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).","This variant has an allele frequency of 0.00003305 (39/1180036 alleles) in the European (Non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). Variant identified as an incidental finding in 1 of 3610 individual exomes sequenced as part of an initiative to identify genetic contribution to complex, quantitative traits in healthy individuals.  No age, cancer history, or health history is provided.",ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
1843,NM_000212.2:c.565C>T,ITGB3,Glanzmann's thrombasthenia,MONDO:0010119,Pathogenic,Autosomal recessive inheritance,Platelet Disorders,2021-01-28,PS3-Moderate,not_met,PubMed:24236036,"The mutation was introduced into a β3 expression construct and transient expression in CHO cells was performed with co-expression of normal human αIIb. There was a 94% reduction in surface expression of the αIIbβ3 receptor in CHO cells expressing P163Sβ3 compared to those expressing WTβ3, measured by flow cytometry.","In PMID: 24236036, the mutation was introduced into a β3 expression construct and transient expression in CHO cells was performed with co-expression of normal human αIIb. There was a 94% reduction in surface expression of the αIIbβ3 receptor in CHO cells expressing P163Sβ3 compared to those expressing WTβ3.","In PMID: 24236036, the mutation was introduced into a β3 expression construct and transient expression in CHO cells was performed with co-expression of normal human αIIb. There was a 94% reduction in surface expression of the αIIbβ3 receptor in CHO cells expressing P163Sβ3 compared to those expressing WTβ3. The mutation was introduced into a β3 expression construct and transient expression in CHO cells was performed with co-expression of normal human αIIb. There was a 94% reduction in surface expression of the αIIbβ3 receptor in CHO cells expressing P163Sβ3 compared to those expressing WTβ3, measured by flow cytometry.",ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2.1_version=2.1.0.csv
1844,NM_000212.2:c.774_775del,ITGB3,Glanzmann's thrombasthenia,MONDO:0010119,Pathogenic,Autosomal recessive inheritance,Platelet Disorders,2021-01-28,PP4-Moderate,not_met,PubMed:25539746,,"From PMID: 25539746 The patient had a history of bleeding, normal platelet number and size, impaired aggregation to ADP and arachidonic acid but normal or only mildly reduced agglutination with ristocetin, and αIIbβ3 expression between 5% and 20% (measured by flow cytometry).",,ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2.1_version=2.1.0.csv
1851,NM_000419.4(ITGA2B):c.2944G>A (p.Val982Met),ITGA2B,Glanzmann's thrombasthenia,MONDO:0010119,Pathogenic,Autosomal recessive inheritance,Platelet Disorders,2021-01-28,PS2,met,PubMed:25539746,"This Val982Met variant was found to occur de novo in patient GT-6. It was not present in the father, mother, or brother of the patient. Paternity and maternity were confirmed. The individual is compound heterozygous with Glu538Ter (classified as Pathogenic by the ClinGen Platelet Disorders VCEP). 2pt","This variant was found to occur de novo in one proband (PMID: 25539746). The individual is compound heterozygous with a pathogenic nonsense, Glu538Ter, variant provisionally classified as Pathogenic by the ClinGen Platelet Disorders VCEP.","This variant was found to occur de novo in one proband (PMID: 25539746). The individual is compound heterozygous with a pathogenic nonsense, Glu538Ter, variant provisionally classified as Pathogenic by the ClinGen Platelet Disorders VCEP. This Val982Met variant was found to occur de novo in patient GT-6. It was not present in the father, mother, or brother of the patient. Paternity and maternity were confirmed. The individual is compound heterozygous with Glu538Ter (classified as Pathogenic by the ClinGen Platelet Disorders VCEP). 2pt",ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2.1_version=2.1.0.csv
