VCI/split_evidence_sufficiency/train_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
76,NM_000277.1(PAH):c.926C>T (p.Ala309Val),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-05,PP4,met,PubMed:26666653,"Genotype-phenotype association in French patients with PKU.  364 patients, 24hr BH4 loading test.","Single patient with classic PKU (>1200umol/L), BH4 defect not excluded","Single patient with classic PKU (>1200umol/L), BH4 defect not excluded Genotype-phenotype association in French patients with PKU.  364 patients, 24hr BH4 loading test.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1693,NM_000277.3(PAH):c.578_579CT[1] (p.Leu194fs),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
32,NM_000277.2(PAH):c.812A>T (p.His271Leu),PAH,phenylketonuria,MONDO:0009861,Uncertain Significance,Autosomal recessive inheritance,Phenylketonuria,2019-04-05,PP4-Moderate,not_met,PubMed:26503515,"A total of 796 unrelated patients from 29 separate newborn screening centres of China were enrolled. These patients were diagnosed at birth either through a neonatal screening program or based on clinical presentation. Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected. H271L was detected in 1 patient.",H271L seen in a Chinese PKU patient. BH4 deficiencies excluded. Upgraded per ClinGen Metabolic workgroup.,"H271L seen in a Chinese PKU patient. BH4 deficiencies excluded. Upgraded per ClinGen Metabolic workgroup. A total of 796 unrelated patients from 29 separate newborn screening centres of China were enrolled. These patients were diagnosed at birth either through a neonatal screening program or based on clinical presentation. Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected. H271L was detected in 1 patient.",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,PP4-Moderate,not_met,PubMed:26322415,"P175S detected in a 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.",P175S detected in a patient with classic PKU. BH4 deficiency was excluded.  PMID: 26322415,"P175S detected in a patient with classic PKU. BH4 deficiency was excluded.  PMID: 26322415 P175S detected in a 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
843,NM_000277.2(PAH):c.547_548delGAinsTT (p.Glu183Leu),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-08-11,PM3,met,PubMed:26666653,"This variant has been observed in trans with the previously assessed pathogenic variant c.143T>C; p.Leu48Ser (ClinVar 608, Pathogenic).","This variant has been observed in trans with the previously assessed pathogenic variant c.143T>C; p.Leu48Ser (ClinVar 608, Pathogenic).","This variant has been observed in trans with the previously assessed pathogenic variant c.143T>C; p.Leu48Ser (ClinVar 608, Pathogenic). This variant has been observed in trans with the previously assessed pathogenic variant c.143T>C; p.Leu48Ser (ClinVar 608, Pathogenic).",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1359,NM_000277.2(PAH):c.694C>T (p.Gln232Ter),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2020-05-31,PM3,met,PubMed:30050108,"Patient genotype: c.442-1G>A (VarID594, P)/p.Q232*",Detected with known pathogenic variant c.442-1G>A  (PMID: 30050108),"Detected with known pathogenic variant c.442-1G>A  (PMID: 30050108) Patient genotype: c.442-1G>A (VarID594, P)/p.Q232*",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,PM3-Supporting,not_met,PubMed:26666653,"Detected with c.1315+1G>A; however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing.","Detected with c.1315+1G>A; however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing.","Detected with c.1315+1G>A; however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Detected with c.1315+1G>A; 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
3272,NM_000277.2(PAH):c.770G>T (p.Gly257Val),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2022-03-11,PM3-Very Strong,not_met,PubMed:26322415,"Genotype: c.[206_208delCTT];[770G>T]/ p.[P69_S70delinsP];[G257V]
