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
26,NM_000277.2(PAH):c.500A>T (p.Asn167Ile),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-06,PP4-Moderate,not_met,PubMed:26666653,364 hyperphenylalaninemic patients from 20 French Centers for Inborn Errors of Metabolism. p.Asn167Ile was found in compound heterozygous patient carrying a second null mutation.,"Found in a French patient with HPA and 2 unrelated UK patients. BH4 deficiencies not assessed/reported. Seen in 1 German patient, Cofactor deficiency was excluded by the BH4 test. 1 Spanish patient, a defect in the synthesis or regeneration pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels and measuring dihydropteridine reductase activity.","Found in a French patient with HPA and 2 unrelated UK patients. BH4 deficiencies not assessed/reported. Seen in 1 German patient, Cofactor deficiency was excluded by the BH4 test. 1 Spanish patient, a defect in the synthesis or regeneration pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels and measuring dihydropteridine reductase activity. 364 hyperphenylalaninemic patients from 20 French Centers for Inborn Errors of Metabolism. p.Asn167Ile was found in compound heterozygous patient carrying a second null mutation.",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
35,NM_000277.2(PAH):c.800A>T (p.Gln267Leu),PAH,phenylketonuria,MONDO:0009861,Uncertain Significance,Autosomal recessive inheritance,Phenylketonuria,2019-04-05,PP4-Moderate,not_met,PubMed:26503515,"Q267L reported, likely same patient as Zhang JJ report.","Q267L found in 1 Japanese PKU allele and in 1 Chinese PKU patient. Analysis of dihydropteridine reductase activity in red blood cells, biopterin loading test and/or pteridine analysis in urine was performed in the Japanese study. Upgraded per ClinGen Metabolic workgroup.","Q267L found in 1 Japanese PKU allele and in 1 Chinese PKU patient. Analysis of dihydropteridine reductase activity in red blood cells, biopterin loading test and/or pteridine analysis in urine was performed in the Japanese study. Upgraded per ClinGen Metabolic workgroup. Q267L reported, likely same patient as Zhang JJ report.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
69,NM_000277.1(PAH):c.1197A>T (p.Val399=),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-05,PP4-Moderate,not_met,PubMed:23271928,"Fifty-nine unrelated children with PKU. The patients (30 males, 29 females) were identified during treatment at the Neonatal Screening Center of the Shanxi Province Women and Childrens Hospital in Taiyuan and came from various regions of Shanxi province. All 59 cases exhibited significant clinical manifestations of PKU and fulfilled the diagnostic criteria for PKU, with blood phenylalanine concentrations > 20 mg/dL. Urinary pterin analysis and blood neopterin dihydropteridine reductase assays were used to exclude tetrahydrobiopterin deficiency. c. 1197A > T was found on 6 alleles",C.1197A>T was found on 7 alleles of PKU patients. BH4 deficiency was excluded. Upgraded per ClinGen Metabolic WG PMID: 23271928; PMID: 11214902,"C.1197A>T was found on 7 alleles of PKU patients. BH4 deficiency was excluded. Upgraded per ClinGen Metabolic WG PMID: 23271928; PMID: 11214902 Fifty-nine unrelated children with PKU. The patients (30 males, 29 females) were identified during treatment at the Neonatal Screening Center of the Shanxi Province Women and Childrens Hospital in Taiyuan and came from various regions of Shanxi province. All 59 cases exhibited significant clinical manifestations of PKU and fulfilled the diagnostic criteria for PKU, with blood phenylalanine concentrations > 20 mg/dL. Urinary pterin analysis and blood neopterin dihydropteridine reductase assays were used to exclude tetrahydrobiopterin deficiency. c. 1197A > T was found on 6 alleles",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,PP4-Moderate,not_met,PubMed:26503515,"Seen in a patient with PKU identified by newborn screening. 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.","Seen in a patient with mild PKU (Phe level 720). BH4 cofactor deficiency was excluded. PMID: 26503515, 28982351","Seen in a patient with mild PKU (Phe level 720). BH4 cofactor deficiency was excluded. PMID: 26503515, 28982351 Seen in a patient with PKU identified by newborn screening. 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.",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,PP4-Moderate,not_met,PubMed:26503515,"p.H21R was detected on 1 allele from Northern China. Plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected.","H271R was detected in PKU patients in Henan, and a classic PKU patient in France. dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected for the Chinese patient. PMID: 21462123, 26666653,  26503515","H271R was detected in PKU patients in Henan, and a classic PKU patient in France. dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected for the Chinese patient. PMID: 21462123, 26666653,  26503515 p.H21R was detected on 1 allele from Northern China. 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
597,NM_000277.2(PAH):c.812A>G (p.His271Arg),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-06,PP4-Moderate,not_met,PubMed:26666653,"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. His271Arg was detected in 1 patient with classic PKU (Phe > 1200 μmol/L).","H271R was detected in PKU patients in Henan, and a classic PKU patient in France. dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected for the Chinese patient. PMID: 21462123, 26666653,  26503515","H271R was detected in PKU patients in Henan, and a classic PKU patient in France. dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected for the Chinese patient. PMID: 21462123, 26666653,  26503515 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. His271Arg was detected in 1 patient with classic PKU (Phe > 1200 μmol/L).",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
622,NM_000277.2(PAH):c.796A>C (p.Thr266Pro),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-05,PP4-Moderate,not_met,PubMed:26666653,"A total of 364 French patients among which, 9 % had mild hyperphenylalaninemia, 17.7 % mild phenylketonuria and 73.1 % classical phenylketonuria had the PAH gene sequenced and analyzed by Multiplex Ligation Probe Amplification. p.Thr266P reported in 1 patient with classic PKU. Likely same patient as Sarkissian due to same reported genotype (V190A/T266P).","T266P idenitifed in 1 classic PKU patient. BH4 deficiency was excluded.  PMID: 26666653, 23430918","T266P idenitifed in 1 classic PKU patient. BH4 deficiency was excluded.  PMID: 26666653, 23430918 A total of 364 French patients among which, 9 % had mild hyperphenylalaninemia, 17.7 % mild phenylketonuria and 73.1 % classical phenylketonuria had the PAH gene sequenced and analyzed by Multiplex Ligation Probe Amplification. p.Thr266P reported in 1 patient with classic PKU. Likely same patient as Sarkissian due to same reported genotype (V190A/T266P).",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
680,NM_000277.2(PAH):c.440C>T (p.Pro147Leu),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-09,PP4-Moderate,not_met,PubMed:26322415,"c.440C>T (p.P147L) identified in 1 patient with mild 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.440C>T (p.P147L) identified in 1 patient with mild PKU. BH4 deficiency was excluded.  PMID: 26322415,"c.440C>T (p.P147L) identified in 1 patient with mild PKU. BH4 deficiency was excluded.  PMID: 26322415 c.440C>T (p.P147L) identified in 1 patient with mild 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
681,NM_000277.2(PAH):c.559T>C (p.Trp187Arg),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-05-04,PP4-Moderate,not_met,PubMed:28982351,"A total of 655 unrelated Han families, in which at least one member was diagnosed with PKU, were recruited at the genetic counseling clinic of the First Affiliated Hospital of Zhengzhou University, the neonatal screening center of the Third Affiliated Hospital of Zhengzhou University, or Zhengzhou Maternity and Child Care Hospital between January 2008 and January 2016. Patients with BH4 cofactor deficiency were excluded. Patient 488: p.Trp187Arg/p.Gln419Arg, 240, mHP.",Found in at least 1 case with classic PKU (PMID: 18956252). Reported in a patient with mild hyperphenylalaninemia (250 umol/L). BH4 cofactor deficiency excluded. PMID: 28982351,"Found in at least 1 case with classic PKU (PMID: 18956252). Reported in a patient with mild hyperphenylalaninemia (250 umol/L). BH4 cofactor deficiency excluded. PMID: 28982351 A total of 655 unrelated Han families, in which at least one member was diagnosed with PKU, were recruited at the genetic counseling clinic of the First Affiliated Hospital of Zhengzhou University, the neonatal screening center of the Third Affiliated Hospital of Zhengzhou University, or Zhengzhou Maternity and Child Care Hospital between January 2008 and January 2016. Patients with BH4 cofactor deficiency were excluded. Patient 488: p.Trp187Arg/p.Gln419Arg, 240, mHP.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
842,NM_000277.2(PAH):c.505C>T (p.Arg169Cys),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-08-11,PP4-Moderate,not_met,PubMed:30050108,Two compound heterozygous patients with Arg169Cys had mild hyperphenylalaninemia (Phe 120-600 umol/L).,At least three compound heterozygous patients with Arg169Cys have been reported with mild hyperphenylalaninemia (Phe 120-600 umol/L). A defect in BH4 cofactor metabolism was excluded in at least one case.,At least three compound heterozygous patients with Arg169Cys have been reported with mild hyperphenylalaninemia (Phe 120-600 umol/L). A defect in BH4 cofactor metabolism was excluded in at least one case. Two compound heterozygous patients with Arg169Cys had mild hyperphenylalaninemia (Phe 120-600 umol/L).,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
980,NM_000277.3(PAH):c.281_283TCA[1] (p.Ile95del),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-10-18,PP4-Moderate,not_met,PubMed:29560316,This variant was documented in 1 hyperphenylalaninemia patient with a homozygous genotype for the PAH variant p.I95del.,"This variant was documented in 8 patients diagnosed with PAH deficiency (PMID: 26503515, 30747360, 30050108, 29560316). Tetrahydrobiopterin (BH4) deficiency was excluded through a BH4 loading test, urinary pterin analysis, DHPR activity assay (PMID: 26503515, 30747360).","This variant was documented in 8 patients diagnosed with PAH deficiency (PMID: 26503515, 30747360, 30050108, 29560316). Tetrahydrobiopterin (BH4) deficiency was excluded through a BH4 loading test, urinary pterin analysis, DHPR activity assay (PMID: 26503515, 30747360). This variant was documented in 1 hyperphenylalaninemia patient with a homozygous genotype for the PAH variant p.I95del.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
980,NM_000277.3(PAH):c.281_283TCA[1] (p.Ile95del),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-10-18,PP4-Moderate,not_met,PubMed:30050108,This variant was documented in 2 patients diagnosed with mild PKU.,"This variant was documented in 8 patients diagnosed with PAH deficiency (PMID: 26503515, 30747360, 30050108, 29560316). Tetrahydrobiopterin (BH4) deficiency was excluded through a BH4 loading test, urinary pterin analysis, DHPR activity assay (PMID: 26503515, 30747360).","This variant was documented in 8 patients diagnosed with PAH deficiency (PMID: 26503515, 30747360, 30050108, 29560316). Tetrahydrobiopterin (BH4) deficiency was excluded through a BH4 loading test, urinary pterin analysis, DHPR activity assay (PMID: 26503515, 30747360). This variant was documented in 2 patients diagnosed with mild PKU.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
980,NM_000277.3(PAH):c.281_283TCA[1] (p.Ile95del),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-10-18,PP4-Moderate,not_met,PubMed:26503515,"This variant was documented twice in Northern Chinese patients with PAH deficiency (PMID: 26503515). In this paper, the variant is referred to as  ‘c.279_281delCAT’, which is the same as the ‘c.281_283delTCA’ 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 in 8 patients diagnosed with PAH deficiency (PMID: 26503515, 30747360, 30050108, 29560316). Tetrahydrobiopterin (BH4) deficiency was excluded through a BH4 loading test, urinary pterin analysis, DHPR activity assay (PMID: 26503515, 30747360).","This variant was documented in 8 patients diagnosed with PAH deficiency (PMID: 26503515, 30747360, 30050108, 29560316). Tetrahydrobiopterin (BH4) deficiency was excluded through a BH4 loading test, urinary pterin analysis, DHPR activity assay (PMID: 26503515, 30747360). This variant was documented twice in Northern Chinese patients with PAH deficiency (PMID: 26503515). In this paper, the variant is referred to as  ‘c.279_281delCAT’, which is the same as the ‘c.281_283delTCA’ 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
981,NM_000277.3(PAH):c.441+3G>C,PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-10-18,PP4-Moderate,not_met,PubMed:26503515,"This variant was documented seven times in Northern Chinese patients and once in a Southern Chinese patient 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 12 times in patients with PAH deficiency (PMID: 26503515, 16256386, 23932990).","This variant was documented 12 times in patients with PAH deficiency (PMID: 26503515, 16256386, 23932990). This variant was documented seven times in Northern Chinese patients and once in a Southern Chinese patient 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
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
1208,NM_000277.2(PAH):c.1172G>C (p.Ser391Thr),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2020-03-07,PP4-Moderate,not_met,PubMed:29316886,,"Seen in an individual with MHP, All patients were excluded from tetrahydrobiopterin deficiency through a BH4 loading test, a urinary pterin analysis, and a DHPR activity assay  PMID: 30747360, 29499199","Seen in an individual with MHP, All patients were excluded from tetrahydrobiopterin deficiency through a BH4 loading test, a urinary pterin analysis, and a DHPR activity assay  PMID: 30747360, 29499199 ",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1251,NM_000277.3(PAH):c.1264G>A (p.Glu422Lys),PAH,phenylketonuria,MONDO:0009861,Uncertain Significance,Autosomal recessive inheritance,Phenylketonuria,2020-03-27,PP4-Moderate,not_met,PubMed:31737040,,"PMID: 31737040 - p.E44K detected in 1 patient via NGS with Phenylketonuria, Phe > 360umol/L, BH4 Deficiency excluded","PMID: 31737040 - p.E44K detected in 1 patient via NGS with Phenylketonuria, Phe > 360umol/L, BH4 Deficiency excluded ",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1258,NM_000277.1(PAH):c.853C>T (p.His285Tyr),PAH,phenylketonuria,MONDO:0009861,Uncertain Significance,Autosomal recessive inheritance,Phenylketonuria,2020-04-03,PP4-Moderate,not_met,PubMed:26503515,,"PMID 9634518 lists it as a classic PKU variant.  PMID: 26503515 detected in a Chinese PKU patient. PAH deficiency had been assessed after exclusion of a defect in tetrahydrobiopterin metabolism.""","PMID 9634518 lists it as a classic PKU variant.  PMID: 26503515 detected in a Chinese PKU patient. PAH deficiency had been assessed after exclusion of a defect in tetrahydrobiopterin metabolism."" ",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
1271,NM_000277.2(PAH):c.977G>A (p.Trp326Ter),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2020-04-13,PP4-Moderate,not_met,PubMed:24705691,BH4 defect excluded,"It has been identified in at least five PKU cases in whom BH4 deficiency was excluded (PP4_Moderate), in four cases in trans with known pathogenic variants (PM3_VeryStrong). It has been identified in at least two Chinese classic PKU cases (PMID: 261600; PMID: 1301927; PMID: 28982351), in trans with the known pathogenic (per PAH VCEP) p.Y356X and p.R243Q variants; as a single heterozygous variant in a Chinese classic PKU case with BH4 deficiency excluded (PMID: 24705691); in trans with the known pathogenic (per PAH VCEP) p.R261Q variant in one Slovak case with classic PKU with BH4 deficiency said to be excluded (PMID: 23764561); one Chinese proband with mild hyperphenylalanemia in trans with c.1197A>T (p.V399V) (PMID: 25456745). It is also listed Pathogenic in ClinVar by three labs (variant ID 579).","It has been identified in at least five PKU cases in whom BH4 deficiency was excluded (PP4_Moderate), in four cases in trans with known pathogenic variants (PM3_VeryStrong). It has been identified in at least two Chinese classic PKU cases (PMID: 261600; PMID: 1301927; PMID: 28982351), in trans with the known pathogenic (per PAH VCEP) p.Y356X and p.R243Q variants; as a single heterozygous variant in a Chinese classic PKU case with BH4 deficiency excluded (PMID: 24705691); in trans with the known pathogenic (per PAH VCEP) p.R261Q variant in one Slovak case with classic PKU with BH4 deficiency said to be excluded (PMID: 23764561); one Chinese proband with mild hyperphenylalanemia in trans with c.1197A>T (p.V399V) (PMID: 25456745). It is also listed Pathogenic in ClinVar by three labs (variant ID 579). BH4 defect excluded",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
1289,NM_000277.3(PAH):c.1066-1G>A,PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2020-05-09,PP4-Moderate,not_met,PubMed:26503515,,The PAH variant c.1066-1G>A (IVS10-1G>A) was found in a Chinese patient with classical PKU (Phe levels >20 mg/dl). BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PMID: 26322415). This variant was also reported in another Chinese patient with undetermined PKU/MHP phenotype (PMID: 26503515),The PAH variant c.1066-1G>A (IVS10-1G>A) was found in a Chinese patient with classical PKU (Phe levels >20 mg/dl). BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PMID: 26322415). This variant was also reported in another Chinese patient with undetermined PKU/MHP phenotype (PMID: 26503515) ,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1289,NM_000277.3(PAH):c.1066-1G>A,PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2020-05-09,PP4-Moderate,not_met,PubMed:26322415,,The PAH variant c.1066-1G>A (IVS10-1G>A) was found in a Chinese patient with classical PKU (Phe levels >20 mg/dl). BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PMID: 26322415). This variant was also reported in another Chinese patient with undetermined PKU/MHP phenotype (PMID: 26503515),The PAH variant c.1066-1G>A (IVS10-1G>A) was found in a Chinese patient with classical PKU (Phe levels >20 mg/dl). BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PMID: 26322415). This variant was also reported in another Chinese patient with undetermined PKU/MHP phenotype (PMID: 26503515) ,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1489,NM_000277.1:c.875C>T,PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2020-06-26,PP4-Moderate,not_met,PubMed:26503515,"Seen in an individual with PKU. 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.","Seen in multiple patients with PKU in 3 studies. One study mentioned BH4 deficiency excluded.  PMID: 26503515,  PMID: 24705691,  PMID: 29413232","Seen in multiple patients with PKU in 3 studies. One study mentioned BH4 deficiency excluded.  PMID: 26503515,  PMID: 24705691,  PMID: 29413232 Seen in an individual with PKU. 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.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1651,NM_000277.3(PAH):c.527G>A (p.Arg176Gln),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2020-10-15,PP4-Moderate,not_met,PubMed:30459323,,"This variant was observed in at least two probands with mild HPA and one proband with mild PKU. Phe > 120 µmol/L in all probands described. 6R-BH4 was ruled out by urinary pterin levels and by measuring dihydropteridine reductase activity in at least one article. PMID: 30459323, 26210745, and 27121329","This variant was observed in at least two probands with mild HPA and one proband with mild PKU. Phe > 120 µmol/L in all probands described. 6R-BH4 was ruled out by urinary pterin levels and by measuring dihydropteridine reductase activity in at least one article. PMID: 30459323, 26210745, and 27121329 ",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1684,NM_000277.3(PAH):c.510-2A>G,PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2020-10-28,PP4-Moderate,not_met,PubMed:26503515,,"This variant is observed in at least one patient with Phe >120 µmol/L in the Southern Chinese population. BH4 deficiency was ruled out using dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and a tetrahydrobiopterin loading test. PMID: 26503515, 23932990, and 19915519","This variant is observed in at least one patient with Phe >120 µmol/L in the Southern Chinese population. BH4 deficiency was ruled out using dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and a tetrahydrobiopterin loading test. PMID: 26503515, 23932990, and 19915519 ",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
1967,NM_000277.3(PAH):c.280A>G (p.Ile94Val),PAH,phenylketonuria,MONDO:0009861,Uncertain Significance,Autosomal recessive inheritance,Phenylketonuria,2020-10-15,PP4-Moderate,not_met,PubMed:28982351,,"Three patients were observed, one with mild HPA, one with mild PKU and the other with moderate PKU. 6R-BH4 was ruled out through a BH4 loading test, a urinary pterin analysis, and a DHPR activity assay in at least one case. PMID: 30747360, 30459323, and 28982351","Three patients were observed, one with mild HPA, one with mild PKU and the other with moderate PKU. 6R-BH4 was ruled out through a BH4 loading test, a urinary pterin analysis, and a DHPR activity assay in at least one case. PMID: 30747360, 30459323, and 28982351 ",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1967,NM_000277.3(PAH):c.280A>G (p.Ile94Val),PAH,phenylketonuria,MONDO:0009861,Uncertain Significance,Autosomal recessive inheritance,Phenylketonuria,2020-10-15,PP4-Moderate,not_met,PubMed:30459323,,"Three patients were observed, one with mild HPA, one with mild PKU and the other with moderate PKU. 6R-BH4 was ruled out through a BH4 loading test, a urinary pterin analysis, and a DHPR activity assay in at least one case. PMID: 30747360, 30459323, and 28982351","Three patients were observed, one with mild HPA, one with mild PKU and the other with moderate PKU. 6R-BH4 was ruled out through a BH4 loading test, a urinary pterin analysis, and a DHPR activity assay in at least one case. PMID: 30747360, 30459323, and 28982351 ",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
2273,NM_000277.3(PAH):c.1262T>C (p.Ile421Thr),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2021-05-29,PP4-Moderate,not_met,PubMed:26503515,"Seen in a patient with PKU. 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.","Seen in patients with mild and classic PKU. BH4 cofactor deficiency ruled out. PMID: 26503515,  PMID: 27121329,  PMID: 23514811","Seen in patients with mild and classic PKU. BH4 cofactor deficiency ruled out. PMID: 26503515,  PMID: 27121329,  PMID: 23514811 Seen in a patient with PKU. 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.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