1984,NM_000540.3(RYR1):c.1021G>A (p.Gly341Arg),RYR1,"malignant hyperthermia, susceptibility to, 1",MONDO:0007783,Pathogenic,Autosomal dominant inheritance,Malignant Hyperthermia Susceptibility,2021-03-31,PS3-Moderate,not_met,PubMed:26115329,HEK293 assays,HEK293 assays,HEK293 assays HEK293 assays,ClinGenMalignantHyperthermiaSusceptibilityExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRYR1Version2_version=2.0.0.csv
2227,NM_001083962.1(TCF4):c.759C>G (p.Ser253Arg),TCF4,Pitt-Hopkins syndrome,MONDO:0012589,Likely Pathogenic,Autosomal dominant inheritance,Rett and Angelman-like Disorders,2021-05-17,PP4,met,PubMed:26993267,The p.Ser253Arg variant in TCF4 has been reported in 2 unconfirmed de novo occurrences in an individual with Pitt–Hopkins syndrome and in an individual with early infantile epileptic encephalopathy.,"The p.Ser253Arg variant in TCF4 has been reported in an individual with a clinical phenotype suggestive of Pitt–Hopkins syndrome (PMID 26993267, described as p.Ser355Arg)","The p.Ser253Arg variant in TCF4 has been reported in an individual with a clinical phenotype suggestive of Pitt–Hopkins syndrome (PMID 26993267, described as p.Ser355Arg) The p.Ser253Arg variant in TCF4 has been reported in 2 unconfirmed de novo occurrences in an individual with Pitt–Hopkins syndrome and in an individual with early infantile epileptic encephalopathy.",ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTCF4Version4.0.0_version=4.0.0.csv
2342,NM_000546.6(TP53):c.997C>T (p.Arg333Cys),TP53,Li-Fraumeni syndrome,MONDO:0018875,Likely Benign,Autosomal dominant inheritance,TP53,2025-02-07,BS3,met,PubMed:39060302,"showed comparable or higher expression levels of CDKN1A, MDM2, GADD45A and PMAIP1 compared to WT condition","In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function(BS3; PMIDs: 12826609, 30224644).","In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function(BS3; PMIDs: 12826609, 30224644). showed comparable or higher expression levels of CDKN1A, MDM2, GADD45A and PMAIP1 compared to WT condition",ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
2668,NM_000546.6(TP53):c.188C>G (p.Ala63Gly),TP53,Li-Fraumeni syndrome,MONDO:0018875,Likely Benign,Autosomal dominant inheritance,TP53,2025-01-16,BS3,met,PubMed:35043155,Predicted functional by TP53_PROF,"In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function
(BS3; PMIDs: 12826609, 29979965, 30224644).
","In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function
(BS3; PMIDs: 12826609, 29979965, 30224644).
 Predicted functional by TP53_PROF",ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
3964,NM_030621.4(DICER1):c.2642T>C (p.Leu881Pro),DICER1,DICER1-related tumor predisposition,MONDO:0017288,Likely Pathogenic,Autosomal dominant inheritance,DICER1 and miRNA-Processing Gene,2024-09-16,PS3-Supporting,not_met,PubMed:37333613,Impaired in vitro cleavage assay,"In vitro cleavage assay carried out using immunopurified DICER1 variant Leu881Pro showed that this variant reduces the capacity of the protein to produce 5p/3p microRNAs from a pre-miRNA, indicating that this variant impacts protein function(PS3_Supporting; PMID: 31342592, 37333613).

31342592: Figure 5c. Case #778. variant causes both reduced and delayed production of 5p and3p miRNA species
37333613: Figure 2E.
","In vitro cleavage assay carried out using immunopurified DICER1 variant Leu881Pro showed that this variant reduces the capacity of the protein to produce 5p/3p microRNAs from a pre-miRNA, indicating that this variant impacts protein function(PS3_Supporting; PMID: 31342592, 37333613).

31342592: Figure 5c. Case #778. variant causes both reduced and delayed production of 5p and3p miRNA species
37333613: Figure 2E.