Genotype 2: c.[1223G>A];[770G>T]/ p.[R408Q] (VarID 612, Pathogenic);[G257V]","Detected with R408Q (P), p.Ser70del (P-3 submitters) All mutations identified in patients were confirmed by analyzing parental DNA PMID: 26322415; R111X (P-7 submitters) parental analysis not reported  PMID: 14722928; p.Arg261Gln (P-11 submitters), parental analysis not reported PMID: 17502162; .1068C>A (p.Y356* P-7 submitters) parental analysis not reported  PMID: 25894915; p.Arg252Trp (P), p.Arg243Gln (P), S70del, p.His107Arg (P/LP), p.Tyr356*, p.Leu255Ser (P/LP). variable sites in patient genes were aligned with the corresponding sites from the respective parents.  PMID: 28982351 9.0 pts","Detected with R408Q (P), p.Ser70del (P-3 submitters) All mutations identified in patients were confirmed by analyzing parental DNA PMID: 26322415; R111X (P-7 submitters) parental analysis not reported  PMID: 14722928; p.Arg261Gln (P-11 submitters), parental analysis not reported PMID: 17502162; .1068C>A (p.Y356* P-7 submitters) parental analysis not reported  PMID: 25894915; p.Arg252Trp (P), p.Arg243Gln (P), S70del, p.His107Arg (P/LP), p.Tyr356*, p.Leu255Ser (P/LP). variable sites in patient genes were aligned with the corresponding sites from the respective parents.  PMID: 28982351 9.0 pts Genotype: c.[206_208delCTT];[770G>T]/ p.[P69_S70delinsP];[G257V]
Genotype 2: c.[1223G>A];[770G>T]/ p.[R408Q] (VarID 612, Pathogenic);[G257V]",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,PM3-Strong,not_met,PubMed:26666653,Table1: p. [Ile65Thr] (Pathogenic in ClinVar;VarID 636); [Arg261Pro]. p. [Arg158Trp]; [Arg261Pro]. p. [Arg261Gln]; [Arg261Pro]. p. [Arg261Pro]; [Tyr414Cys]. c. [782G > C]; [1315 + 1G > A]. Parental analysis not reported.,"Detected with 5 known pathogenic variants  PMID: 26666653, Parental analysis not reported. 2.5 points = PM3 strong","Detected with 5 known pathogenic variants  PMID: 26666653, Parental analysis not reported. 2.5 points = PM3 strong Table1: p. [Ile65Thr] (Pathogenic in ClinVar;VarID 636); [Arg261Pro]. p. [Arg158Trp]; [Arg261Pro]. p. [Arg261Gln]; [Arg261Pro]. p. [Arg261Pro]; [Tyr414Cys]. c. [782G > C]; [1315 + 1G > A]. Parental analysis not reported.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_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,PM3,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"
647,NM_206933.2(USH2A):c.4510dupA (p.Arg1504Lysfs),USH2A,Usher syndrome,MONDO:0019501,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,BP2,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.",," 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"
639,NM_000441.1(SLC26A4):c.919-2A>G,SLC26A4,Pendred syndrome,MONDO:0010134,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PM3-Very Strong,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.,16 Chinese SNHL probands are compound heterozygous for the c.919-2A>G and p.H723R variants in SLC26A4.,16 Chinese SNHL probands are compound heterozygous for the c.919-2A>G and p.H723R variants 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"
643,NM_206933.2(USH2A):c.5581G>A (p.Gly1861Ser),USH2A,Usher syndrome,MONDO:0019501,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,BS4,not_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.,, 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"
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,PS4,met,PubMed:31160754,"See Table 2 from this publication
This study collected data from 15 different clinical sequencing sites and identified a total of 391 probands with the M34T allele out of 17,635 affected probands screened for GJB2. Additionally they found that 29/17,635 affected probands were homozygous for the M34T relative to 81/802,339 homozygous M34T individuals from the general population. This indicates that the homozygous genotype was significantly increased in the affected population. This was replicated in the European subpopulations, and it was also found that there were a highly significant amount of compound heterozygous individuals in the European affected subpopulation relative to that of Counsyl's carrier screening cohort. Both p values were <0.0001.",The homozygous genotype and compound het genotype with another path variant in GJB2 has been shown to be statistically enriched in patients with nonsydromic sensorineural hearing loss compared to individuals representative of the general population from carrier screening from Counsyl and/or gnomAD data.,"The homozygous genotype and compound het genotype with another path variant in GJB2 has been shown to be statistically enriched in patients with nonsydromic sensorineural hearing loss compared to individuals representative of the general population from carrier screening from Counsyl and/or gnomAD data. See Table 2 from this publication