2302,NM_000277.3(PAH):c.1252A>C (p.Thr418Pro),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2021-06-09,PP4-Moderate,not_met,PubMed:26503515,"Seen in multiple individuals with PKU, 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.","Seen in multiple 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 multiple 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 multiple individuals with PKU, 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.",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
2304,NM_000277.2(PAH):c.1030G>A (p.Gly344Ser),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2021-06-11,PP4-Moderate,not_met,PubMed:26503515,"Found in one individual from China and one individual from Northern China. Both with PKU, identified using NGS. Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected.","found in multiple individuals with PKU and mild PKU in two studies. BH4 deficiency assesed with dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading.  PMID: 26503515, 29390883, 9634518","found in multiple individuals with PKU and mild PKU in two studies. BH4 deficiency assesed with dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading.  PMID: 26503515, 29390883, 9634518 Found in one individual from China and one individual from Northern China. Both with PKU, identified using NGS. 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
2640,NM_000277.1:c.1256A>G,PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2021-09-19,PP4-Moderate,not_met,PubMed:26503515,"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.","Seen in multiple individuals (18) with PKU. 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.  PMID: 17096675, PMID: 26503515","Seen in multiple individuals (18) with PKU. 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.  PMID: 17096675, PMID: 26503515 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.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
2645,NM_000277.1(PAH):c.665A>G (p.Asp222Gly),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2021-09-19,PP4-Moderate,not_met,PubMed:23842451,1 PKU patient had genotype c.1066-11G>A1/p.D222G,"D222G found on 3 PKU patients (PMID: 24510552, PMID: 9429153). One had BH4 cofactor deficiency excluded (PMID: 15589814).","D222G found on 3 PKU patients (PMID: 24510552, PMID: 9429153). One had BH4 cofactor deficiency excluded (PMID: 15589814). 1 PKU patient had genotype c.1066-11G>A1/p.D222G",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
3151,NM_000277.2(PAH):c.699C>A (p.Phe233Leu),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2022-02-20,PP4-Moderate,not_met,PubMed:24705691,"The cohort study consisted of 93 subjects from 32 families, including 33 patients diagnosed with PKU and two patients diagnosed with BH4 deficiency according to the diagnostic criteria published in Blau et al., 2011. the 39 exons of PAH, PTS, GCH1, QDPR, PCBD1 and GFRP genes, including 50 bp in the intron-exon boundaries were directly sequenced. c.699C>A (F233L) was seen in patient 11 with mild HPA.","F233L seen on 4 PKU alleles. PTPS deficiency excluded in 1 patient (PAH, PTS, GCH1, QDPR, PCBD1 and GFRP genes, including 50 bp in the intron-exon boundaries were directly sequenced).  PMID: 24705691","F233L seen on 4 PKU alleles. PTPS deficiency excluded in 1 patient (PAH, PTS, GCH1, QDPR, PCBD1 and GFRP genes, including 50 bp in the intron-exon boundaries were directly sequenced).  PMID: 24705691 The cohort study consisted of 93 subjects from 32 families, including 33 patients diagnosed with PKU and two patients diagnosed with BH4 deficiency according to the diagnostic criteria published in Blau et al., 2011. the 39 exons of PAH, PTS, GCH1, QDPR, PCBD1 and GFRP genes, including 50 bp in the intron-exon boundaries were directly sequenced. c.699C>A (F233L) was seen in patient 11 with mild HPA.",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,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. G257V was detected on 11 alleles.","G257V identified in on at least 11 PKU alleles, plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected. PMID: 26503515","G257V identified in on at least 11 PKU alleles, plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected. PMID: 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. G257V was detected on 11 alleles.",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
26,NM_000277.2(PAH):c.500A>T (p.Asn167Ile),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-06,PM3-Strong,not_met,PubMed:26666653,Genotype: c. [500A > T] (p.Asn167Ile); [1066-11G > A].,"Patient 664  with genotype N167I/Rl58Q (Pathogenic in ClinVar). Detected with G272X and R408W, known pathogenic variants.","Patient 664  with genotype N167I/Rl58Q (Pathogenic in ClinVar). Detected with G272X and R408W, known pathogenic variants. Genotype: c. [500A > T] (p.Asn167Ile); [1066-11G > A].",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
561,NM_000277.2(PAH):c.1217T>C (p.Ile406Thr),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-06,PM3-Strong,not_met,PubMed:28754886,"Patient M1770: p.[IVS4-1G > A] (VarID 102671, P/LP); [Ile406Thr].",Seen in trans with I65T (PMID: 10234516) and IVS4-1G>A (PMID: 28754886).,"Seen in trans with I65T (PMID: 10234516) and IVS4-1G>A (PMID: 28754886). Patient M1770: p.[IVS4-1G > A] (VarID 102671, P/LP); [Ile406Thr].",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
581,NM_000277.2(PAH):c.848T>A (p.Ile283Asn),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-06,PM3-Strong,not_met,PubMed:26413448,"Single patient, homozygous, with classic PKU","2 patients in (PMID: 9521426), 1 with mild PKU in trans with Y414C and 1 with classic PKU in trans with c.1066-11>G, and 1 homozygous c.848T>A patient with classic PKU in Biglari, 2015 (PMID26413448))","2 patients in (PMID: 9521426), 1 with mild PKU in trans with Y414C and 1 with classic PKU in trans with c.1066-11>G, and 1 homozygous c.848T>A patient with classic PKU in Biglari, 2015 (PMID26413448)) Single patient, homozygous, with classic PKU",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
587,NM_000277.2(PAH):c.434A>T (p.Asp145Val),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-06,PM3-Strong,not_met,PubMed:26666653,Genotype: c. [434A>T]; [1222C>T]/p. [Asp145Val];[Arg408Trp],"Detected with known pathogenic variants: V388M (PMID: 8659548), I65T (PMID: 24368688), and R408W (PMID: 26666653).","Detected with known pathogenic variants: V388M (PMID: 8659548), I65T (PMID: 24368688), and R408W (PMID: 26666653). Genotype: c. [434A>T]; [1222C>T]/p. [Asp145Val];[Arg408Trp]",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
621,NM_000277.2(PAH):c.823C>T (p.Pro275Ser),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-05,PM3-Strong,not_met,PubMed:24705691,in trans with c.669delC,"R408W (Cassio, 2010)
c.669delC (Gu, 2014)","R408W (Cassio, 2010)
c.669delC (Gu, 2014) in trans with c.669delC",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
631,NM_000277.1(PAH):c.841C>T (p.Pro281Ser),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-08-17,PM3-Strong,not_met,PubMed:26666653,"Patient genotype: c. [841C>T]; [1315+1G>A] (VarID576, Pathogenic).","Detected with c.1315+1G>A & p.Arg243Ter, pathogenic in ClinVar","Detected with c.1315+1G>A & p.Arg243Ter, pathogenic in ClinVar Patient genotype: c. [841C>T]; [1315+1G>A] (VarID576, Pathogenic).",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
680,NM_000277.2(PAH):c.440C>T (p.Pro147Leu),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-09,PM3-Strong,not_met,PubMed:28982351,3 patients with p.Pro147Leu in trans with: S70del; p.His170Arg; p.Arg53His. Peripheral blood samples were collected from the patients and parents. Variable sites in patient genes were aligned with the corresponding sites from the respective parents.,"Detected in trans with p.R261Ter (P, 5 submitters)  PMID: 27121329; c.611A>G (P/LP, 4 submitters)  PMID: 30050108; p.S70del (P, 3 submitters) PMID: 28982351","Detected in trans with p.R261Ter (P, 5 submitters)  PMID: 27121329; c.611A>G (P/LP, 4 submitters)  PMID: 30050108; p.S70del (P, 3 submitters) PMID: 28982351 3 patients with p.Pro147Leu in trans with: S70del; p.His170Arg; p.Arg53His. Peripheral blood samples were collected from the patients and parents. Variable sites in patient genes were aligned with the corresponding sites from the respective parents.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
680,NM_000277.2(PAH):c.440C>T (p.Pro147Leu),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-09,PM3-Strong,not_met,PubMed:26322415,"Patient genotype: c.[440C>T ];[1215_1219delAATAC], p.[P147L];[I406Sfs*17]. 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.R261Ter (P, 5 submitters)  PMID: 27121329; c.611A>G (P/LP, 4 submitters)  PMID: 30050108; p.S70del (P, 3 submitters) PMID: 28982351","Detected in trans with p.R261Ter (P, 5 submitters)  PMID: 27121329; c.611A>G (P/LP, 4 submitters)  PMID: 30050108; p.S70del (P, 3 submitters) PMID: 28982351 Patient genotype: c.[440C>T ];[1215_1219delAATAC], p.[P147L];[I406Sfs*17]. 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
686,NM_000277.2(PAH):c.168+5G>A,PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-05-26,PM3-Strong,not_met,PubMed:26413448,c.168+5G>A was observed in the homozygous state in one proband.,"c.168+5G>A has been observed in trans with R297H (ClinVar 92750, Pathogenic), I65T (ClinVar 636, Pathogenic), and S349P (ClinVar 615, Pathogenic/Likely Pathogenic), and once in the homozygous state.","c.168+5G>A has been observed in trans with R297H (ClinVar 92750, Pathogenic), I65T (ClinVar 636, Pathogenic), and S349P (ClinVar 615, Pathogenic/Likely Pathogenic), and once in the homozygous state. c.168+5G>A was observed in the homozygous state in one proband.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
840,NM_000277.2(PAH):c.912G>A (p.Gln304=),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-08-07,PM3-Strong,not_met,PubMed:26413448,"Detected on 2 alleles (table 2, ""polymorphism"", 2.56% frequency in cohort), once in a patient with genotype c.838G>Ap.E280K/c.838G>Ap.E280K","Detected with R241H (VarID102804, P). Parental testing not reported. PMID: 27413125. Detected with K363fsdelG (c.1089delG, VarID102518, P/LP)  Parental testing not reported. PMID: 8659548. Detected with I65T (VarID636, P) in 2 unrelated patients and A300S (VarID92751, P). Parental confirmation not stated.  PMID: 2351481. Detected with p.R176L (VarID631, P) in 1 patient. Parental confirmation not stated. PMID: 23500595","Detected with R241H (VarID102804, P). Parental testing not reported. PMID: 27413125. Detected with K363fsdelG (c.1089delG, VarID102518, P/LP)  Parental testing not reported. PMID: 8659548. Detected with I65T (VarID636, P) in 2 unrelated patients and A300S (VarID92751, P). Parental confirmation not stated.  PMID: 2351481. Detected with p.R176L (VarID631, P) in 1 patient. Parental confirmation not stated. PMID: 23500595 Detected on 2 alleles (table 2, ""polymorphism"", 2.56% frequency in cohort), once in a patient with genotype c.838G>Ap.E280K/c.838G>Ap.E280K",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
840,NM_000277.2(PAH):c.912G>A (p.Gln304=),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-08-07,PM3-Strong,not_met,PubMed:27413125,Detected with R241H in subject 6. Parental testing not reported.,"Detected with R241H (VarID102804, P). Parental testing not reported. PMID: 27413125. Detected with K363fsdelG (c.1089delG, VarID102518, P/LP)  Parental testing not reported. PMID: 8659548. Detected with I65T (VarID636, P) in 2 unrelated patients and A300S (VarID92751, P). Parental confirmation not stated.  PMID: 2351481. Detected with p.R176L (VarID631, P) in 1 patient. Parental confirmation not stated. PMID: 23500595","Detected with R241H (VarID102804, P). Parental testing not reported. PMID: 27413125. Detected with K363fsdelG (c.1089delG, VarID102518, P/LP)  Parental testing not reported. PMID: 8659548. Detected with I65T (VarID636, P) in 2 unrelated patients and A300S (VarID92751, P). Parental confirmation not stated.  PMID: 2351481. Detected with p.R176L (VarID631, P) in 1 patient. Parental confirmation not stated. PMID: 23500595 Detected with R241H in subject 6. Parental testing not reported.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
842,NM_000277.2(PAH):c.505C>T (p.Arg169Cys),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-08-11,PM3-Strong,not_met,PubMed:30050108,"Two compound heterozygotes were reported. One patient with Arg169Cys and Arg243Gln (ClinVar 591, Pathogenic) and another with Arg169Cys and Arg408Gln (ClinVar 577, Pathogenic). Parents were tested to confirm carrier status.","Arg169Cys has been reported in trans with pathogenic variants Arg243Gln (ClinVar 591), Arg408Gln (ClinVar 577), and c.208_210del (ClinVar 102632). Parents were tested to confirm carrier status.","Arg169Cys has been reported in trans with pathogenic variants Arg243Gln (ClinVar 591), Arg408Gln (ClinVar 577), and c.208_210del (ClinVar 102632). Parents were tested to confirm carrier status. Two compound heterozygotes were reported. One patient with Arg169Cys and Arg243Gln (ClinVar 591, Pathogenic) and another with Arg169Cys and Arg408Gln (ClinVar 577, Pathogenic). Parents were tested to confirm carrier status.",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
980,NM_000277.3(PAH):c.281_283TCA[1] (p.Ile95del),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-10-18,PM3-Strong,not_met,PubMed:26666653,"This variant was documented in a French patient diagnosed with mild hyperphenylalaninemia (MHP, 180 < Phe < 600 μmol/L) who was a compound heterozygote with the pathogenic c.1243G>A variant in trans; this variant was also found in a patient diagnosed with classic PKU (cPKU, Phe > 1200 μmol/L) who was a compound heterozygote with the pathogenic c.441+5G>T variant in trans (PMID: 26666653). In this paper, the variant is referred to as  ‘c.284_286delTCA’, which is the same as the ‘c.281_283delTCA’ variant. Parental analysis was not performed to confirm heterozygosity.","This variant was detected in trans with a pathogenic or likely pathogenic PAH variant in 3 patients with PKU and 3 patients with hyperphenylalaninemia (PMID: 19292873, 24368688, 25894915, 26666653, 29316886).","This variant was detected in trans with a pathogenic or likely pathogenic PAH variant in 3 patients with PKU and 3 patients with hyperphenylalaninemia (PMID: 19292873, 24368688, 25894915, 26666653, 29316886). This variant was documented in a French patient diagnosed with mild hyperphenylalaninemia (MHP, 180 < Phe < 600 μmol/L) who was a compound heterozygote with the pathogenic c.1243G>A variant in trans; this variant was also found in a patient diagnosed with classic PKU (cPKU, Phe > 1200 μmol/L) who was a compound heterozygote with the pathogenic c.441+5G>T variant in trans (PMID: 26666653). In this paper, the variant is referred to as  ‘c.284_286delTCA’, which is the same as the ‘c.281_283delTCA’ variant. Parental analysis was not performed to confirm heterozygosity.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1195,NM_000277.1(PAH):c.913-7A>G,PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2020-02-16,PM3-Strong,not_met,PubMed:26666653,,"Detected in trans with R261Q (P, 9 submitters)  PMID: 16601866 confirmed by analysing parental DNA. Detected with p.N133Rfs (not in ClinVar). Detected with R408W (P, 14 submitters)  PMID: 24350308 parental analysis not reported. Detected with IVS9+5G>A (no assertion in ClinVar)  PMID: 24048906. Detected in trans with p.G312R (VUS) confirmed on parental DNA  PMID: 24130151 Detected with R241C (P, 7 submitters) and G312V (not in ClinVar) parental analysis not confirmed  PMID: 24401910 Detected with p.Arg243Gln (P, 9 submitters) and p.Arg261Gly (LP) parental analysis not reported  PMID: 26666653 Total of 3.75 pts","Detected in trans with R261Q (P, 9 submitters)  PMID: 16601866 confirmed by analysing parental DNA. Detected with p.N133Rfs (not in ClinVar). Detected with R408W (P, 14 submitters)  PMID: 24350308 parental analysis not reported. Detected with IVS9+5G>A (no assertion in ClinVar)  PMID: 24048906. Detected in trans with p.G312R (VUS) confirmed on parental DNA  PMID: 24130151 Detected with R241C (P, 7 submitters) and G312V (not in ClinVar) parental analysis not confirmed  PMID: 24401910 Detected with p.Arg243Gln (P, 9 submitters) and p.Arg261Gly (LP) parental analysis not reported  PMID: 26666653 Total of 3.75 pts ",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1195,NM_000277.1(PAH):c.913-7A>G,PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2020-02-16,PM3-Strong,not_met,PubMed:26322415,,"Detected in trans with R261Q (P, 9 submitters)  PMID: 16601866 confirmed by analysing parental DNA. Detected with p.N133Rfs (not in ClinVar). Detected with R408W (P, 14 submitters)  PMID: 24350308 parental analysis not reported. Detected with IVS9+5G>A (no assertion in ClinVar)  PMID: 24048906. Detected in trans with p.G312R (VUS) confirmed on parental DNA  PMID: 24130151 Detected with R241C (P, 7 submitters) and G312V (not in ClinVar) parental analysis not confirmed  PMID: 24401910 Detected with p.Arg243Gln (P, 9 submitters) and p.Arg261Gly (LP) parental analysis not reported  PMID: 26666653 Total of 3.75 pts","Detected in trans with R261Q (P, 9 submitters)  PMID: 16601866 confirmed by analysing parental DNA. Detected with p.N133Rfs (not in ClinVar). Detected with R408W (P, 14 submitters)  PMID: 24350308 parental analysis not reported. Detected with IVS9+5G>A (no assertion in ClinVar)  PMID: 24048906. Detected in trans with p.G312R (VUS) confirmed on parental DNA  PMID: 24130151 Detected with R241C (P, 7 submitters) and G312V (not in ClinVar) parental analysis not confirmed  PMID: 24401910 Detected with p.Arg243Gln (P, 9 submitters) and p.Arg261Gly (LP) parental analysis not reported  PMID: 26666653 Total of 3.75 pts ",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,PM3-Strong,not_met,PubMed:28982351,,"Detected in trans with Q267E (P, PAH VCEP) PMID: 26600521 p.Arg158Trp (P, 4 submitters) . PMID: 28982351 variable sites in patient genes were aligned with the corresponding sites from the respective parents","Detected in trans with Q267E (P, PAH VCEP) PMID: 26600521 p.Arg158Trp (P, 4 submitters) . PMID: 28982351 variable sites in patient genes were aligned with the corresponding sites from the respective parents ",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1489,NM_000277.1:c.875C>T,PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2020-06-26,PM3-Strong,not_met,PubMed:31178897,,Detected in trans with c.913-7A>G (LP) confirmed by analyzing parental DNA  PMID: 26322415 and p.Arg243Gln detected with Trio-WES (P 10 submitters)  PMID: 31178897,Detected in trans with c.913-7A>G (LP) confirmed by analyzing parental DNA  PMID: 26322415 and p.Arg243Gln detected with Trio-WES (P 10 submitters)  PMID: 31178897 ,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1489,NM_000277.1:c.875C>T,PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2020-06-26,PM3-Strong,not_met,PubMed:26322415,,Detected in trans with c.913-7A>G (LP) confirmed by analyzing parental DNA  PMID: 26322415 and p.Arg243Gln detected with Trio-WES (P 10 submitters)  PMID: 31178897,Detected in trans with c.913-7A>G (LP) confirmed by analyzing parental DNA  PMID: 26322415 and p.Arg243Gln detected with Trio-WES (P 10 submitters)  PMID: 31178897 ,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
1874,NM_000277.3(PAH):c.532G>A (p.Glu178Lys),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2021-02-12,PM3-Strong,not_met,PubMed:29316886,"Patient 496: IVS4-1G＞A/p.Glu178Lys. Peripheral blood samples were collected from the patients and parents in each of the 643 core families. To determine sequence variability, variable sites in patient genes were aligned with the corresponding sites from the respective parents.","detected in trans with F39del (PMID: 26542770, Parental testing confirmed that the two mutations identified in the 368 patients all were present in trans.) and R408W (PMID: 28771436, parental testing not performed) and IVS4-1G>A (PMID: 29316886, variable sites in patient genes were aligned with the corresponding sites from the respective parents.)","detected in trans with F39del (PMID: 26542770, Parental testing confirmed that the two mutations identified in the 368 patients all were present in trans.) and R408W (PMID: 28771436, parental testing not performed) and IVS4-1G>A (PMID: 29316886, variable sites in patient genes were aligned with the corresponding sites from the respective parents.) Patient 496: IVS4-1G＞A/p.Glu178Lys. Peripheral blood samples were collected from the patients and parents in each of the 643 core families. To determine sequence variability, variable sites in patient genes were aligned with the corresponding sites from the respective parents.",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
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
615,NM_000277.2(PAH):c.632delC (p.Pro211Hisfs),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-08-17,PP4,met,PubMed:26666653,Single patient,"Described in multiple independent patients, all with classic PKU (Phe >1200umol/L), BH4 defect not specifically excluded in any pub. (Guldberg, 1996;  PMID: 26413448;  PMID: 26666653; Sarkissian, 2011)","Described in multiple independent patients, all with classic PKU (Phe >1200umol/L), BH4 defect not specifically excluded in any pub. (Guldberg, 1996;  PMID: 26413448;  PMID: 26666653; Sarkissian, 2011) Single patient",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
615,NM_000277.2(PAH):c.632delC (p.Pro211Hisfs),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-08-17,PP4,met,PubMed:26413448,single homozygous patient with classic PKU,"Described in multiple independent patients, all with classic PKU (Phe >1200umol/L), BH4 defect not specifically excluded in any pub. (Guldberg, 1996;  PMID: 26413448;  PMID: 26666653; Sarkissian, 2011)","Described in multiple independent patients, all with classic PKU (Phe >1200umol/L), BH4 defect not specifically excluded in any pub. (Guldberg, 1996;  PMID: 26413448;  PMID: 26666653; Sarkissian, 2011) single homozygous patient with classic PKU",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
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
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
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
1359,NM_000277.2(PAH):c.694C>T (p.Gln232Ter),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2020-05-31,PP4,met,PubMed:30050108,"c.694C>T detected on 6 alleles. 796 unrelated patients were enrolled. Biochemical testing data, including plasma phenylalanine levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected.",c.694C>T detected on 6 alleles in a PKU Chinese cohort.  PMID: 30050108,"c.694C>T detected on 6 alleles in a PKU Chinese cohort.  PMID: 30050108 c.694C>T detected on 6 alleles. 796 unrelated patients were enrolled. Biochemical testing data, including plasma phenylalanine levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected.",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
1675,NM_000277.3(PAH):c.124_126del (p.Lys42del),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2020-10-16,PP4,met,PubMed:30050108,,"PP4_met: This variant was reported in 1 patient with PAH deficiency (PMID: 27243974) and 1 patient with classic phenylketonuria (PMID: 30050108)