 Impaired in vitro cleavage assay",ClinGenDICER1andmiRNA-ProcessingGeneExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDICER1Version1.3.0_version=1.3.0.csv
4941,NM_024675.4(PALB2):c.3049G>A (p.Ala1017Thr),PALB2,hereditary breast cancer,MONDO:0016419,Uncertain Significance,Autosomal dominant inheritance,"Hereditary Breast, Ovarian and Pancreatic Cancer",2023-04-07,BS3,not_met,PubMed:31586400,Low levels of expression but PARPi sensitivity comparable to WT (97.77% Olaparib relative survival),"This variant is functional in a protein assay (PMID: 31586400); however due to a lack of known positive missense controls with known clinical impact, protein assays do not meet the requirements for use by the HBOP VCEP.","This variant is functional in a protein assay (PMID: 31586400); however due to a lack of known positive missense controls with known clinical impact, protein assays do not meet the requirements for use by the HBOP VCEP. Low levels of expression but PARPi sensitivity comparable to WT (97.77% Olaparib relative survival)","ClinGenHereditaryBreast,OvarianandPancreaticCancerExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPALB2Version1.1.0_version=1.1.0.csv"
4950,NM_024675.4(PALB2):c.109C>A (p.Arg37Ser),PALB2,hereditary breast cancer,MONDO:0016419,Uncertain Significance,Autosomal dominant inheritance,"Hereditary Breast, Ovarian and Pancreatic Cancer",2023-04-07,BS3,not_met,PubMed:31636395,"Table 1: This variant had a 4.5-fold change in a homology directed DNA repair assay which above 2.4, the authors threshold for benign variation (PMID 31636395). This is ascribed moderate (aka 2 supporting) benign evidence","This variant is non-functional in multiple different protein assays (31636395); however due to a lack of known positive missense controls with known clinical impact, protein assays do not meet the requirements for use by the ClinGen HBOP VCEP.","This variant is non-functional in multiple different protein assays (31636395); however due to a lack of known positive missense controls with known clinical impact, protein assays do not meet the requirements for use by the ClinGen HBOP VCEP. Table 1: This variant had a 4.5-fold change in a homology directed DNA repair assay which above 2.4, the authors threshold for benign variation (PMID 31636395). This is ascribed moderate (aka 2 supporting) benign evidence","ClinGenHereditaryBreast,OvarianandPancreaticCancerExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPALB2Version1.1.0_version=1.1.0.csv"
4960,NM_024675.4:c.2734T>G,PALB2,hereditary breast cancer,MONDO:0016419,Uncertain Significance,Autosomal dominant inheritance,"Hereditary Breast, Ovarian and Pancreatic Cancer",2023-04-07,PS3,not_met,PubMed:31757951,"Homology-directed repair function in mES cells showed 6.6% relative efficiency, which falls in the  threshold for an abnormal protein function established by the HBOP VCEP.  PARP inhibitor sensitivity function in mES cells showed 7.73% relative resistance to PARPi, which falls in the  threshold for an abnormal protein function established by the HBOP VCEP. However due to a lack of known positive missense controls with known clinical impact, protein assays do not meet the requirements for use by the HBOP VCEP","This variant showed an abnormal read out in multiple protein assays (PMID 31757951); however due to a lack of known positive missense controls with known clinical impact, protein assays do not meet the requirements for use by the HBOP VCEP. ","This variant showed an abnormal read out in multiple protein assays (PMID 31757951); however due to a lack of known positive missense controls with known clinical impact, protein assays do not meet the requirements for use by the HBOP VCEP.  Homology-directed repair function in mES cells showed 6.6% relative efficiency, which falls in the  threshold for an abnormal protein function established by the HBOP VCEP.  PARP inhibitor sensitivity function in mES cells showed 7.73% relative resistance to PARPi, which falls in the  threshold for an abnormal protein function established by the HBOP VCEP. However due to a lack of known positive missense controls with known clinical impact, protein assays do not meet the requirements for use by the HBOP VCEP","ClinGenHereditaryBreast,OvarianandPancreaticCancerExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPALB2Version1.1.0_version=1.1.0.csv"
4965,NM_024675.3(PALB2):c.3113G>A (p.Trp1038Ter),PALB2,hereditary breast cancer,MONDO:0016419,Pathogenic,Autosomal dominant inheritance,"Hereditary Breast, Ovarian and Pancreatic Cancer",2023-04-07,PS3,not_met,PubMed:31757951,"HR efficiency: 6.98%
PARPi resistance: 12.35%","This variant is non-functional in multiple different protein assays (PMID 31757951); however due to a lack of positive missense controls with known clinical impact, protein assays do not meet the requirements for use by the HBOP VCEP.
","This variant is non-functional in multiple different protein assays (PMID 31757951); however due to a lack of positive missense controls with known clinical impact, protein assays do not meet the requirements for use by the HBOP VCEP.