This study collected data from 15 different clinical sequencing sites and identified a total of 391 probands with the M34T allele out of 17,635 affected probands screened for GJB2. Additionally they found that 29/17,635 affected probands were homozygous for the M34T relative to 81/802,339 homozygous M34T individuals from the general population. This indicates that the homozygous genotype was significantly increased in the affected population. This was replicated in the European subpopulations, and it was also found that there were a highly significant amount of compound heterozygous individuals in the European affected subpopulation relative to that of Counsyl's carrier screening cohort. Both p values were <0.0001.","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,PP1-Strong,not_met,PubMed:31160754,,The collected literature review in Shen et al has found that the p.Val37Ile variant segregates with disease in at least 21 individuals.,The collected literature review in Shen et al has found that the p.Val37Ile variant segregates with disease in at least 21 individuals. ,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.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,PM6,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
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,PS2-Moderate,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
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,BS3,not_met,PubMed:22729224,patient derived cell lines showed increased PI3K activity and S6 phosphorylation versus control cells,, patient derived cell lines showed increased PI3K activity and S6 phosphorylation versus control cells,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,PS3,not_met,PubMed:22729224,patient derived cell lines showed increased PI3K activity and S6 phosphorylation versus control cells,, patient derived cell lines showed increased PI3K activity and S6 phosphorylation versus control cells,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,PS4,met,PubMed:29988677,"57‐year‐old man who came to our attention for an asymmetric segmental overgrowth of the left foot and ankle, characterized by the presence of bone and connective tissue hyperplastic lesions, the patient showed macrosomia of the left foot and ankle, varus leg deformity and lumps around the knee, and hyperplasia on the left sole",over 15 tumor samples in COSMIC,"over 15 tumor samples in COSMIC 57‐year‐old man who came to our attention for an asymmetric segmental overgrowth of the left foot and ankle, characterized by the presence of bone and connective tissue hyperplastic lesions, the patient showed macrosomia of the left foot and ankle, varus leg deformity and lumps around the knee, and hyperplasia on the left sole",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,PS2,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
182,NM_000257.3(MYH7):c.2722C>G (p.Leu908Val),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
254,NM_000257.3(MYH7):c.1207C>T (p.Arg403Trp),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
191,NM_000257.3(MYH7):c.2221G>T (p.Gly741Trp),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PS4,met,PubMed:27532257,Variant found in probands with HCM,>15 probands including ClinVar SCV000203910.4 and ClinVar SCV000212638.1,>15 probands including ClinVar SCV000203910.4 and ClinVar SCV000212638.1 Variant found in probands with HCM,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
374,NM_005633.3(SOS1):c.1642A>C (p.Ser548Arg),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
729,NM_002834.5(PTPN11):c.188A>G (p.Tyr63Cys),PTPN11,Noonan syndrome,MONDO:0018997,Pathogenic,Autosomal dominant inheritance,RASopathy,2024-10-01,PS3,met,PubMed:22711529,Functional characterization identifies that the p.Tyr63Cys variant perturb the stability of the N-SH2/PTP interaction required to maintain SHP2 in its catalytically inactive conformation.,In vitro functional studies provide some evidence that the p.Tyr63Cys variant may impact protein function (PS3; PMID: 22711529).,In vitro functional studies provide some evidence that the p.Tyr63Cys variant may impact protein function (PS3; PMID: 22711529). Functional characterization identifies that the p.Tyr63Cys variant perturb the stability of the N-SH2/PTP interaction required to maintain SHP2 in its catalytically inactive conformation.,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTPN11Version2.3.0_version=2.3.0.csv
1234,NM_004333.6(BRAF):c.1796C>T (p.Thr599Ile),BRAF,RASopathy,MONDO:0021060,Pathogenic,Autosomal dominant inheritance,RASopathy,2020-03-24,PS4-Supporting,not_met,PubMed:30732632,,1 published case diagnosed with CFC syndrome (PMID: 30732632).,1 published case diagnosed with CFC syndrome (PMID: 30732632). ,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