27243974, Yubero - This variant was documented in 1 patient with PAH deficiency. To compare the diagnostic yield obtained after NGS, patients were classified into two groups depending on the level of evidence supporting the suspicion and independently of the NGS analysis results. Group 1 (n = 81) included patients who presented with consistent clinical and biochemical data supporting their having an IEM studied in the panel. This patient with this variant was a part of this group. Tetrahydrobiopterin (BH4) deficiency was not excluded through a BH4 loading test, urinary pterin analysis and DHPR activity assay.

30050108, Li - This variant was documented in 1 patient with classic phenylketonuria. Tetrahydrobipterin (BH4) deficiency was not excluded through a BH4 loading test, urinary pterin analysis and DHPR activity although that data was collected if available.","PP4_met: This variant was reported in 1 patient with PAH deficiency (PMID: 27243974) and 1 patient with classic phenylketonuria (PMID: 30050108)

27243974, Yubero - This variant was documented in 1 patient with PAH deficiency. To compare the diagnostic yield obtained after NGS, patients were classified into two groups depending on the level of evidence supporting the suspicion and independently of the NGS analysis results. Group 1 (n = 81) included patients who presented with consistent clinical and biochemical data supporting their having an IEM studied in the panel. This patient with this variant was a part of this group. Tetrahydrobiopterin (BH4) deficiency was not excluded through a BH4 loading test, urinary pterin analysis and DHPR activity assay.

30050108, Li - This variant was documented in 1 patient with classic phenylketonuria. Tetrahydrobipterin (BH4) deficiency was not excluded through a BH4 loading test, urinary pterin analysis and DHPR activity although that data was collected if available. ",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1675,NM_000277.3(PAH):c.124_126del (p.Lys42del),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2020-10-16,PP4,met,PubMed:27243974,,"PP4_met: This variant was reported in 1 patient with PAH deficiency (PMID: 27243974) and 1 patient with classic phenylketonuria (PMID: 30050108)

27243974, Yubero - This variant was documented in 1 patient with PAH deficiency. To compare the diagnostic yield obtained after NGS, patients were classified into two groups depending on the level of evidence supporting the suspicion and independently of the NGS analysis results. Group 1 (n = 81) included patients who presented with consistent clinical and biochemical data supporting their having an IEM studied in the panel. This patient with this variant was a part of this group. Tetrahydrobiopterin (BH4) deficiency was not excluded through a BH4 loading test, urinary pterin analysis and DHPR activity assay.

30050108, Li - This variant was documented in 1 patient with classic phenylketonuria. Tetrahydrobipterin (BH4) deficiency was not excluded through a BH4 loading test, urinary pterin analysis and DHPR activity although that data was collected if available.","PP4_met: This variant was reported in 1 patient with PAH deficiency (PMID: 27243974) and 1 patient with classic phenylketonuria (PMID: 30050108)

27243974, Yubero - This variant was documented in 1 patient with PAH deficiency. To compare the diagnostic yield obtained after NGS, patients were classified into two groups depending on the level of evidence supporting the suspicion and independently of the NGS analysis results. Group 1 (n = 81) included patients who presented with consistent clinical and biochemical data supporting their having an IEM studied in the panel. This patient with this variant was a part of this group. Tetrahydrobiopterin (BH4) deficiency was not excluded through a BH4 loading test, urinary pterin analysis and DHPR activity assay.