 HR efficiency: 6.98%
PARPi resistance: 12.35%","ClinGenHereditaryBreast,OvarianandPancreaticCancerExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPALB2Version1.1.0_version=1.1.0.csv"
5611,NM_000059.4(BRCA2):c.831T>G (p.Asn277Lys),BRCA2,BRCA2-related cancer predisposition,MONDO:0012933,Benign,Autosomal dominant inheritance,ENIGMA BRCA1 and BRCA2,2024-06-12,BS3,met,PubMed:33293522,Variant labelled as functional,Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID: 33293522) (BS3 met). ,Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID: 33293522) (BS3 met).  Variant labelled as functional,ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA2Version1.2.0_version=1.2.0.csv
5619,NM_007294.4(BRCA1):c.191G>A (p.Cys64Tyr),BRCA1,BRCA1-related cancer predisposition,MONDO:0011450,Pathogenic,Autosomal dominant inheritance,ENIGMA BRCA1 and BRCA2,2024-06-11,PS3,met,PubMed:30209399,Deleterious,Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID: 30209399) (PS3 met). ,Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID: 30209399) (PS3 met).  Deleterious,ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA1Version1.2.0_version=1.2.0.csv
5645,NM_000059.4(BRCA2):c.9227G>T (p.Gly3076Val),BRCA2,BRCA2-related cancer predisposition,MONDO:0012933,Pathogenic,Autosomal dominant inheritance,ENIGMA BRCA1 and BRCA2,2024-06-12,PS3,met,PubMed:33609447,Non functional,Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID: 33609447) (PS3 met). ,Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID: 33609447) (PS3 met).  Non functional,ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA2Version1.2.0_version=1.2.0.csv
5648,NM_000059.4(BRCA2):c.9976A>T (p.Lys3326Ter),BRCA2,BRCA2-related cancer predisposition,MONDO:0012933,Benign,Autosomal dominant inheritance,ENIGMA BRCA1 and BRCA2,2024-06-12,BS3,met,PubMed:29988080,"Reported by one calibrated study to affect protein function similar to benign control variants (PMID:29988080) (BS3 met).
","Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID: 29988080) (BS3 met). 

Reported by Mesman et al., 2019 (PMID: 29988080) to have no impact on function.","Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID: 29988080) (BS3 met). 

Reported by Mesman et al., 2019 (PMID: 29988080) to have no impact on function. Reported by one calibrated study to affect protein function similar to benign control variants (PMID:29988080) (BS3 met).
",ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA2Version1.2.0_version=1.2.0.csv
6919,NM_001204.7(BMPR2):c.1042G>A (p.Val348Ile),BMPR2,pulmonary arterial hypertension,MONDO:0015924,Likely Benign,Autosomal dominant inheritance,Pulmonary Hypertension,2024-05-03,PS3-Supporting,not_met,PubMed:36675162,"Functional assessment by densitometry analysis demonstrates p-SMAD levels are moderately diminished in cells transfected with p.V348I, in relation to nonsyndromic oligodontia","Densitometry analysis showed a modest reduction of p-SMAD expression (PMID: 36675162) but this was not confirmed by an independent assay, therefore PS3 is downgraded to supporting.","Densitometry analysis showed a modest reduction of p-SMAD expression (PMID: 36675162) but this was not confirmed by an independent assay, therefore PS3 is downgraded to supporting. Functional assessment by densitometry analysis demonstrates p-SMAD levels are moderately diminished in cells transfected with p.V348I, in relation to nonsyndromic oligodontia",ClinGenPulmonaryHypertensionExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBMPR2Version1.1.0_version=1.1.0.csv