878,NM_004360.4(CDH1):c.8C>G (p.Pro3Arg),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Likely Benign,Autosomal dominant inheritance,CDH1,2023-08-17,PS4,not_met,PubMed:20921021,This variant was identified in an individual with lobular breast cancer at 38 years and family history of breast cancer.,This variant was identified in an individual with LBC at 38 years and family history of breast cancer (PMID: 20921021). This variant has also been identified in four individuals with LBC but whose families did not meet HDGC clinical criteria.,This variant was identified in an individual with LBC at 38 years and family history of breast cancer (PMID: 20921021). This variant has also been identified in four individuals with LBC but whose families did not meet HDGC clinical criteria. This variant was identified in an individual with lobular breast cancer at 38 years and family history of breast cancer.,ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
878,NM_004360.4(CDH1):c.8C>G (p.Pro3Arg),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Likely Benign,Autosomal dominant inheritance,CDH1,2023-08-17,BS3,not_met,PubMed:20921021,This variant is located in the signal peptide of the E-cadherin pre-protein and would be predicted to impact membrane localization. Localization to the plasma membrane was not affected when this variant was expressed in cells lacking endogenous expression E-cadherin.,This variant is located in the signal peptide of the E-cadherin pre-protein and would be predicted to impact membrane localization. Localization to the plasma membrane was not affected when this variant was expressed in cells lacking endogenous expression E-cadherin (PMID: 20921021).,This variant is located in the signal peptide of the E-cadherin pre-protein and would be predicted to impact membrane localization. Localization to the plasma membrane was not affected when this variant was expressed in cells lacking endogenous expression E-cadherin (PMID: 20921021). This variant is located in the signal peptide of the E-cadherin pre-protein and would be predicted to impact membrane localization. Localization to the plasma membrane was not affected when this variant was expressed in cells lacking endogenous expression E-cadherin.,ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
878,NM_004360.4(CDH1):c.8C>G (p.Pro3Arg),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Likely Benign,Autosomal dominant inheritance,CDH1,2023-08-17,PS3,not_met,PubMed:20921021,This variant is located in the signal peptide of the E-cadherin pre-protein and would be predicted to impact membrane localization. Localization to the plasma membrane was not affected when this variant was expressed in cells lacking endogenous expression E-cadherin.,, This variant is located in the signal peptide of the E-cadherin pre-protein and would be predicted to impact membrane localization. Localization to the plasma membrane was not affected when this variant was expressed in cells lacking endogenous expression E-cadherin.,ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
904,NM_004360.4(CDH1):c.2293C>T (p.Gln765Ter),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Pathogenic,Autosomal dominant inheritance,CDH1,2023-08-29,PS4-Supporting,not_met,PubMed:29156750,Somatic variant in a breast tumour from a white female,"One family that meets HDGC criteria (SCV000839094.1).
Proband with unknown whether family fulfills HDGC criteria (SCV000274004.4).","One family that meets HDGC criteria (SCV000839094.1).
Proband with unknown whether family fulfills HDGC criteria (SCV000274004.4). Somatic variant in a breast tumour from a white female",ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_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,BS3,not_met,PubMed:22171747,,, ,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,PS4,not_met,PubMed:28086757,Per M. Perpich: 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.,Proband specificity score of 5 for child = 1 point. PS4 weight was removed here and combined with PM6 to upweight to PM6_Strong. See PM6_Strong.,Proband specificity score of 5 for child = 1 point. PS4 weight was removed here and combined with PM6 to upweight to PM6_Strong. See PM6_Strong. Per M. Perpich: 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.,ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