30050108, Li - This variant was documented in 1 patient with classic phenylketonuria. Tetrahydrobipterin (BH4) deficiency was not excluded through a BH4 loading test, urinary pterin analysis and DHPR activity although that data was collected if available. ",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
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
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
615,NM_000277.2(PAH):c.632delC (p.Pro211Hisfs),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-08-17,PM3,met,PubMed:26413448,single patient described with classic PKU,"Homozygous (Bilgiari, 2015) and in trans with 1066-11G>A (pathogenic, Jeannesson-Thivisol, 2015)","Homozygous (Bilgiari, 2015) and in trans with 1066-11G>A (pathogenic, Jeannesson-Thivisol, 2015) single patient described with classic PKU",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
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
1052,NM_000277.3(PAH):c.460T>C (p.Tyr154His),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-12-22,PM3,met,PubMed:26322415,,"The PAH variant c.460T>C (p.Tyr154His) was found in trans with the PAH pathogenic variant c.331C>T (p.Arg111Ter)(ClinVar ID: 581) in a Chinese patient with classical PKU (Phe levels >20 mg/dl) . All mutations identified in patients were confirmed by analyzing parental DNA. (PM3 Points= 1*1=1) (PMID: 26322415). The PAH variant c.460T>C (p.Tyr154His) was found as a homozygous occurrence in a Chinese patient with classical PKU (Phe ≥1200 μmol/L) (PM3 Points= 1*0.5=0.5) (PMID:16256386)
PM3 points awarded in total: 1.5","The PAH variant c.460T>C (p.Tyr154His) was found in trans with the PAH pathogenic variant c.331C>T (p.Arg111Ter)(ClinVar ID: 581) in a Chinese patient with classical PKU (Phe levels >20 mg/dl) . All mutations identified in patients were confirmed by analyzing parental DNA. (PM3 Points= 1*1=1) (PMID: 26322415). The PAH variant c.460T>C (p.Tyr154His) was found as a homozygous occurrence in a Chinese patient with classical PKU (Phe ≥1200 μmol/L) (PM3 Points= 1*0.5=0.5) (PMID:16256386)
PM3 points awarded in total: 1.5 ",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
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
1681,NM_000277.1(PAH):c.716G>T (p.Gly239Val),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2020-10-23,PM3,met,PubMed:32106880,,detected with p.R408W (P 14 submitters) PMID: 31623983 IVS10–11g>a (P 7 submitters) PMID: 32106880 parental analysis not reported,detected with p.R408W (P 14 submitters) PMID: 31623983 IVS10–11g>a (P 7 submitters) PMID: 32106880 parental analysis not reported ,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
36,NM_000277.2(PAH):c.745C>T (p.Leu249Phe),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-05,PM3-Very Strong,not_met,PubMed:24765287,"The diagnosis was confirmed through molecular analysis of the patient as well as the parents. Genetic analysis showed that she is compound heterozygous for the following mutations: p.L249F and p.R261Q (VarID 582, P/LP). The father carries the first mutation and the mother the second.","Seen with R261X, A309V, V388M, R261Q. All Pathogenic/Likely Pathogenic in ClinVar. Upgraded per ClinGen SVI Workgroup","Seen with R261X, A309V, V388M, R261Q. All Pathogenic/Likely Pathogenic in ClinVar. Upgraded per ClinGen SVI Workgroup The diagnosis was confirmed through molecular analysis of the patient as well as the parents. Genetic analysis showed that she is compound heterozygous for the following mutations: p.L249F and p.R261Q (VarID 582, P/LP). The father carries the first mutation and the mother the second.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
981,NM_000277.3(PAH):c.441+3G>C,PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-10-18,PM3-Very Strong,not_met,PubMed:28982351,"This  variant was documented in one patient with classic PKU, with the likely pathogenic p.Ala434Asp variant in trans. This variant was documented in one patient with mild PKU, with the VUS Leu444Phe in trans. This variant was documented in one patient with PAH deficiency, with the IVS4-2A>G variant in trans. This variant was documented in one patient with mild hyperphenylalaninemia (MHP), the variant in trans was not specified. This variant was documented in one patient with mild PKU, with the pathogenic p.Arg400Thr variant in trans. Parental analysis was performed to confirm compound heterozygosity.","This variant was documented at least 7 times in patients with PAH deficiency with a pathogenic or likely pathogenic variant in trans (PMID: 28982351, 5894915, 30050108).  This variant was also documented in two patients homozygous for the c.441+3G>C variant, one diagnosed with mild PKU and one diagnosed with classic  PKU (PMID: 30050108)","This variant was documented at least 7 times in patients with PAH deficiency with a pathogenic or likely pathogenic variant in trans (PMID: 28982351, 5894915, 30050108).  This variant was also documented in two patients homozygous for the c.441+3G>C variant, one diagnosed with mild PKU and one diagnosed with classic  PKU (PMID: 30050108) This  variant was documented in one patient with classic PKU, with the likely pathogenic p.Ala434Asp variant in trans. This variant was documented in one patient with mild PKU, with the VUS Leu444Phe in trans. This variant was documented in one patient with PAH deficiency, with the IVS4-2A>G variant in trans. This variant was documented in one patient with mild hyperphenylalaninemia (MHP), the variant in trans was not specified. This variant was documented in one patient with mild PKU, with the pathogenic p.Arg400Thr variant in trans. Parental analysis was performed to confirm compound heterozygosity.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
981,NM_000277.3(PAH):c.441+3G>C,PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-10-18,PM3-Very Strong,not_met,PubMed:30050108,"This variant was documented in two patients homozygous for this c.441+3G>C variant, one diagnosed with mild PKU and one diagnosed with classic  PKU. This variant was documented in 2 patients with classic PKU, with the pathogenic c.442-1G>A variant in trans. This variant was documented in 1 patient with classic PKU with the p.EX6-96A>G variant in trans. This variant was documented in 1 patient with mild PKU and 1 patient with classic PKU, both with the pathogenic p.Arg243Gln variant in trans. This variant was documented in 1 patient with mild PKU, with the pathogenic p.Arg241Cys variant in trans. This variant was documented in 1 patient with mild PKU with the pathogenic p.Arg408Gln variant in trans. Validation tests on parents were performed using Sanger sequencing.","This variant was documented at least 7 times in patients with PAH deficiency with a pathogenic or likely pathogenic variant in trans (PMID: 28982351, 5894915, 30050108).  This variant was also documented in two patients homozygous for the c.441+3G>C variant, one diagnosed with mild PKU and one diagnosed with classic  PKU (PMID: 30050108)","This variant was documented at least 7 times in patients with PAH deficiency with a pathogenic or likely pathogenic variant in trans (PMID: 28982351, 5894915, 30050108).  This variant was also documented in two patients homozygous for the c.441+3G>C variant, one diagnosed with mild PKU and one diagnosed with classic  PKU (PMID: 30050108) This variant was documented in two patients homozygous for this c.441+3G>C variant, one diagnosed with mild PKU and one diagnosed with classic  PKU. This variant was documented in 2 patients with classic PKU, with the pathogenic c.442-1G>A variant in trans. This variant was documented in 1 patient with classic PKU with the p.EX6-96A>G variant in trans. This variant was documented in 1 patient with mild PKU and 1 patient with classic PKU, both with the pathogenic p.Arg243Gln variant in trans. This variant was documented in 1 patient with mild PKU, with the pathogenic p.Arg241Cys variant in trans. This variant was documented in 1 patient with mild PKU with the pathogenic p.Arg408Gln variant in trans. Validation tests on parents were performed using Sanger sequencing.",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,PM3-Very Strong,not_met,PubMed:28982351,This variant was documented in a mild PKU patient with the pathogenic p.Arg241His variant in trans. This variant was also documented in a patient with mild PKU with the likely pathogenic p.His107Arg variant in trans. This variant was documented in a mild PKU patient with the likely pathogenic c.722delG variant in trans. This variant was documented in a patient with mild PKU with the pathogenic p.Tyr356* variant in trans. Parental analysis was performed to confirm compound heterozygosity (PMID: 28982351).,"This variant was documented in at least 7 Chinese patients with PAH deficiency, with a pathogenic or likely pathogenic PAH variant in trans (PMID: 16256386, 23932990).","This variant was documented in at least 7 Chinese patients with PAH deficiency, with a pathogenic or likely pathogenic PAH variant in trans (PMID: 16256386, 23932990). This variant was documented in a mild PKU patient with the pathogenic p.Arg241His variant in trans. This variant was also documented in a patient with mild PKU with the likely pathogenic p.His107Arg variant in trans. This variant was documented in a mild PKU patient with the likely pathogenic c.722delG variant in trans. This variant was documented in a patient with mild PKU with the pathogenic p.Tyr356* variant in trans. Parental analysis was performed to confirm compound heterozygosity (PMID: 28982351).",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1054,NM_000277.3(PAH):c.969+5G>A,PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-12-22,PM3-Very Strong,not_met,PubMed:26413448,,"From PMID: 30159852, 32 Iranian patients genetically diagnosed with PKU were identified with this variant. This includes 23 homozygotes with serum Phe 11-54 mg/dL:  patients 73, 140, 142, 166, 237, 314, 341, 370, 390, 405, 422, 435, 446, 558, 563, 574, 582, 589, 591, 600, 601, 612, 613 (1pt). Another 9 compound heterozygous patients with unconfirmed phase were also identified. Two patients with genotype c.1066-11G>A (ClinVar: 607, Pathogenic);c.969+5G>A: patient 53 serum Phe 15 mg/dL and patient 564 serum Phe 5.4 mg/dL (1pt). Patient 562 with genotype c.168+5G>C (ClinVar 102606, Pathogenic);c.969+5G>A abd serum Phe 14.2 mg/dL (0.5pt). Four patients with genotype p.Arg176Ter (ClinVar: 102723, Pathogenic);c.969+5G>A: patient 260 serum Phe 20 mg/dL, patient 106 serum Phe 15 mg/dL, patient 584 serum Phe NA, patient 628 serum Phe 20 mg/dL (1.5pt for 3 patients with Phe levels). Patient 628 with genotype c.969+5G>A;p.L258R (not previously classified) and serum Phe NA, (0pt). And patient 196 with genotype p.E280K (ClinVar 580, Pathogenic);c.969+5G>A and serum Phe 21 mg/dL (0.5pt).

This variant has also been identified in trans with variants ClinVar: 102894, Likely Pathogenic) 0.25pt (PMID: 24048906) and Ala300Ser (ClinVar: 92751, Pathogenic) 0.5pt (PMID: 10947211).

TOTAL: At least 26 homozygotes plus compound heterozygotes with at least 6 different Likely Pathogenic/Pathogenic variants. 5.5pt","From PMID: 30159852, 32 Iranian patients genetically diagnosed with PKU were identified with this variant. This includes 23 homozygotes with serum Phe 11-54 mg/dL:  patients 73, 140, 142, 166, 237, 314, 341, 370, 390, 405, 422, 435, 446, 558, 563, 574, 582, 589, 591, 600, 601, 612, 613 (1pt). Another 9 compound heterozygous patients with unconfirmed phase were also identified. Two patients with genotype c.1066-11G>A (ClinVar: 607, Pathogenic);c.969+5G>A: patient 53 serum Phe 15 mg/dL and patient 564 serum Phe 5.4 mg/dL (1pt). Patient 562 with genotype c.168+5G>C (ClinVar 102606, Pathogenic);c.969+5G>A abd serum Phe 14.2 mg/dL (0.5pt). Four patients with genotype p.Arg176Ter (ClinVar: 102723, Pathogenic);c.969+5G>A: patient 260 serum Phe 20 mg/dL, patient 106 serum Phe 15 mg/dL, patient 584 serum Phe NA, patient 628 serum Phe 20 mg/dL (1.5pt for 3 patients with Phe levels). Patient 628 with genotype c.969+5G>A;p.L258R (not previously classified) and serum Phe NA, (0pt). And patient 196 with genotype p.E280K (ClinVar 580, Pathogenic);c.969+5G>A and serum Phe 21 mg/dL (0.5pt).

This variant has also been identified in trans with variants ClinVar: 102894, Likely Pathogenic) 0.25pt (PMID: 24048906) and Ala300Ser (ClinVar: 92751, Pathogenic) 0.5pt (PMID: 10947211).