6945,NM_001040142.2(SCN2A):c.5317G>A (p.Ala1773Thr),SCN2A,complex neurodevelopmental disorder,MONDO:0100038,Pathogenic,Autosomal dominant inheritance,Epilepsy Sodium Channel,2024-05-07,PS3,met,PubMed:32400968,Whole-cell patch-clamp e-physiology recordings of voltage-gated Na+ currents in HEK293T cell expressing the A1773T and WT Na+ channels showed that the A1773T channel exhibited a significant hyperpolarizing shift in the voltage dependence of the activation curve and a depolarizing shift of steady-state fast inactivation accompanied by decreased current density with a half-maximal activation potential at ~10 mV the of −68.76 ± 2.01 mV for the A1773T compared to (−58.57 ± 1.40 mV) in the WT (Figure 2d). The mutant showed a longer recovery time constant τ1 from fast-inactivation compared to WT. ,"Whole-cell patch-clamp recordings of voltage-gated Na+ currents in HEK293T cell in showed  a significant hyperpolarizing shift in the voltage dependence of the activation curve and a depolarizing shift of steady-state fast inactivation accompanied by decreased current density indicating that this variant impacts protein function (PMIDs: 32400968, 32400968)(PS3_Strong)","Whole-cell patch-clamp recordings of voltage-gated Na+ currents in HEK293T cell in showed  a significant hyperpolarizing shift in the voltage dependence of the activation curve and a depolarizing shift of steady-state fast inactivation accompanied by decreased current density indicating that this variant impacts protein function (PMIDs: 32400968, 32400968)(PS3_Strong) Whole-cell patch-clamp e-physiology recordings of voltage-gated Na+ currents in HEK293T cell expressing the A1773T and WT Na+ channels showed that the A1773T channel exhibited a significant hyperpolarizing shift in the voltage dependence of the activation curve and a depolarizing shift of steady-state fast inactivation accompanied by decreased current density with a half-maximal activation potential at ~10 mV the of −68.76 ± 2.01 mV for the A1773T compared to (−58.57 ± 1.40 mV) in the WT (Figure 2d). The mutant showed a longer recovery time constant τ1 from fast-inactivation compared to WT. ",ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN2AVersion2.0.0_version=2.0.0.csv
6969,NM_001330260.2(SCN8A):c.5615G>A (p.Arg1872Gln),SCN8A,complex neurodevelopmental disorder,MONDO:0100038,Pathogenic,Autosomal dominant inheritance,Epilepsy Sodium Channel,2024-05-09,PS3,met,PubMed:26900580,The variant was studied via patch clamping in ND7/23 cells and found to have mild increase in peak current (criterion not met); no significant difference in persistent current; significant hyperpolarizing shift in voltage dependence of activation; significant depolarizing shift of voltage dependence of fast inactivation.,The variant was studied via patch clamping in ND7/23 cells and found to have mild increase in peak current (criterion not met); no significant difference in persistent current; significant hyperpolarizing shift in voltage dependence of activation; significant depolarizing shift of voltage dependence of fast inactivation.,The variant was studied via patch clamping in ND7/23 cells and found to have mild increase in peak current (criterion not met); no significant difference in persistent current; significant hyperpolarizing shift in voltage dependence of activation; significant depolarizing shift of voltage dependence of fast inactivation. The variant was studied via patch clamping in ND7/23 cells and found to have mild increase in peak current (criterion not met); no significant difference in persistent current; significant hyperpolarizing shift in voltage dependence of activation; significant depolarizing shift of voltage dependence of fast inactivation.,ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN8AVersion2.0.0_version=2.0.0.csv
6983,NM_021007.3:c.2558G>A,SCN2A,complex neurodevelopmental disorder,MONDO:0100038,Pathogenic,Autosomal dominant inheritance,Epilepsy Sodium Channel,2024-05-09,PS3,met,PubMed:31558572,Peak current 51% of WT,"Heterologous expression with voltage clamping showed decreased peak current, 51% of wildtype. This exceeds the threshold of <72.7% for PS3. ","Heterologous expression with voltage clamping showed decreased peak current, 51% of wildtype. This exceeds the threshold of <72.7% for PS3.  Peak current 51% of WT",ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN2AVersion2.0.0_version=2.0.0.csv