757,NM_000314.6(PTEN):c.634+5G>C,PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2023-12-18,PS3,met,PubMed:28677221,Variant shown to cause exon 6 skipping in pt cells.,RNA assay shows impact on splicing. Variant shown to cause exon 6 skipping in pt cells (PMID: 28677221).,RNA assay shows impact on splicing. Variant shown to cause exon 6 skipping in pt cells (PMID: 28677221). Variant shown to cause exon 6 skipping in pt cells.,ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
3786,NC_012920.1:m.3890G>A,MT-ND1,mitochondrial disease,MONDO:0044970,Likely Pathogenic,Mitochondrial inheritance,Mitochondrial Diseases,2022-06-30,PS3-Supporting,not_met,PubMed:23246842,"Cybrid studies of Caporali 2013 showed significantly decreased activities of mitochondrial complex I, complex III, and complex IV. Cell line is available in GenBank, Sequence ID JQ408982.","Cybrid studies showed that the homoplasmic mutant clones had statistically significant decreases in Complex I and ATP synthesis activities (PS3_supporting, PMID: 2324842). ","Cybrid studies showed that the homoplasmic mutant clones had statistically significant decreases in Complex I and ATP synthesis activities (PS3_supporting, PMID: 2324842).  Cybrid studies of Caporali 2013 showed significantly decreased activities of mitochondrial complex I, complex III, and complex IV. Cell line is available in GenBank, Sequence ID JQ408982.",ClinGenMitochondrialDiseaseNuclearandMitochondrialExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_mtDNA_version=1.0.0.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,PP4,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. 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 muscular dystrophy has been reported to be compound heterozygous for  c.1352C>G (p.Pro451Arg) and an intronic variant, c.1438-7_1438-5delTGT (PMID 29149851). No GAA activity was provided for the patient. Therefore, this criterion is not met.","A patient with limb-girdle muscular dystrophy has been reported to be compound heterozygous for  c.1352C>G (p.Pro451Arg) and an intronic variant, c.1438-7_1438-5delTGT (PMID 29149851). No GAA activity was provided for the patient. 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. 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
1326,NM_000152.5(GAA):c.876C>G (p.Tyr292Ter),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-11-12,PM3,not_met,PubMed:31510962,,"Two patients with this variant have been reported (PMID 31510962). Both of them have infantile onset Pompe disease. The residual GAA activity is reported for one of them, meeting PP4. This patient is compound heterozygous for the variant and c.1003G>A (p.Gly335Arg). The in trans data from this patient was used in the assessment of p.Gly335Arg and is not included here in order to avoid circular logic. The other patient is homozygous but PP4 is not met because the residual GAA activity was not reported. Therefore, PM3 is currently not met, based on the available data.","Two patients with this variant have been reported (PMID 31510962). Both of them have infantile onset Pompe disease. The residual GAA activity is reported for one of them, meeting PP4. This patient is compound heterozygous for the variant and c.1003G>A (p.Gly335Arg). The in trans data from this patient was used in the assessment of p.Gly335Arg and is not included here in order to avoid circular logic. The other patient is homozygous but PP4 is not met because the residual GAA activity was not reported. Therefore, PM3 is currently not met, based on the available data. ",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
3184,NM_000261.2:c.1412A>G,MYOC,primary open angle glaucoma,MONDO:0007665,Uncertain Significance,Autosomal dominant inheritance,Glaucoma,2022-07-11,BS3,not_met,PubMed:27092720,"The Y471C 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 Tyr471Cys 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 Tyr471Cys 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 Y471C protein is secreted.
This study does not meet the OddsPath threshold for  BS3_Supporting (< 0.48).",ClinGenGlaucomaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYOCVersion2.0.0_version=2.0.0.csv
3184,NM_000261.2:c.1412A>G,MYOC,primary open angle glaucoma,MONDO:0007665,Uncertain Significance,Autosomal dominant inheritance,Glaucoma,2022-07-11,PS3,not_met,PubMed:27092720,"The Y471C 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 Y471C protein is secreted.