TOTAL: At least 26 homozygotes plus compound heterozygotes with at least 6 different Likely Pathogenic/Pathogenic variants. 5.5pt ",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1286,NM_000277.3(PAH):c.722del (p.Arg241fs),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2020-05-09,PM3-Very Strong,not_met,PubMed:30459323,,"The variant c.722del (p.Arg241fs) was detected in trans (confirmed by parental DNA analyses) in five Chinese patients with the following PAH pathogenic variants: 
c.498C>G (p.Tyr166Ter) (ClinVar ID: 371373), c.728G>A (p.Arg243Gln) (ClinVar ID: 591), and c.1223G>A (p.Arg408Gln) (ClinVar ID: 612) (PM3 Points: 5) (PMID: 26322415).
The variant c.722del (p.Arg241fs)  was also detected in three compound heterozygous Chinese patients with the following PAH pathogenic and likely pathogenic variants: c.611A>G (p.Tyr204Cys) (ClinVar ID: 590), c.1223G>A (p.Arg408Gln) (ClinVar ID: 612) (PM3 Points: 1.75)(PMID: 30459323). PM3_Very Strong (6.75)","The variant c.722del (p.Arg241fs) was detected in trans (confirmed by parental DNA analyses) in five Chinese patients with the following PAH pathogenic variants: 
c.498C>G (p.Tyr166Ter) (ClinVar ID: 371373), c.728G>A (p.Arg243Gln) (ClinVar ID: 591), and c.1223G>A (p.Arg408Gln) (ClinVar ID: 612) (PM3 Points: 5) (PMID: 26322415).
The variant c.722del (p.Arg241fs)  was also detected in three compound heterozygous Chinese patients with the following PAH pathogenic and likely pathogenic variants: c.611A>G (p.Tyr204Cys) (ClinVar ID: 590), c.1223G>A (p.Arg408Gln) (ClinVar ID: 612) (PM3 Points: 1.75)(PMID: 30459323). PM3_Very Strong (6.75) ",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1286,NM_000277.3(PAH):c.722del (p.Arg241fs),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2020-05-09,PM3-Very Strong,not_met,PubMed:26322415,,"The variant c.722del (p.Arg241fs) was detected in trans (confirmed by parental DNA analyses) in five Chinese patients with the following PAH pathogenic variants: 
c.498C>G (p.Tyr166Ter) (ClinVar ID: 371373), c.728G>A (p.Arg243Gln) (ClinVar ID: 591), and c.1223G>A (p.Arg408Gln) (ClinVar ID: 612) (PM3 Points: 5) (PMID: 26322415).
The variant c.722del (p.Arg241fs)  was also detected in three compound heterozygous Chinese patients with the following PAH pathogenic and likely pathogenic variants: c.611A>G (p.Tyr204Cys) (ClinVar ID: 590), c.1223G>A (p.Arg408Gln) (ClinVar ID: 612) (PM3 Points: 1.75)(PMID: 30459323). PM3_Very Strong (6.75)","The variant c.722del (p.Arg241fs) was detected in trans (confirmed by parental DNA analyses) in five Chinese patients with the following PAH pathogenic variants: 
c.498C>G (p.Tyr166Ter) (ClinVar ID: 371373), c.728G>A (p.Arg243Gln) (ClinVar ID: 591), and c.1223G>A (p.Arg408Gln) (ClinVar ID: 612) (PM3 Points: 5) (PMID: 26322415).
The variant c.722del (p.Arg241fs)  was also detected in three compound heterozygous Chinese patients with the following PAH pathogenic and likely pathogenic variants: c.611A>G (p.Tyr204Cys) (ClinVar ID: 590), c.1223G>A (p.Arg408Gln) (ClinVar ID: 612) (PM3 Points: 1.75)(PMID: 30459323). PM3_Very Strong (6.75) ",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
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
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
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
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
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"
642,NM_000441.1(SLC26A4):c.349C>T,SLC26A4,Pendred syndrome,MONDO:0010134,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2023-01-25,BP2,not_met,PubMed:26969326,"1119 patients with hearing loss tested. Found one compound heterozygote with this variant in trans with a splicing c.-4+1G>C variant with severe to profound hearing loss, but not noted if they tested temporal bone imaging. Shouldn't be used for PM3, as the splice variant is VUS.",," 1119 patients with hearing loss tested. Found one compound heterozygote with this variant in trans with a splicing c.-4+1G>C variant with severe to profound hearing loss, but not noted if they tested temporal bone imaging. Shouldn't be used for PM3, as the splice variant is VUS.","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,BP2,not_met,PubMed:26338283,67 Chinese families with Usher syndrome were tested for variants in 196 retinal disease genes. The p.Gly1861Ser variant was identified 1 patient with c.8559-2A>G in trans.,, 67 Chinese families with Usher syndrome were tested for variants in 196 retinal disease genes. The p.Gly1861Ser variant was identified 1 patient with c.8559-2A>G in trans.,"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,BP2,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"
643,NM_206933.2(USH2A):c.5581G>A (p.Gly1861Ser),USH2A,Usher syndrome,MONDO:0019501,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,BP2,not_met,PubMed:23737954,"5 unrelated Chinese families with Usher syndrome were tested using a panel of 144 known genes for deep exome resequencing. The p.Gly1861Ser variant was identified in family F2 in trans with a novel frameshift c.8602delA, but was in cis with a second missense variant p.R5143C. The cis variants were also present in an unaffected sib.",," 5 unrelated Chinese families with Usher syndrome were tested using a panel of 144 known genes for deep exome resequencing. The p.Gly1861Ser variant was identified in family F2 in trans with a novel frameshift c.8602delA, but was in cis with a second missense variant p.R5143C. The cis variants were also present in an unaffected sib.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
645,NM_000441.1(SLC26A4):c.1229C>T (p.Thr410Met),SLC26A4,Pendred syndrome,MONDO:0010134,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,BP2,not_met,PubMed:25372295,"Seqeunced 1057 Chinese HL patients. Identified 27 patients with the c.919-2A>G variant in trans with the p.T410M. 8 patients with the genotype: c.2168A.G(p.H723R) c.1229C.T(pT410M). 4 homozygotes. 3 patients with the genotype p.V659L/p.T410M. Identified 2 cases of the varaint in trans with the p.N392Y variant. Identified 2 patients with the c.1687_1692insA variant in trans with the p.T140M variant. One case in trans with the p.T94I variant. One case in trans with the p.V650D variant. One case in trans with the c.1693insA variant. One patient with the p.S448X variant in trans. One patient with the IVS19+2T>A variant in trans. There were many more variants in trans and 4 cases with wt in trans, but since the PM3 points are maxed, they will not be noted here.",," Seqeunced 1057 Chinese HL patients. Identified 27 patients with the c.919-2A>G variant in trans with the p.T410M. 8 patients with the genotype: c.2168A.G(p.H723R) c.1229C.T(pT410M). 4 homozygotes. 3 patients with the genotype p.V659L/p.T410M. Identified 2 cases of the varaint in trans with the p.N392Y variant. Identified 2 patients with the c.1687_1692insA variant in trans with the p.T140M variant. One case in trans with the p.T94I variant. One case in trans with the p.V650D variant. One case in trans with the c.1693insA variant. One patient with the p.S448X variant in trans. One patient with the IVS19+2T>A variant in trans. There were many more variants in trans and 4 cases with wt in trans, but since the PM3 points are maxed, they will not be noted here.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
645,NM_000441.1(SLC26A4):c.1229C>T (p.Thr410Met),SLC26A4,Pendred syndrome,MONDO:0010134,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,BP2,not_met,PubMed:21961810,"This study investigated 144 patients with SNHL adn temporal bone malformations and found that 6 patients had the p.T410M variant. There was one comp. het. indiviudal with a p.A360V variant in trans, 4 compound het individuals with the c.919-2 A>G splice variant, 1 individual with the p.SF532, 545* variant, and one indivudal with the c.1343C>A p.S448X variant.",," This study investigated 144 patients with SNHL adn temporal bone malformations and found that 6 patients had the p.T410M variant. There was one comp. het. indiviudal with a p.A360V variant in trans, 4 compound het individuals with the c.919-2 A>G splice variant, 1 individual with the p.SF532, 545* variant, and one indivudal with the c.1343C>A p.S448X variant.","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"
649,NM_206933.2(USH2A):c.8559-2A>G,USH2A,Usher syndrome,MONDO:0019501,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,BP2,not_met,PubMed:25133613,consanguineous family ARRP04: Identified in a homozygous state in one affected individual. Absent from 30 controls. Cite that this variant is a founder variant in East Asian populations.,, consanguineous family ARRP04: Identified in a homozygous state in one affected individual. Absent from 30 controls. Cite that this variant is a founder variant in East Asian populations.,"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,BP2,not_met,PubMed:26338283,This study of 67 Chinese Usher syndrome probands identified 11 probands with the variant. They declare that the variant is a founder mutation that accounts for 265 of all Western Japanese USH patients but was never observed in Europeans. The varaint was observed in 5 individuals who were compound het via missense and 6 individuals with nonsense or frameshift variants.,, This study of 67 Chinese Usher syndrome probands identified 11 probands with the variant. They declare that the variant is a founder mutation that accounts for 265 of all Western Japanese USH patients but was never observed in Europeans. The varaint was observed in 5 individuals who were compound het via missense and 6 individuals with nonsense or frameshift variants.,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
651,NM_206933.2(USH2A):c.1036A>C (p.Asn346His),USH2A,Usher syndrome,MONDO:0019501,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,BP2,not_met,PubMed:26969326,detected in trans with c.2299del,, detected in trans with c.2299del,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
651,NM_206933.2(USH2A):c.1036A>C (p.Asn346His),USH2A,Usher syndrome,MONDO:0019501,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,BP2,not_met,PubMed:22135276,"detected in trans with p.Glu3305ArgfsX41, p.Trp3521Arg, and Lys419Phe",," detected in trans with p.Glu3305ArgfsX41, p.Trp3521Arg, and Lys419Phe","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"
855,NM_206933.2(USH2A):c.4714C>T (p.Leu1572Phe),USH2A,Usher syndrome,MONDO:0019501,Likely Benign,Autosomal recessive inheritance,Hearing Loss,2019-08-16,BP2,met,PubMed:26969326,"In 5 patients: in cis with c.2299delG + another het variant.
In one patient: in cis with homozygous c.2299delG",observed in cis with c.2299delG.,"observed in cis with c.2299delG. In 5 patients: in cis with c.2299delG + another het variant.
In one patient: in cis with homozygous c.2299delG","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
855,NM_206933.2(USH2A):c.4714C>T (p.Leu1572Phe),USH2A,Usher syndrome,MONDO:0019501,Likely Benign,Autosomal recessive inheritance,Hearing Loss,2019-08-16,BP2,met,PubMed:28944237,"observed in trans with one patient with Usher syndrome. No segregation was done but in direct communication with author he mentioned: If phasing by segregation analyses was not possible, compound-heterozygosity could only be assumed based on mutation types, previous descriptions",observed in cis with c.2299delG.,"observed in cis with c.2299delG. observed in trans with one patient with Usher syndrome. No segregation was done but in direct communication with author he mentioned: If phasing by segregation analyses was not possible, compound-heterozygosity could only be assumed based on mutation types, previous descriptions","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
1748,NM_206933.2(USH2A):c.2522C>A (p.Ser841Tyr),USH2A,Usher syndrome,MONDO:0019501,Benign,Autosomal recessive inheritance,Hearing Loss,2020-12-24,BP2,not_met,PubMed:25773295,"Proband, female onset at 50 years, with amyotrophic lateral sclerosis (ALS) is compound het. for p.S841Y variant and an USH2A p.P4660L variant that is present in 1/30614 South Asian alleles in gnomAD. This observation is irrelevant given that the p.Pro4660Leu variant is not classified as pathogenic. Phenotype is not relevant in a carrier.",," Proband, female onset at 50 years, with amyotrophic lateral sclerosis (ALS) is compound het. for p.S841Y variant and an USH2A p.P4660L variant that is present in 1/30614 South Asian alleles in gnomAD. This observation is irrelevant given that the p.Pro4660Leu variant is not classified as pathogenic. Phenotype is not relevant in a carrier.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
1748,NM_206933.2(USH2A):c.2522C>A (p.Ser841Tyr),USH2A,Usher syndrome,MONDO:0019501,Benign,Autosomal recessive inheritance,Hearing Loss,2020-12-24,BP2,not_met,PubMed:28944237,"German proband, 59 y/o, carrying the p.Ser841Tyr variant on one allele and no variant identified on the second allele.",," German proband, 59 y/o, carrying the p.Ser841Tyr variant on one allele and no variant identified on the second allele.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
635,NM_004086.2(COCH):c.151C>T (p.Pro51Ser),COCH,nonsyndromic genetic deafness,MONDO:0019497,Pathogenic,Autosomal dominant inheritance,Hearing Loss,2019-07-17,PS4,met,PubMed:28733840,Identified an Austrian family with AD segregating progressive late onset hearing loss who had WES identifiy the c.151C>T missense (p.Pro51Ser) variant. The family consists of 4 generations.,"Decided to use PS4 because there were  at least 12 probands with the variant and only one individual in gnomAd therefore we can use PS4

However, this is an instance where the hearing loss is progressive and late onset and therefore it is highly probable that that individual just has a mild case of HL or will develop it later on.","Decided to use PS4 because there were  at least 12 probands with the variant and only one individual in gnomAd therefore we can use PS4

However, this is an instance where the hearing loss is progressive and late onset and therefore it is highly probable that that individual just has a mild case of HL or will develop it later on. Identified an Austrian family with AD segregating progressive late onset hearing loss who had WES identifiy the c.151C>T missense (p.Pro51Ser) variant. The family consists of 4 generations.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
642,NM_000441.1(SLC26A4):c.349C>T,SLC26A4,Pendred syndrome,MONDO:0010134,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2023-01-25,PS4,not_met,PubMed:26969326,"1119 patients with hearing loss tested. Found one compound heterozygote with this variant in trans with a splicing c.-4+1G>C variant with severe to profound hearing loss, but not noted if they tested temporal bone imaging. Shouldn't be used for PM3, as the splice variant is VUS.","This variant was found in 3 patients in the published literature. It has also been reported in ClinVar in another case from Prof. Karen Avraham @ Tel Aviv Univ.'s lab with congenital profound HL.


There are 9 cases in the LMM database with HL/HL + EVA and this variant, however one of them also has a pathogenic AD KCNQ4 variant so this proband was not counted.


Reardon 1/114 alleles in HL+ EVA cohort
Albert 1/218 alleles in HL + EVA cohort
Sloan Heggen: 1/2238 in HL cohort
LMM internal 5/3884 SLC26A4 tested alleles as of last NVA 

8/6454 Alleles Tested in HL/HL+EVA cohorts

vs.

gnomAD: 22/126640 European alleles in gnomAD. AND 52/10150 Ashkenazi alleles in gnomAD = 74/136790  ~ 67/123456

In contingency table: 8 to 6446 vs 67 to 123389 p = 0.0448. Applied Moderate evidence.

Note: if you add in the internal proband with the KCNQ4 variant the significance is higher but it doesn't seem logical to use a proband with alternate cause in this exercise. Also, Karen Avraham's proband was not counted here because the denominator is unknown.

I removed this criteria (was previously scored as PS4_Moderate), but we did not use it in our final classification listed in the Human Mutation manuscript.  - Andrea 7.31.18","This variant was found in 3 patients in the published literature. It has also been reported in ClinVar in another case from Prof. Karen Avraham @ Tel Aviv Univ.'s lab with congenital profound HL.


There are 9 cases in the LMM database with HL/HL + EVA and this variant, however one of them also has a pathogenic AD KCNQ4 variant so this proband was not counted.


Reardon 1/114 alleles in HL+ EVA cohort
Albert 1/218 alleles in HL + EVA cohort
Sloan Heggen: 1/2238 in HL cohort
LMM internal 5/3884 SLC26A4 tested alleles as of last NVA 

8/6454 Alleles Tested in HL/HL+EVA cohorts

vs.

gnomAD: 22/126640 European alleles in gnomAD. AND 52/10150 Ashkenazi alleles in gnomAD = 74/136790  ~ 67/123456

In contingency table: 8 to 6446 vs 67 to 123389 p = 0.0448. Applied Moderate evidence.

Note: if you add in the internal proband with the KCNQ4 variant the significance is higher but it doesn't seem logical to use a proband with alternate cause in this exercise. Also, Karen Avraham's proband was not counted here because the denominator is unknown.