7035,NM_000448.3(RAG1):c.2690G>A (p.Arg897Gln),RAG1,recombinase activating gene 1 deficiency,MONDO:0000572,Uncertain Significance,Autosomal recessive inheritance,Severe Combined Immunodeficiency Disease,2024-05-28,PS3-Moderate,not_met,PubMed:32655540,RAG activity was found to be 3.7 ± 0.2 by flow cytometry. (PS3_Moderate) PMID: 32655540,"RAG activity was found to be 3.7 ± 0.2 by flow cytometry. (PS3_Moderate) PMID: 32655540
","RAG activity was found to be 3.7 ± 0.2 by flow cytometry. (PS3_Moderate) PMID: 32655540
 RAG activity was found to be 3.7 ± 0.2 by flow cytometry. (PS3_Moderate) PMID: 32655540",ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRAG1Version1.0.0_version=1.0.0.csv
7204,NM_000551.4(VHL):c.264G>T (p.Trp88Cys),VHL,von Hippel-Lindau disease,MONDO:0008667,Likely Pathogenic,Autosomal dominant inheritance,VHL,2024-06-25,PM1,met,PubMed:35475554,"Figure 4, hotspot analysis shows Trp88Cys is a germline hotspot in VHL. ","This variant is located in a mutational hotspot (PMID:35475554). There are multiple other nucleotide and amino acid substitutions at this position in ClinVar, including:  NM_000551.4(VHL):c.264G>C (p.Trp88Cys), NM_000551.4(VHL):c.263G>C (p.Trp88Ser), NM_000551.4(VHL):c.262T>A (p.Trp88Arg), NM_000551.4(VHL):c.262T>C (p.Trp88Arg). (PM1)","This variant is located in a mutational hotspot (PMID:35475554). There are multiple other nucleotide and amino acid substitutions at this position in ClinVar, including:  NM_000551.4(VHL):c.264G>C (p.Trp88Cys), NM_000551.4(VHL):c.263G>C (p.Trp88Ser), NM_000551.4(VHL):c.262T>A (p.Trp88Arg), NM_000551.4(VHL):c.262T>C (p.Trp88Arg). (PM1) Figure 4, hotspot analysis shows Trp88Cys is a germline hotspot in VHL. ",ClinGenVHLExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforVHLVersion1.1.0_version=1.1.0.csv
7223,NM_000551.4(VHL):c.273C>A (p.Phe91Leu),VHL,von Hippel-Lindau disease,MONDO:0008667,Uncertain Significance,Autosomal dominant inheritance,VHL,2024-06-25,PS3-Supporting,not_met,PubMed:31337753,"In vitro evidence suggests the P91L variant disrupts binding to both HIF1a or HIF2alpha. Other variants at the P91 codon were tested. 
-P91W had similar binding to HIF1/2a compared to wild-type
-F91Y bound less HIF2a compared to WT ","In Tarade et al, an in vitro pVHL-HIFa binding assay followed by immunoblotting showed
the the F91L variant abolished all binding to HIF1a and HIF2a (PMID: 31337753)(PS3_Supporting).","In Tarade et al, an in vitro pVHL-HIFa binding assay followed by immunoblotting showed
the the F91L variant abolished all binding to HIF1a and HIF2a (PMID: 31337753)(PS3_Supporting). In vitro evidence suggests the P91L variant disrupts binding to both HIF1a or HIF2alpha. Other variants at the P91 codon were tested. 
-P91W had similar binding to HIF1/2a compared to wild-type
-F91Y bound less HIF2a compared to WT ",ClinGenVHLExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforVHLVersion1.1.0_version=1.1.0.csv
7659,NM_000552.5(VWF):c.3946G>A (p.Val1316Met),VWF,von Willebrand disease type 2B,MONDO:0015629,Pathogenic,Autosomal dominant inheritance,von Willebrand Disease,2024-08-19,PS3,met,PubMed:27212476,"A knock-in mouse model expressing VWF p.Val1316Met showed prolonged bleeding time (Figure 3A), absence of high-MW multimers (Figure 2D), large platelet aggregates (Figure 2C), decreased in vitro platelet adhesion to thrombin or collagen (Figure 4), and enhanced in vivo VWF/platelet string formation (Figure 5), indicating that this variant has a damaging effect on protein function that is consistent with phenotypes of VWD Type 2B (PMID: 27212476, PS3).","A knock-in mouse model expressing VWF p.Val1316Met showed prolonged bleeding time (Figure 3A), absence of high-MW multimers (Figure 2D), large platelet aggregates (Figure 2C), decreased in vitro platelet adhesion to thrombin or collagen (Figure 4), and enhanced in vivo VWF/platelet string formation (Figure 5), indicating that this variant has a damaging effect on protein function that is consistent