This study does not meet the OddsPath threshold for  BS3_Supporting (< 0.48).",ClinGenGlaucomaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYOCVersion2.0.0_version=2.0.0.csv
7994,NM_001754.5(RUNX1):c.1139A>G (p.Tyr380Cys),RUNX1,hereditary thrombocytopenia and hematologic cancer predisposition syndrome,MONDO:0011071,Uncertain Significance,Autosomal dominant inheritance,Myeloid Malignancy,2024-09-12,PS3,not_met,PubMed:32943879,Altered subnuclear distribution,"This variant has demonstrated altered subnuclear distribution, but other secondary assays have not been tested.","This variant has demonstrated altered subnuclear distribution, but other secondary assays have not been tested. Altered subnuclear distribution",ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
7994,NM_001754.5(RUNX1):c.1139A>G (p.Tyr380Cys),RUNX1,hereditary thrombocytopenia and hematologic cancer predisposition syndrome,MONDO:0011071,Uncertain Significance,Autosomal dominant inheritance,Myeloid Malignancy,2024-09-12,BS3,not_met,PubMed:32943879,Altered subnuclear distribution,This variant has not been featured in in vitro or in vivo functional studies that show no damaging effect on protein function or splicing.,This variant has not been featured in in vitro or in vivo functional studies that show no damaging effect on protein function or splicing. Altered subnuclear distribution,ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
6612,NM_033508.3:c.447C>A,GCK,monogenic diabetes,MONDO:0015967,Likely Pathogenic,Semidominant inheritance,Monogenic Diabetes,2024-03-22,PS3-Moderate,not_met,PubMed:28842611,"WT parameters met:  Kcat = 43.8, S0.5 (ATP 5mM) = 8.82, Hill number = 1.72, ATP Km = 0.47 (at 50 mM glucose), 
RAI = 0.13 calculated by Matschinsky 2009 method (post Matschinsky 2004)
","MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.13, which is below the MDEP cutoff (<0.5) (PS3_Moderate; PMID: 28842611).","MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.13, which is below the MDEP cutoff (<0.5) (PS3_Moderate; PMID: 28842611). WT parameters met:  Kcat = 43.8, S0.5 (ATP 5mM) = 8.82, Hill number = 1.72, ATP Km = 0.47 (at 50 mM glucose), 
RAI = 0.13 calculated by Matschinsky 2009 method (post Matschinsky 2004)
",ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforGCKVersion2.0.0_version=2.0.0.csv
4046,NM_000527.4(LDLR):c.-136C>G,LDLR,"hypercholesterolemia, familial",MONDO:0007750,Uncertain Significance,Semidominant inheritance,Familial Hypercholesterolemia,2022-08-28,PS3-Moderate,not_met,PubMed:31395865,"Level 3: saturation mutagenesis in HepG2 cells, luciferase high throughput study: 16% and 11% luciferase expression","2 Level 3 FS: 
(1) De Castro-Orós et al. 2011 (PMID: 21538688): Heterologous cells (HepG2), luciferase assays - results: 12% reporter gene expression
(2) Kircher et al. 2019 (PMID: 31395865): saturation mutagenesis in HepG2 cells, luciferase high throughput study - results: 16% and 11% luciferase expression
--- in both studies, transcription levels are below 50% of wild-type, so PS3_Moderate is met","2 Level 3 FS: 
(1) De Castro-Orós et al. 2011 (PMID: 21538688): Heterologous cells (HepG2), luciferase assays - results: 12% reporter gene expression
(2) Kircher et al. 2019 (PMID: 31395865): saturation mutagenesis in HepG2 cells, luciferase high throughput study - results: 16% and 11% luciferase expression
--- in both studies, transcription levels are below 50% of wild-type, so PS3_Moderate is met Level 3: saturation mutagenesis in HepG2 cells, luciferase high throughput study: 16% and 11% luciferase expression",ClinGenFamilialHypercholesterolemiaExpertPanelSpecificationstotheACMGAMPVariantClassificationGuidelinesVersion1.2_version=1.2.0.csv
8403,NM_000251.3(MSH2):c.2075G>T (p.Gly692Val),MSH2,Lynch syndrome 1,MONDO:0007356,Pathogenic,Autosomal dominant inheritance,InSiGHT Hereditary Colorectal Cancer/Polyposis,2024-10-11,PS3,met,PubMed:32849802,The CIMRA Functional Odds for Pathogenicity is 150.82 which is higher than 18.72 (PS3).   Data_Sheet_1,The CIMRA Functional Odds for Pathogenicity is 150.82 which is higher than 18.72 (PS3).,The CIMRA Functional Odds for Pathogenicity is 150.82 which is higher than 18.72 (PS3). The CIMRA Functional Odds for Pathogenicity is 150.82 which is higher than 18.72 (PS3).   Data_Sheet_1,ClinGenInSiGHTHereditaryColorectalCancerPolyposisExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMSH2Version1.0.0_version=1.0.0.csv