I removed this criteria (was previously scored as PS4_Moderate), but we did not use it in our final classification listed in the Human Mutation manuscript.  - Andrea 7.31.18 1119 patients with hearing loss tested. Found one compound heterozygote with this variant in trans with a splicing c.-4+1G>C variant with severe to profound hearing loss, but not noted if they tested temporal bone imaging. Shouldn't be used for PM3, as the splice variant is VUS.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
645,NM_000441.1(SLC26A4):c.1229C>T (p.Thr410Met),SLC26A4,Pendred syndrome,MONDO:0010134,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PS4,not_met,PubMed:26763877,This publication identiifed the variant in a patient from a hearing loss cohort and said they found it affecting the individual in an AD manner.,"Though there were proband counts indicating that this variant may affect the protein in an AD manner, this is not the established mechanism for Pendred syndrome and SLC26A4.","Though there were proband counts indicating that this variant may affect the protein in an AD manner, this is not the established mechanism for Pendred syndrome and SLC26A4. This publication identiifed the variant in a patient from a hearing loss cohort and said they found it affecting the individual in an AD manner.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
646,NM_000441.1(SLC26A4):c.412G>T (p.Val138Phe),SLC26A4,Pendred syndrome,MONDO:0010134,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PS4,met,PubMed:26683941,"Meta analysis of frequencies of SLLC26A4 variants among cases and controlsThis study found 185 indiviudals with the variant and found that the frequency in hearing loss was significantly higher (p<0.001) Used data from 24 articles from Asia, Europe and North America including 2294 cases and 3193 controls in multiethnic cohorts. Furthermore, there was a statistically signficant increase in frequency of the variant within just European cases-European controls. The difference in frequencies for EVA vs non-EVA populations was insignificant for this variant.",This meta analysis of SLC26A4 variants showed that p.V138F had a significantly higher frequency in hearing loss populations than in controls. They used a cohort of 2294 HL cases and 3193 multiethnic controls. They also found that this difference was sig among just European affected vs controls.,"This meta analysis of SLC26A4 variants showed that p.V138F had a significantly higher frequency in hearing loss populations than in controls. They used a cohort of 2294 HL cases and 3193 multiethnic controls. They also found that this difference was sig among just European affected vs controls. Meta analysis of frequencies of SLLC26A4 variants among cases and controlsThis study found 185 indiviudals with the variant and found that the frequency in hearing loss was significantly higher (p<0.001) Used data from 24 articles from Asia, Europe and North America including 2294 cases and 3193 controls in multiethnic cohorts. Furthermore, there was a statistically signficant increase in frequency of the variant within just European cases-European controls. The difference in frequencies for EVA vs non-EVA populations was insignificant for this variant.","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"
735,NM_022124.5(CDH23):c.3625A>G (p.Thr1209Ala),CDH23,Usher syndrome,MONDO:0019501,Benign,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PS4,not_met,PubMed:21569298,This paper sequenced all the coding exons of the 9 USH genes in 54 patients and found the variant in the cohort. The zygosity of the variant is unclear but they state that it is a presumably neutral missense variant due to its presence in 5/486 contorl alleles from French and Maghreban populations. They do cite two other papers that have identified this variant as pathogenic.,There are 4 heterozygotes and 4 homozygotes reported in literature. The highest subpopulation in gnomAD was 14% in African alleles. The highest frequency of this variant in any affected cohort was the 2 heterozygotes in 75 Italian patients which is only 2.6%.,There are 4 heterozygotes and 4 homozygotes reported in literature. The highest subpopulation in gnomAD was 14% in African alleles. The highest frequency of this variant in any affected cohort was the 2 heterozygotes in 75 Italian patients which is only 2.6%. This paper sequenced all the coding exons of the 9 USH genes in 54 patients and found the variant in the cohort. The zygosity of the variant is unclear but they state that it is a presumably neutral missense variant due to its presence in 5/486 contorl alleles from French and Maghreban populations. They do cite two other papers that have identified this variant as pathogenic.,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
743,NM_004004.5(GJB2):c.571T>C (p.Phe191Leu),GJB2,nonsyndromic genetic deafness,MONDO:0019497,Uncertain Significance,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PS4,not_met,PubMed:26178431,"An unselected cohort of 509 healthy Japanese individuals were sequenced for GJB2 to determine carrier frequencies. 56/509 subjects had subjectively experienced hearing difficulties
Phe191leu was found in 1 heterozygote. 0.1% (1/1018) Japanese alleles.","There was no statistical significance between the number of cases versus controls by a Chi squared analysis with Yates correction.  This comparison was done by comparing the cases and controls from the below publications and comparing cases from the same publications and the East Asian alleles in gnomAD (36/18870)

Dai_2009_19366456
Ming-Kun_2007_NO PMID
Oguchi_2005_15700112
Wei_2013_23826813
Zheng_2016_27247933
Gao_2016_27792752
Hwa_2003_12792423
Ohtsuka_2003_12560944
hHan_2008_19043807
Mori_2016_27627659
Tsukada_2010_20497192","There was no statistical significance between the number of cases versus controls by a Chi squared analysis with Yates correction.  This comparison was done by comparing the cases and controls from the below publications and comparing cases from the same publications and the East Asian alleles in gnomAD (36/18870)

Dai_2009_19366456
Ming-Kun_2007_NO PMID
Oguchi_2005_15700112
Wei_2013_23826813
Zheng_2016_27247933
Gao_2016_27792752
Hwa_2003_12792423
Ohtsuka_2003_12560944
hHan_2008_19043807
Mori_2016_27627659
Tsukada_2010_20497192 An unselected cohort of 509 healthy Japanese individuals were sequenced for GJB2 to determine carrier frequencies. 56/509 subjects had subjectively experienced hearing difficulties
Phe191leu was found in 1 heterozygote. 0.1% (1/1018) Japanese alleles.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
743,NM_004004.5(GJB2):c.571T>C (p.Phe191Leu),GJB2,nonsyndromic genetic deafness,MONDO:0019497,Uncertain Significance,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PS4,not_met,PubMed:23826813,"658 unrelated patients with SNHL from China (Han) were sequenced for GJB2. 
462 normal hearing controls were also included. 
F191L identified in 4/658 patients with HL, all 4 were hets only (allele freq 0.3%, 4/1316). 
Was not identified in controls.","There was no statistical significance between the number of cases versus controls by a Chi squared analysis with Yates correction.  This comparison was done by comparing the cases and controls from the below publications and comparing cases from the same publications and the East Asian alleles in gnomAD (36/18870)

Dai_2009_19366456
Ming-Kun_2007_NO PMID
Oguchi_2005_15700112
Wei_2013_23826813
Zheng_2016_27247933
Gao_2016_27792752
Hwa_2003_12792423
Ohtsuka_2003_12560944
hHan_2008_19043807
Mori_2016_27627659
Tsukada_2010_20497192","There was no statistical significance between the number of cases versus controls by a Chi squared analysis with Yates correction.  This comparison was done by comparing the cases and controls from the below publications and comparing cases from the same publications and the East Asian alleles in gnomAD (36/18870)

Dai_2009_19366456
Ming-Kun_2007_NO PMID
Oguchi_2005_15700112
Wei_2013_23826813
Zheng_2016_27247933
Gao_2016_27792752
Hwa_2003_12792423
Ohtsuka_2003_12560944
hHan_2008_19043807
Mori_2016_27627659
Tsukada_2010_20497192 658 unrelated patients with SNHL from China (Han) were sequenced for GJB2. 
462 normal hearing controls were also included. 
F191L identified in 4/658 patients with HL, all 4 were hets only (allele freq 0.3%, 4/1316). 
Was not identified in controls.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
743,NM_004004.5(GJB2):c.571T>C (p.Phe191Leu),GJB2,nonsyndromic genetic deafness,MONDO:0019497,Uncertain Significance,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PS4,not_met,PubMed:27247933,"339 patients with HL from Linyi (city in Shandong province, China) underwent SNP arrays designed to capture 115 mutations in GJB2, SLC26A4, and MTRNR1. 
Phe191Leu identified in 3 patients, 2nd mutation was not identified in any (3/678, 0.44%).","There was no statistical significance between the number of cases versus controls by a Chi squared analysis with Yates correction.  This comparison was done by comparing the cases and controls from the below publications and comparing cases from the same publications and the East Asian alleles in gnomAD (36/18870)

Dai_2009_19366456
Ming-Kun_2007_NO PMID
Oguchi_2005_15700112
Wei_2013_23826813
Zheng_2016_27247933
Gao_2016_27792752
Hwa_2003_12792423
Ohtsuka_2003_12560944
hHan_2008_19043807
Mori_2016_27627659
Tsukada_2010_20497192","There was no statistical significance between the number of cases versus controls by a Chi squared analysis with Yates correction.  This comparison was done by comparing the cases and controls from the below publications and comparing cases from the same publications and the East Asian alleles in gnomAD (36/18870)

Dai_2009_19366456
Ming-Kun_2007_NO PMID
Oguchi_2005_15700112
Wei_2013_23826813
Zheng_2016_27247933
Gao_2016_27792752
Hwa_2003_12792423
Ohtsuka_2003_12560944
hHan_2008_19043807
Mori_2016_27627659
Tsukada_2010_20497192 339 patients with HL from Linyi (city in Shandong province, China) underwent SNP arrays designed to capture 115 mutations in GJB2, SLC26A4, and MTRNR1. 
Phe191Leu identified in 3 patients, 2nd mutation was not identified in any (3/678, 0.44%).","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
743,NM_004004.5(GJB2):c.571T>C (p.Phe191Leu),GJB2,nonsyndromic genetic deafness,MONDO:0019497,Uncertain Significance,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PS4,not_met,PubMed:27627659,"717  unrelated Japanese patients with hearing loss were screened for a list of 154 mutations using genotyping and NGS sequencing.  No patients were found to harbor mutation, but it was identified in 0.19% (1/538) control chromosomes","There was no statistical significance between the number of cases versus controls by a Chi squared analysis with Yates correction.  This comparison was done by comparing the cases and controls from the below publications and comparing cases from the same publications and the East Asian alleles in gnomAD (36/18870)

Dai_2009_19366456
Ming-Kun_2007_NO PMID
Oguchi_2005_15700112
Wei_2013_23826813
Zheng_2016_27247933
Gao_2016_27792752
Hwa_2003_12792423
Ohtsuka_2003_12560944
hHan_2008_19043807
Mori_2016_27627659
Tsukada_2010_20497192","There was no statistical significance between the number of cases versus controls by a Chi squared analysis with Yates correction.  This comparison was done by comparing the cases and controls from the below publications and comparing cases from the same publications and the East Asian alleles in gnomAD (36/18870)

Dai_2009_19366456
Ming-Kun_2007_NO PMID
Oguchi_2005_15700112
Wei_2013_23826813
Zheng_2016_27247933
Gao_2016_27792752
Hwa_2003_12792423
Ohtsuka_2003_12560944
hHan_2008_19043807
Mori_2016_27627659
Tsukada_2010_20497192 717  unrelated Japanese patients with hearing loss were screened for a list of 154 mutations using genotyping and NGS sequencing.  No patients were found to harbor mutation, but it was identified in 0.19% (1/538) control chromosomes","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
743,NM_004004.5(GJB2):c.571T>C (p.Phe191Leu),GJB2,nonsyndromic genetic deafness,MONDO:0019497,Uncertain Significance,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PS4,not_met,PubMed:27792752,"695 Chinese patients recruited and underwent screening using a SNP chip to identify a set list of variants in GJB2, SLC, MTRNR1.
2 patients were heterozygous for the Phe191Leu variant (Allele frequency in cases 0.14% (2/1390).
Authors show that the allele frequency in their patient cohort is not higher than in East Asian in exac (0.2%), or in  1000 Genomes (0.49% Han Chinese).","There was no statistical significance between the number of cases versus controls by a Chi squared analysis with Yates correction.  This comparison was done by comparing the cases and controls from the below publications and comparing cases from the same publications and the East Asian alleles in gnomAD (36/18870)

Dai_2009_19366456
Ming-Kun_2007_NO PMID
Oguchi_2005_15700112
Wei_2013_23826813
Zheng_2016_27247933
Gao_2016_27792752
Hwa_2003_12792423
Ohtsuka_2003_12560944
hHan_2008_19043807
Mori_2016_27627659
Tsukada_2010_20497192","There was no statistical significance between the number of cases versus controls by a Chi squared analysis with Yates correction.  This comparison was done by comparing the cases and controls from the below publications and comparing cases from the same publications and the East Asian alleles in gnomAD (36/18870)

Dai_2009_19366456
Ming-Kun_2007_NO PMID
Oguchi_2005_15700112
Wei_2013_23826813
Zheng_2016_27247933
Gao_2016_27792752
Hwa_2003_12792423
Ohtsuka_2003_12560944
hHan_2008_19043807
Mori_2016_27627659
Tsukada_2010_20497192 695 Chinese patients recruited and underwent screening using a SNP chip to identify a set list of variants in GJB2, SLC, MTRNR1.
2 patients were heterozygous for the Phe191Leu variant (Allele frequency in cases 0.14% (2/1390).
Authors show that the allele frequency in their patient cohort is not higher than in East Asian in exac (0.2%), or in  1000 Genomes (0.49% Han Chinese).","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
743,NM_004004.5(GJB2):c.571T>C (p.Phe191Leu),GJB2,nonsyndromic genetic deafness,MONDO:0019497,Uncertain Significance,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PS4,not_met,PubMed:19366456,"2063 unrelated Chinese patients with hearing loss were sequenced for GJB2.
301 Han control individuals also included.
1 patient with F191L, V198Met (not categorized in ClinVar, 3 papers in HGMD entry, absent from gnomAD) and V27I (benign) was identified in the study. (no points for PM3, phase WAS NOT determined).","There was no statistical significance between the number of cases versus controls by a Chi squared analysis with Yates correction.  This comparison was done by comparing the cases and controls from the below publications and comparing cases from the same publications and the East Asian alleles in gnomAD (36/18870)

Dai_2009_19366456
Ming-Kun_2007_NO PMID
Oguchi_2005_15700112
Wei_2013_23826813
Zheng_2016_27247933
Gao_2016_27792752
Hwa_2003_12792423
Ohtsuka_2003_12560944
hHan_2008_19043807
Mori_2016_27627659
Tsukada_2010_20497192","There was no statistical significance between the number of cases versus controls by a Chi squared analysis with Yates correction.  This comparison was done by comparing the cases and controls from the below publications and comparing cases from the same publications and the East Asian alleles in gnomAD (36/18870)