with phenotypes of VWD Type 2B (PMID: 27212476, PS3).","A knock-in mouse model expressing VWF p.Val1316Met showed prolonged bleeding time (Figure 3A), absence of high-MW multimers (Figure 2D), large platelet aggregates (Figure 2C), decreased in vitro platelet adhesion to thrombin or collagen (Figure 4), and enhanced in vivo VWF/platelet string formation (Figure 5), indicating that this variant has a damaging effect on protein function that is consistent with phenotypes of VWD Type 2B (PMID: 27212476, PS3). A knock-in mouse model expressing VWF p.Val1316Met showed prolonged bleeding time (Figure 3A), absence of high-MW multimers (Figure 2D), large platelet aggregates (Figure 2C), decreased in vitro platelet adhesion to thrombin or collagen (Figure 4), and enhanced in vivo VWF/platelet string formation (Figure 5), indicating that this variant has a damaging effect on protein function that is consistent with phenotypes of VWD Type 2B (PMID: 27212476, PS3).",ClinGenvonWillebrandDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforVWFVersion1.0.0_version=1.0.0.csv
8319,NM_001164508.2(NEB):c.22144A>C (p.Thr7382Pro),NEB,nemaline myopathy,MONDO:0018958,Pathogenic,Autosomal recessive inheritance,Congenital Myopathies,2024-10-01,PS3,not_met,PubMed:25110572,"Binding experiments for the nebulin super repeats, using co-sedimentation and GST (glutathione-S-transferase) pull-down assays (PMID: 25110572 ) showed weaker binding than WT proteins to tropomyosin. However, this assay does not meet the requirements for use by the ClinGen Congenital Myopathies VCEP.","Binding experiments for the nebulin super repeats, using co-sedimentation and GST (glutathione-S-transferase) pull-down assays (PMID: 25110572 ) showed weaker binding than WT proteins to tropomyosin. However, this assay does not meet the requirements for use by the ClinGen Congenital Myopathies VCEP.","Binding experiments for the nebulin super repeats, using co-sedimentation and GST (glutathione-S-transferase) pull-down assays (PMID: 25110572 ) showed weaker binding than WT proteins to tropomyosin. However, this assay does not meet the requirements for use by the ClinGen Congenital Myopathies VCEP. Binding experiments for the nebulin super repeats, using co-sedimentation and GST (glutathione-S-transferase) pull-down assays (PMID: 25110572 ) showed weaker binding than WT proteins to tropomyosin. However, this assay does not meet the requirements for use by the ClinGen Congenital Myopathies VCEP.",ClinGenCongenitalMyopathiesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforNEBVersion1.0.0_version=1.0.0.csv
8702,NM_000552.5:c.4586_4591del,VWF,von Willebrand disease type 2A,MONDO:0015628,Pathogenic,Autosomal dominant inheritance,von Willebrand Disease,2024-11-06,PS3,met,PubMed:22479377,"Multimerization assay performed with the Asp1529_Val1530del recombinant mutant vWF expressed by HEK293 showed abnormal multimers with less HMW multimers (consistent with the multimer assay in the patient), indicating that this variant has a damaging effect on protein function (PMID:22479377; PS3).

Immunofluorescence indicated that a significant portion of the mutant VWF molecules were retained in the ER.","Multimerization assay performed with the Asp1529_Val1530del recombinant mutant vWF expressed by HEK293 showed abnormal multimers with less HMW multimers, indicating that this variant has a damaging effect on protein function (PMID:22479377; PS3).","Multimerization assay performed with the Asp1529_Val1530del recombinant mutant vWF expressed by HEK293 showed abnormal multimers with less HMW multimers, indicating that this variant has a damaging effect on protein function (PMID:22479377; PS3). Multimerization assay performed with the Asp1529_Val1530del recombinant mutant vWF expressed by HEK293 showed abnormal multimers with less HMW multimers (consistent with the multimer assay in the patient), indicating that this variant has a damaging effect on protein function (PMID:22479377; PS3).

Immunofluorescence indicated that a significant portion of the mutant VWF molecules were retained in the ER.",ClinGenvonWillebrandDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforVWFVersion1.0.0_version=1.0.0.csv
8705,NM_001204.7(BMPR2):c.1157A>C (p.Glu386Ala),BMPR2,pulmonary arterial hypertension,MONDO:0015924,Likely Pathogenic,Autosomal dominant inheritance,Pulmonary Hypertension,2024-11-06,PM1-Strong,not_met,PubMed:34400635,p.Glu386 is indispensable to kinase structure and function.,The p.Glu386 residue is located in the functionally relevant catalytic kinase domain and impacts an amino acid indispensable to kinase structure and function (Agnew et al. 2021).,The p.Glu386 residue is located in the functionally relevant catalytic kinase domain and impacts an amino acid indispensable to kinase structure and function (Agnew et al. 2021). p.Glu386 is indispensable to kinase structure and function.,ClinGenPulmonaryHypertensionExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBMPR2Version1.1.0_version=1.1.0.csv
8706,NM_001204.7(BMPR2):c.1157A>G (p.Glu386Gly),BMPR2,pulmonary arterial hypertension,MONDO:0015924,Likely Pathogenic,Autosomal dominant inheritance,Pulmonary Hypertension,2024-11-06,PM1-Strong,not_met,PubMed:34400635,p.Glu386 is indispensable to kinase structure and function.,The p.Glu386 residue is located in the functionally relevant catalytic kinase domain and impacts an amino acid indispensable to kinase structure and function (Agnew et al. 2021).,The p.Glu386 residue is located in the functionally relevant catalytic kinase domain and impacts an amino acid indispensable to kinase structure and function (Agnew et al. 2021). p.Glu386 is indispensable to kinase structure and function.,ClinGenPulmonaryHypertensionExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBMPR2Version1.1.0_version=1.1.0.csv
9137,NM_001130987.2(DYSF):c.1906G>C (p.Gly636Arg),DYSF,autosomal recessive limb-girdle muscular dystrophy,MONDO:0015152,Pathogenic,Autosomal recessive inheritance,Limb Girdle Muscular Dystrophy,2025-01-08,PS3,met,PubMed:35028538,"Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Gly636Arg protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). ","Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Gly636Arg protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). 
","Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Gly636Arg protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). 
 Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Gly636Arg protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). ",ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDYSFVersion1.0.0_version=1.0.0.csv
9142,NM_001130987.2(DYSF):c.953T>A (p.Val318Glu),DYSF,autosomal recessive limb-girdle muscular dystrophy,MONDO:0015152,Pathogenic,Autosomal recessive inheritance,Limb Girdle Muscular Dystrophy,2025-01-08,PS3-Moderate,not_met,PubMed:35028538,"Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the variant protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate).","Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the variant protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate).","Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the variant protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the variant protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate).",ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDYSFVersion1.0.0_version=1.0.0.csv
9144,NM_001130987.2(DYSF):c.1906G>A (p.Gly636Arg),DYSF,autosomal recessive limb-girdle muscular dystrophy,MONDO:0015152,Pathogenic,Autosomal recessive inheritance,Limb Girdle Muscular Dystrophy,2025-01-08,PS3-Moderate,not_met,PubMed:35028538,"Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the variant protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). ","Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the variant protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). ","Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the variant protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate).  Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the variant protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). ",ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDYSFVersion1.0.0_version=1.0.0.csv
9155,NM_001130987.2(DYSF):c.1717C>T (p.Arg573Trp),DYSF,autosomal recessive limb-girdle muscular dystrophy,MONDO:0015152,Pathogenic,Autosomal recessive inheritance,Limb Girdle Muscular Dystrophy,2025-01-08,PS3-Moderate,not_met,PubMed:35028538,Classified as non-functional in both assays,"Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Arg555Trp protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). ","Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Arg555Trp protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate).  Classified as non-functional in both assays",ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDYSFVersion1.0.0_version=1.0.0.csv
9200,NM_000232.5(SGCB):c.452C>G (p.Thr151Arg),SGCB,autosomal recessive limb-girdle muscular dystrophy,MONDO:0015152,Pathogenic,Autosomal recessive inheritance,Limb Girdle Muscular Dystrophy,2025-01-09,PS3-Moderate,not_met,PubMed:37317968,"	
Disrupts sarcoglycan complex cell surface localization in a cell culture assay.","In vitro assays of membrane localization in HEK293 and HER-911 cells showed that expression of p.Thr151Arg in β-sarcoglycan disrupted localization of both the β-sarcoglycan subunit and the sarcoglycan complex to the plasma membrane, indicating an impact of the c.452C>G p.(Thr151Arg) variant on protein function (PMID: 37317968, 22095924) (PS3_Moderate). ","In vitro assays of membrane localization in HEK293 and HER-911 cells showed that expression of p.Thr151Arg in β-sarcoglycan disrupted localization of both the β-sarcoglycan subunit and the sarcoglycan complex to the plasma membrane, indicating an impact of the c.452C>G p.(Thr151Arg) variant on protein function (PMID: 37317968, 22095924) (PS3_Moderate).  	
Disrupts sarcoglycan complex cell surface localization in a cell culture assay.",ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSGCBVersion1.0.0_version=1.0.0.csv