Dai_2009_19366456
Ming-Kun_2007_NO PMID
Oguchi_2005_15700112
Wei_2013_23826813
Zheng_2016_27247933
Gao_2016_27792752
Hwa_2003_12792423
Ohtsuka_2003_12560944
hHan_2008_19043807
Mori_2016_27627659
Tsukada_2010_20497192 2063 unrelated Chinese patients with hearing loss were sequenced for GJB2.
301 Han control individuals also included.
1 patient with F191L, V198Met (not categorized in ClinVar, 3 papers in HGMD entry, absent from gnomAD) and V27I (benign) was identified in the study. (no points for PM3, phase WAS NOT determined).","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"
974,NM_206933.2(USH2A):c.15433G>A (p.Val5145Ile),USH2A,Usher syndrome,MONDO:0019501,Benign,Autosomal recessive inheritance,Hearing Loss,2019-10-18,PS4,not_met,PubMed:25999674,"In a group of 250 patients with RP, the p.Val5145Ile variant was found in one individual.",2x2 Contingency table done  with Yates' correlation: 201/25124 versus 6/1085. Not statistically significant.,"2x2 Contingency table done  with Yates' correlation: 201/25124 versus 6/1085. Not statistically significant. In a group of 250 patients with RP, the p.Val5145Ile variant was found in one individual.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
974,NM_206933.2(USH2A):c.15433G>A (p.Val5145Ile),USH2A,Usher syndrome,MONDO:0019501,Benign,Autosomal recessive inheritance,Hearing Loss,2019-10-18,PS4,not_met,PubMed:27353947,"Variant found in heterozygosity in an individual with Leber congenital amaurosis, but deemed benign along with a het. variant in the following genes: VPS13B, RPGRIP1, BBS10 and MKS1.",2x2 Contingency table done  with Yates' correlation: 201/25124 versus 6/1085. Not statistically significant.,"2x2 Contingency table done  with Yates' correlation: 201/25124 versus 6/1085. Not statistically significant. Variant found in heterozygosity in an individual with Leber congenital amaurosis, but deemed benign along with a het. variant in the following genes: VPS13B, RPGRIP1, BBS10 and MKS1.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
642,NM_000441.1(SLC26A4):c.349C>T,SLC26A4,Pendred syndrome,MONDO:0010134,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2023-01-25,PM3-Very Strong,not_met,PubMed:26969326,"1119 patients with hearing loss tested. Found one compound heterozygote with this variant in trans with a splicing c.-4+1G>C variant with severe to profound hearing loss, but not noted if they tested temporal bone imaging. Shouldn't be used for PM3, as the splice variant is VUS.","This variant has been detected in 8 individuals with hearing loss. For 5 of those individuals, they were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and all of those were confirmed in trans by (c.1246A>C (p.Thr416Pro), c.1708G>A (p.Val570Ile), c.1522A>G (p.Thr508Ala), c.578C>T (p.Thr193Ile), 5.75 PM3 points, SCV000060146.7, SCV000282017.1). (PM3_VeryStrong).","This variant has been detected in 8 individuals with hearing loss. For 5 of those individuals, they were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and all of those were confirmed in trans by (c.1246A>C (p.Thr416Pro), c.1708G>A (p.Val570Ile), c.1522A>G (p.Thr508Ala), c.578C>T (p.Thr193Ile), 5.75 PM3 points, SCV000060146.7, SCV000282017.1). (PM3_VeryStrong). 1119 patients with hearing loss tested. Found one compound heterozygote with this variant in trans with a splicing c.-4+1G>C variant with severe to profound hearing loss, but not noted if they tested temporal bone imaging. Shouldn't be used for PM3, as the splice variant is VUS.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
645,NM_000441.1(SLC26A4):c.1229C>T (p.Thr410Met),SLC26A4,Pendred syndrome,MONDO:0010134,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PM3-Very Strong,not_met,PubMed:25372295,"Seqeunced 1057 Chinese HL patients. Identified 27 patients with the c.919-2A>G variant in trans with the p.T410M. 8 patients with the genotype: c.2168A.G(p.H723R) c.1229C.T(pT410M). 4 homozygotes. 3 patients with the genotype p.V659L/p.T410M. Identified 2 cases of the varaint in trans with the p.N392Y variant. Identified 2 patients with the c.1687_1692insA variant in trans with the p.T140M variant. One case in trans with the p.T94I variant. One case in trans with the p.V650D variant. One case in trans with the c.1693insA variant. One patient with the p.S448X variant in trans. One patient with the IVS19+2T>A variant in trans. There were many more variants in trans and 4 cases with wt in trans, but since the PM3 points are maxed, they will not be noted here.",This variant meets the criteria for PM3_VS,"This variant meets the criteria for PM3_VS Seqeunced 1057 Chinese HL patients. Identified 27 patients with the c.919-2A>G variant in trans with the p.T410M. 8 patients with the genotype: c.2168A.G(p.H723R) c.1229C.T(pT410M). 4 homozygotes. 3 patients with the genotype p.V659L/p.T410M. Identified 2 cases of the varaint in trans with the p.N392Y variant. Identified 2 patients with the c.1687_1692insA variant in trans with the p.T140M variant. One case in trans with the p.T94I variant. One case in trans with the p.V650D variant. One case in trans with the c.1693insA variant. One patient with the p.S448X variant in trans. One patient with the IVS19+2T>A variant in trans. There were many more variants in trans and 4 cases with wt in trans, but since the PM3 points are maxed, they will not be noted here.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
645,NM_000441.1(SLC26A4):c.1229C>T (p.Thr410Met),SLC26A4,Pendred syndrome,MONDO:0010134,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PM3-Very Strong,not_met,PubMed:21961810,"This study investigated 144 patients with SNHL adn temporal bone malformations and found that 6 patients had the p.T410M variant. There was one comp. het. indiviudal with a p.A360V variant in trans, 4 compound het individuals with the c.919-2 A>G splice variant, 1 individual with the p.SF532, 545* variant, and one indivudal with the c.1343C>A p.S448X variant.",This variant meets the criteria for PM3_VS,"This variant meets the criteria for PM3_VS This study investigated 144 patients with SNHL adn temporal bone malformations and found that 6 patients had the p.T410M variant. There was one comp. het. indiviudal with a p.A360V variant in trans, 4 compound het individuals with the c.919-2 A>G splice variant, 1 individual with the p.SF532, 545* variant, and one indivudal with the c.1343C>A p.S448X variant.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
646,NM_000441.1(SLC26A4):c.412G>T (p.Val138Phe),SLC26A4,Pendred syndrome,MONDO:0010134,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PM3-Very Strong,not_met,PubMed:23965030,4 Patients with Pendred syndrome sequenced for SLC26A4 variants as well as FOXI1 and KCNJ10. They found 3 p.Val138Phe homozygotes and 1 compound heterozygote (p.Leu597Ser). Leu597Ser is actually classified as a Benign/LB variant in ClinVar by 4 labs.,PM3_VS met. There were at least 6 cases of homozygous p.V138F induced PS/EVA and there were at least 10 cases of the variant being in trans with a P/LP variant.,PM3_VS met. There were at least 6 cases of homozygous p.V138F induced PS/EVA and there were at least 10 cases of the variant being in trans with a P/LP variant. 4 Patients with Pendred syndrome sequenced for SLC26A4 variants as well as FOXI1 and KCNJ10. They found 3 p.Val138Phe homozygotes and 1 compound heterozygote (p.Leu597Ser). Leu597Ser is actually classified as a Benign/LB variant in ClinVar by 4 labs.,"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,PM3-Very 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.","This variant has been detected in >4 patients with Usher syndrome who were  compound heterozygous for the c.8559-2A>G in trans with a truncating variant  (PM3_VS; PMID: 25356976, 19737284, 26338283, 19023448).","This variant has been detected in >4 patients with Usher syndrome who were  compound heterozygous for the c.8559-2A>G in trans with a truncating variant  (PM3_VS; PMID: 25356976, 19737284, 26338283, 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"
649,NM_206933.2(USH2A):c.8559-2A>G,USH2A,Usher syndrome,MONDO:0019501,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PM3-Very Strong,not_met,PubMed:25133613,consanguineous family ARRP04: Identified in a homozygous state in one affected individual. Absent from 30 controls. Cite that this variant is a founder variant in East Asian populations.,"This variant has been detected in >4 patients with Usher syndrome who were  compound heterozygous for the c.8559-2A>G in trans with a truncating variant  (PM3_VS; PMID: 25356976, 19737284, 26338283, 19023448).","This variant has been detected in >4 patients with Usher syndrome who were  compound heterozygous for the c.8559-2A>G in trans with a truncating variant  (PM3_VS; PMID: 25356976, 19737284, 26338283, 19023448). consanguineous family ARRP04: Identified in a homozygous state in one affected individual. Absent from 30 controls. Cite that this variant is a founder variant in East Asian populations.","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,PM3-Very Strong,not_met,PubMed:26338283,This study of 67 Chinese Usher syndrome probands identified 11 probands with the variant. They declare that the variant is a founder mutation that accounts for 265 of all Western Japanese USH patients but was never observed in Europeans. The varaint was observed in 5 individuals who were compound het via missense and 6 individuals with nonsense or frameshift variants.,"This variant has been detected in >4 patients with Usher syndrome who were  compound heterozygous for the c.8559-2A>G in trans with a truncating variant  (PM3_VS; PMID: 25356976, 19737284, 26338283, 19023448).","This variant has been detected in >4 patients with Usher syndrome who were  compound heterozygous for the c.8559-2A>G in trans with a truncating variant  (PM3_VS; PMID: 25356976, 19737284, 26338283, 19023448). This study of 67 Chinese Usher syndrome probands identified 11 probands with the variant. They declare that the variant is a founder mutation that accounts for 265 of all Western Japanese USH patients but was never observed in Europeans. The varaint was observed in 5 individuals who were compound het via missense and 6 individuals with nonsense or frameshift variants.","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"
651,NM_206933.2(USH2A):c.1036A>C (p.Asn346His),USH2A,Usher syndrome,MONDO:0019501,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PM3-Very Strong,not_met,PubMed:26969326,detected in trans with c.2299del,"This could actually be upgraded to PM3_very strong. There are >4 cases of this variant being identified in trans with a known pathogenic variant. I've added more publications below.

-MD","This could actually be upgraded to PM3_very strong. There are >4 cases of this variant being identified in trans with a known pathogenic variant. I've added more publications below.

-MD detected in trans with c.2299del","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
651,NM_206933.2(USH2A):c.1036A>C (p.Asn346His),USH2A,Usher syndrome,MONDO:0019501,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PM3-Very Strong,not_met,PubMed:22135276,"detected in trans with p.Glu3305ArgfsX41, p.Trp3521Arg, and Lys419Phe","This could actually be upgraded to PM3_very strong. There are >4 cases of this variant being identified in trans with a known pathogenic variant. I've added more publications below.

-MD","This could actually be upgraded to PM3_very strong. There are >4 cases of this variant being identified in trans with a known pathogenic variant. I've added more publications below.

-MD detected in trans with p.Glu3305ArgfsX41, p.Trp3521Arg, and Lys419Phe","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
652,NM_206933.2(USH2A):c.8682-9A>G,USH2A,Usher syndrome,MONDO:0019501,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PM3-Very Strong,not_met,PubMed:28944237,"1 cpd het with Glu767SerfsX21 that is P by ClinVar (multiple submitters, no conflicts2 stars out of maximum of 4 stars). also identified 1 cpd het with Trp4175X also not classified not scored, and 1 additional het identified from same cohort (Germans)","See Neuhaus 2017 JM

ANDREA: I think that we can score the truncating variants as at least Likely pathogenic, therefore for Neuhaus and Glockle, I scored a total of 3 points for PM3.  Adding all of my points I got 4 points for PM3, which is enough to apply PM3_VeryStrong.  However, there is no option to do so in the variant curation interface.","See Neuhaus 2017 JM

ANDREA: I think that we can score the truncating variants as at least Likely pathogenic, therefore for Neuhaus and Glockle, I scored a total of 3 points for PM3.  Adding all of my points I got 4 points for PM3, which is enough to apply PM3_VeryStrong.  However, there is no option to do so in the variant curation interface. 1 cpd het with Glu767SerfsX21 that is P by ClinVar (multiple submitters, no conflicts2 stars out of maximum of 4 stars). also identified 1 cpd het with Trp4175X also not classified not scored, and 1 additional het identified from same cohort (Germans)","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"
877,NM_206933.4(USH2A):c.956G>A (p.Cys319Tyr),USH2A,Usher syndrome,MONDO:0019501,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2022-08-03,PM3-Very Strong,not_met,PubMed:26969326,1 proband het. with VUS variant c.5329C>T (p.Arg1777Trp),"This variant has been detected in 5 individuals with Usher syndrome. For 5 of those individuals, 4 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and all of those were confirmed in trans by family testing (c.3408T>A (p.Ser1136Arg), c.12067-2A>G, c.5329C>T (p.Arg1777Trp), c.15089C>A (p.S5030X)), (4 PM3 points, PMID: 26969326, 33089500, LMM internal data, EGL internal data). One individual was homozygous for the variant (0.5 PM3 points, PMID:10729113) (PM3_VeryStrong).","This variant has been detected in 5 individuals with Usher syndrome. For 5 of those individuals, 4 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and all of those were confirmed in trans by family testing (c.3408T>A (p.Ser1136Arg), c.12067-2A>G, c.5329C>T (p.Arg1777Trp), c.15089C>A (p.S5030X)), (4 PM3 points, PMID: 26969326, 33089500, LMM internal data, EGL internal data). One individual was homozygous for the variant (0.5 PM3 points, PMID:10729113) (PM3_VeryStrong). 1 proband het. with VUS variant c.5329C>T (p.Arg1777Trp)","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,PM3-Strong,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.,"I gave 1 point for the splicing variant in trans, 1 point for the nonsense variant, and 0.5 for two of the missense variants= 2.5 pts

There is also an LMM case that has the same -2 splice variant as Jiang et al, but this would still not bump up to VS.","I gave 1 point for the splicing variant in trans, 1 point for the nonsense variant, and 0.5 for two of the missense variants= 2.5 pts

There is also an LMM case that has the same -2 splice variant as Jiang et al, but this would still not bump up to VS. 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"
643,NM_206933.2(USH2A):c.5581G>A (p.Gly1861Ser),USH2A,Usher syndrome,MONDO:0019501,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PM3-Strong,not_met,PubMed:23737954,"5 unrelated Chinese families with Usher syndrome were tested using a panel of 144 known genes for deep exome resequencing. The p.Gly1861Ser variant was identified in family F2 in trans with a novel frameshift c.8602delA, but was in cis with a second missense variant p.R5143C. The cis variants were also present in an unaffected sib.","I gave 1 point for the splicing variant in trans, 1 point for the nonsense variant, and 0.5 for two of the missense variants= 2.5 pts

There is also an LMM case that has the same -2 splice variant as Jiang et al, but this would still not bump up to VS.","I gave 1 point for the splicing variant in trans, 1 point for the nonsense variant, and 0.5 for two of the missense variants= 2.5 pts

There is also an LMM case that has the same -2 splice variant as Jiang et al, but this would still not bump up to VS. 5 unrelated Chinese families with Usher syndrome were tested using a panel of 144 known genes for deep exome resequencing. The p.Gly1861Ser variant was identified in family F2 in trans with a novel frameshift c.8602delA, but was in cis with a second missense variant p.R5143C. The cis variants were also present in an unaffected sib.","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"
931,NM_000260.3(MYO7A):c.3503G>A (p.Arg1168Gln),MYO7A,Usher syndrome,MONDO:0019501,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-09-16,PM3-Strong,not_met,PubMed:28944237,Two patients with atypical usher syndrome. Patient 13: Arg1168Gln / 6025delG. Patient 14: Arg1168Gln / Leu1839Pro (vus).,"1 point from Aparisi 2014 (Gln1798X / Arg1168Gln, variants likely phased). 0.5 points from Bonnet 2016 (p.Arg1168Gln / exon 46 del (in frame), variants phased), 0.5 points from Neuhaus (Arg1168Gln / 6025delG, unclear if phased).","1 point from Aparisi 2014 (Gln1798X / Arg1168Gln, variants likely phased). 0.5 points from Bonnet 2016 (p.Arg1168Gln / exon 46 del (in frame), variants phased), 0.5 points from Neuhaus (Arg1168Gln / 6025delG, unclear if phased). Two patients with atypical usher syndrome. Patient 13: Arg1168Gln / 6025delG. Patient 14: Arg1168Gln / Leu1839Pro (vus).","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
931,NM_000260.3(MYO7A):c.3503G>A (p.Arg1168Gln),MYO7A,Usher syndrome,MONDO:0019501,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-09-16,PM3-Strong,not_met,PubMed:25404053,Arg1168Gln was identified in 2 patients with Usher syndrome. RP-807 harbored Arg1168Gln / Leu1839Pro (vus). RP-1924 harbored Gln1798X / Arg1168Gln. Both patients were reported to have segregation analysis performed in family members.,"1 point from Aparisi 2014 (Gln1798X / Arg1168Gln, variants likely phased). 0.5 points from Bonnet 2016 (p.Arg1168Gln / exon 46 del (in frame), variants phased), 0.5 points from Neuhaus (Arg1168Gln / 6025delG, unclear if phased).","1 point from Aparisi 2014 (Gln1798X / Arg1168Gln, variants likely phased). 0.5 points from Bonnet 2016 (p.Arg1168Gln / exon 46 del (in frame), variants phased), 0.5 points from Neuhaus (Arg1168Gln / 6025delG, unclear if phased). Arg1168Gln was identified in 2 patients with Usher syndrome. RP-807 harbored Arg1168Gln / Leu1839Pro (vus). RP-1924 harbored Gln1798X / Arg1168Gln. Both patients were reported to have segregation analysis performed in family members.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
931,NM_000260.3(MYO7A):c.3503G>A (p.Arg1168Gln),MYO7A,Usher syndrome,MONDO:0019501,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-09-16,PM3-Strong,not_met,PubMed:27460420,"Patient with USH type 1 compound het for MYO7A:c.3503G4A 
 (p.Arg1168Gln)+deletion of exon 46, and was
heterozygous for USH2A:c.2299delG (p.Glu767Serfs*21). According to entry in LOVD USHbases, deletion of exon 46 is c.6238-?_6354+?del (in frame exon deletion)","1 point from Aparisi 2014 (Gln1798X / Arg1168Gln, variants likely phased). 0.5 points from Bonnet 2016 (p.Arg1168Gln / exon 46 del (in frame), variants phased), 0.5 points from Neuhaus (Arg1168Gln / 6025delG, unclear if phased).","1 point from Aparisi 2014 (Gln1798X / Arg1168Gln, variants likely phased). 0.5 points from Bonnet 2016 (p.Arg1168Gln / exon 46 del (in frame), variants phased), 0.5 points from Neuhaus (Arg1168Gln / 6025delG, unclear if phased). Patient with USH type 1 compound het for MYO7A:c.3503G4A 
 (p.Arg1168Gln)+deletion of exon 46, and was
heterozygous for USH2A:c.2299delG (p.Glu767Serfs*21). According to entry in LOVD USHbases, deletion of exon 46 is c.6238-?_6354+?del (in frame exon deletion)","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
967,NM_022124.5(CDH23):c.719C>T (p.Pro240Leu),CDH23,nonsyndromic genetic deafness,MONDO:0019497,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-10-17,PM3-Strong,not_met,PubMed:25963016,"Pro240Leu Identified in 7 homozygotes and 7 cmp hets. All patients had hearing loss. Fundoscopy performed in 4 probands and was normal. Normal motor milestones. Was not sure if some of these individuals with same variants were related. Also, there is overlap with Wagatsuma 2007. Cmp hets scored conservatively at 1 point. 
p.P240L / p.R2029W (VUS, 0.017% in EA);
p.P240L / p.R2029W;
p.P240L / p.E956K;
p.P240L / p.E956K;
p.P240L / p.E956K;
p.P240L / p.E956K;
p.P240L / c.6712 + 1G > A;
p.P240L / c.6712 + 1G > A;","1 point from homozygotes
PM3_Strong (3.75 points scored)","1 point from homozygotes
PM3_Strong (3.75 points scored) Pro240Leu Identified in 7 homozygotes and 7 cmp hets. All patients had hearing loss. Fundoscopy performed in 4 probands and was normal. Normal motor milestones. Was not sure if some of these individuals with same variants were related. Also, there is overlap with Wagatsuma 2007. Cmp hets scored conservatively at 1 point. 
p.P240L / p.R2029W (VUS, 0.017% in EA);
p.P240L / p.R2029W;
p.P240L / p.E956K;
p.P240L / p.E956K;
p.P240L / p.E956K;
p.P240L / p.E956K;
p.P240L / c.6712 + 1G > A;
p.P240L / c.6712 + 1G > A;","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
967,NM_022124.5(CDH23):c.719C>T (p.Pro240Leu),CDH23,nonsyndromic genetic deafness,MONDO:0019497,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-10-17,PM3-Strong,not_met,PubMed:26264712,"4 Korean children with profound hearing loss. 2 homozygotes, 2 compound hets. 
Compound hets: 
- Patient SH59-133  : p.P240L / p.T1618K (VUS) (linkage performed, but phase does not appear to be confirmed for variants)
- Patient SB56-103:  c.C719T; c.8574delC p.P240L;p.Asp2858GlufsX8 phase not confirmed

1.75 points (1 from homozygotes, 0.75 from cmp hets)","1 point from homozygotes
PM3_Strong (3.75 points scored)","1 point from homozygotes
PM3_Strong (3.75 points scored) 4 Korean children with profound hearing loss. 2 homozygotes, 2 compound hets. 
Compound hets: 
- Patient SH59-133  : p.P240L / p.T1618K (VUS) (linkage performed, but phase does not appear to be confirmed for variants)
- Patient SB56-103:  c.C719T; c.8574delC p.P240L;p.Asp2858GlufsX8 phase not confirmed

1.75 points (1 from homozygotes, 0.75 from cmp hets)","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
967,NM_022124.5(CDH23):c.719C>T (p.Pro240Leu),CDH23,nonsyndromic genetic deafness,MONDO:0019497,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-10-17,PM3-Strong,not_met,PubMed:24618850,Patient with Usher syndrome who had a homozygous missense variant in MYO7A and was also heterozygous for Pro240Leu in CDH23,"1 point from homozygotes
PM3_Strong (3.75 points scored)","1 point from homozygotes
PM3_Strong (3.75 points scored) Patient with Usher syndrome who had a homozygous missense variant in MYO7A and was also heterozygous for Pro240Leu in CDH23","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,PM3-Strong,not_met,PubMed:25649381,"European male (35 yo) with nyctalopia, RP, and Group 3 audiology but no subjective hearing loss --> 0 points (phase unknown) - other variant is c.2299delG (p.Glu767Serfs*21) 

European male (50 yo) with nyctalopia, RP, and Group 2 audiology but no subjective hearing loss --> 0.5 points (phase unknown) - other variant is c.2299delG (p.Glu767Serfs*21) 

European male (54 yo) with nyctalopia and Group 1B audiology but no subjective hearing loss --> 0 points - other variant is c.12093C>A (p.Tyr4031*)","10/2022 NOTES: We re-reviewed the literature and counted all three individuals from PMID: 25649381 (2x0.5pt for phase unknown, 1pt for phase determined vie RT PCR sequencing. The fourth individual from PMID: 22135276, phase unknown. Total of 2.5 points

10/2019 NOTES: Total of 6 cases (from publications and 1 from LMM internal data). LMM internal case did not have another variant but had profound sensorineural hearing loss with delayed walking so was not scored. Total of 1 point leads to a PM3 classification.","10/2022 NOTES: We re-reviewed the literature and counted all three individuals from PMID: 25649381 (2x0.5pt for phase unknown, 1pt for phase determined vie RT PCR sequencing. The fourth individual from PMID: 22135276, phase unknown. Total of 2.5 points

10/2019 NOTES: Total of 6 cases (from publications and 1 from LMM internal data). LMM internal case did not have another variant but had profound sensorineural hearing loss with delayed walking so was not scored. Total of 1 point leads to a PM3 classification. European male (35 yo) with nyctalopia, RP, and Group 3 audiology but no subjective hearing loss --> 0 points (phase unknown) - other variant is c.2299delG (p.Glu767Serfs*21) 

European male (50 yo) with nyctalopia, RP, and Group 2 audiology but no subjective hearing loss --> 0.5 points (phase unknown) - other variant is c.2299delG (p.Glu767Serfs*21) 

European male (54 yo) with nyctalopia and Group 1B audiology but no subjective hearing loss --> 0 points - other variant is c.12093C>A (p.Tyr4031*)","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
1024,NM_000260.4(MYO7A):c.5618G>A (p.Arg1873Gln),MYO7A,Usher syndrome,MONDO:0019501,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-11-26,PM3-Strong,not_met,PubMed:29196752,,"There are 4 compound het observations: 2 with a known path/lp variant in trans (Schrauwen 2013 and Zazo Seco 2017, 2 pts), one with a VUS in trans (Baux 2017, 0.25 pts), and one with a LP/P variant phase unknown (LMM internal data SCV000059849.6, 0.5pts) 2.75pts total, Strong.","There are 4 compound het observations: 2 with a known path/lp variant in trans (Schrauwen 2013 and Zazo Seco 2017, 2 pts), one with a VUS in trans (Baux 2017, 0.25 pts), and one with a LP/P variant phase unknown (LMM internal data SCV000059849.6, 0.5pts) 2.75pts total, Strong. ","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,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"
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"
742,NM_000260.4(MYO7A):c.2476G>A (p.Ala826Thr),MYO7A,Usher syndrome,MONDO:0019501,Uncertain Significance,Autosomal recessive inheritance,Hearing Loss,2023-02-06,PM3,met,PubMed:27460420,427 individuals with Usher syndrome from various European medical centers were exome sequenced. The p.Ala826Thr was identified in the homozygous state in one individual. This individual was also heterozygous for p.Ser3590Cys in ADGRV1.,"The p.Ala826Thr variant has been identified in 9 homozygous individuals and 2 compound heterozygous individuals (with two pathogenic variants). 3 points for PM3, meeting strong criteria, but was downgraded to moderate based on high FAF. ","The p.Ala826Thr variant has been identified in 9 homozygous individuals and 2 compound heterozygous individuals (with two pathogenic variants). 3 points for PM3, meeting strong criteria, but was downgraded to moderate based on high FAF.  427 individuals with Usher syndrome from various European medical centers were exome sequenced. The p.Ala826Thr was identified in the homozygous state in one individual. This individual was also heterozygous for p.Ser3590Cys in ADGRV1.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
742,NM_000260.4(MYO7A):c.2476G>A (p.Ala826Thr),MYO7A,Usher syndrome,MONDO:0019501,Uncertain Significance,Autosomal recessive inheritance,Hearing Loss,2023-02-06,PM3,met,PubMed:22135276,"188 individuals with Usher were tested for variants in MYO7A, CDH23, PCDH15,
USH1C, USH1G, USH2A, GPR98, WHRN, CLRN1, and SLC4A7. The p.Ala826Thr variant was identified in 1 Caucasian compound heterozygous individual who also harbored the p.Trp1431X variant.","The p.Ala826Thr variant has been identified in 9 homozygous individuals and 2 compound heterozygous individuals (with two pathogenic variants). 3 points for PM3, meeting strong criteria, but was downgraded to moderate based on high FAF. ","The p.Ala826Thr variant has been identified in 9 homozygous individuals and 2 compound heterozygous individuals (with two pathogenic variants). 3 points for PM3, meeting strong criteria, but was downgraded to moderate based on high FAF.  188 individuals with Usher were tested for variants in MYO7A, CDH23, PCDH15,
USH1C, USH1G, USH2A, GPR98, WHRN, CLRN1, and SLC4A7. The p.Ala826Thr variant was identified in 1 Caucasian compound heterozygous individual who also harbored the p.Trp1431X variant.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
855,NM_206933.2(USH2A):c.4714C>T (p.Leu1572Phe),USH2A,Usher syndrome,MONDO:0019501,Likely Benign,Autosomal recessive inheritance,Hearing Loss,2019-08-16,PM3,not_met,PubMed:26969326,"In 5 patients: in cis with c.2299delG + another het variant.
In one patient: in cis with homozygous c.2299delG",observed in trans with c.2299delG in 2 reports,"observed in trans with c.2299delG in 2 reports In 5 patients: in cis with c.2299delG + another het variant.
In one patient: in cis with homozygous c.2299delG","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
855,NM_206933.2(USH2A):c.4714C>T (p.Leu1572Phe),USH2A,Usher syndrome,MONDO:0019501,Likely Benign,Autosomal recessive inheritance,Hearing Loss,2019-08-16,PM3,not_met,PubMed:28944237,"observed in trans with one patient with Usher syndrome. No segregation was done but in direct communication with author he mentioned: If phasing by segregation analyses was not possible, compound-heterozygosity could only be assumed based on mutation types, previous descriptions",observed in trans with c.2299delG in 2 reports,"observed in trans with c.2299delG in 2 reports observed in trans with one patient with Usher syndrome. No segregation was done but in direct communication with author he mentioned: If phasing by segregation analyses was not possible, compound-heterozygosity could only be assumed based on mutation types, previous descriptions","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
1698,NM_022124.6(CDH23):c.902G>A (p.Arg301Gln),CDH23,nonsyndromic genetic deafness,MONDO:0019497,Uncertain Significance,Autosomal recessive inheritance,Hearing Loss,2020-11-02,PM3,met,PubMed:22899989,,This variant was present in 5 different individuals from 4 families all with the P240L variant in CDH23 present in trans. All individuals had sensorineural hearing loss. Because this variant was always found with the P240L variant the HL-EP decided to keep the code at the moderate level.,This variant was present in 5 different individuals from 4 families all with the P240L variant in CDH23 present in trans. All individuals had sensorineural hearing loss. Because this variant was always found with the P240L variant the HL-EP decided to keep the code at the moderate level. ,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
1748,NM_206933.2(USH2A):c.2522C>A (p.Ser841Tyr),USH2A,Usher syndrome,MONDO:0019501,Benign,Autosomal recessive inheritance,Hearing Loss,2020-12-24,PM3,not_met,PubMed:28944237,"German proband, 59 y/o, carrying the p.Ser841Tyr variant on one allele and no variant identified on the second allele.",," German proband, 59 y/o, carrying the p.Ser841Tyr variant on one allele and no variant identified on the second allele.","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"
651,NM_206933.2(USH2A):c.1036A>C (p.Asn346His),USH2A,Usher syndrome,MONDO:0019501,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,BS4,not_met,PubMed:22135276,"Four compound hets reported; variants on remaining allele were Thr4439Ile, Glu3305fs, Trp3521Arg, Cys419Phe.  One individual was het only.",," Four compound hets reported; variants on remaining allele were Thr4439Ile, Glu3305fs, Trp3521Arg, Cys419Phe.  One individual was het only.","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,BS4,not_met,PubMed:31160754,This paper described 16 segregations of the p.Met34Thr variant in homozygous/compound het occurrences in Supplementary table S2,Decreased penetrance is expected of this variant so BS4 wouldn't apply,Decreased penetrance is expected of this variant so BS4 wouldn't apply This paper described 16 segregations of the p.Met34Thr variant in homozygous/compound het occurrences in Supplementary table S2,"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"
644,NM_004700.3(KCNQ4):c.853G>A (p.Gly285Ser),KCNQ4,nonsyndromic genetic deafness,MONDO:0019497,Pathogenic,Autosomal dominant inheritance,Hearing Loss,2019-07-17,PP1-Strong,not_met,PubMed:25116015,"The variant was identified in a large Chinese family with postlingual, progressive hearing loss. 15 affected family members had the variant. Targeted next-gen sequencing panel of 30 ADHL-associated genes were tested.","Segregated with hearing loss in autosomal dominant manner in 2 and 14 affected family members in families from Kubisch 1999 and Wang 2014, respectively","Segregated with hearing loss in autosomal dominant manner in 2 and 14 affected family members in families from Kubisch 1999 and Wang 2014, respectively The variant was identified in a large Chinese family with postlingual, progressive hearing loss. 15 affected family members had the variant. Targeted next-gen sequencing panel of 30 ADHL-associated genes were tested.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
651,NM_206933.2(USH2A):c.1036A>C (p.Asn346His),USH2A,Usher syndrome,MONDO:0019501,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PP1-Strong,not_met,PubMed:22135276,"Four compound hets reported; variants on remaining allele were Thr4439Ile, Glu3305fs, Trp3521Arg, Cys419Phe.  One individual was het only.","Cosegretation with the phenotype were observed in at least 7 families including 13 affected members.

Agree with this code usage. MD","Cosegretation with the phenotype were observed in at least 7 families including 13 affected members.

Agree with this code usage. MD Four compound hets reported; variants on remaining allele were Thr4439Ile, Glu3305fs, Trp3521Arg, Cys419Phe.  One individual was het only.","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"
967,NM_022124.5(CDH23):c.719C>T (p.Pro240Leu),CDH23,nonsyndromic genetic deafness,MONDO:0019497,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-10-17,PP1-Strong,not_met,PubMed:22899989,"2 SEGREGATIONS FROM 2308/2309, 2337/2338. Did not score 2885/2886 from Miyagawa because it is the same family as #3 from Wagasuma.","This variant has also segregated in 3 siblings with hearing loss (PP1_Strong, PMID: 17850630, 22899989).","This variant has also segregated in 3 siblings with hearing loss (PP1_Strong, PMID: 17850630, 22899989). 2 SEGREGATIONS FROM 2308/2309, 2337/2338. Did not score 2885/2886 from Miyagawa because it is the same family as #3 from Wagasuma.","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,PS3,not_met,PubMed:27884957,"However, c.101T>C transfected HeLa cells were able to load the dye in response to nonphysiological zero extracellular Ca2+ stimulus, suggesting that p.Met34Thr variant connexin hemichannels may retain some residual function under unusual circumstances.","Several studies have shown that the p.M34T variant has an impact on the formation and function of the Cx26 channel via dye transfer assays and electrical coupling assays. There were no mouse/ animal models found via lit search. It has also been suggested that this variant may have a dominant negative impact functionally as well though this hasn't really been supported in human cases. PMIDs: 16849369, 12189493, 10556284, 16300957, 15033936, 12189493. This criteria was not counted however because in de Wolf et al. 2016 there was residual function of the p.M34T Cx26 protein, therefore we decided to be conservative and not score this criterion.","Several studies have shown that the p.M34T variant has an impact on the formation and function of the Cx26 channel via dye transfer assays and electrical coupling assays. There were no mouse/ animal models found via lit search. It has also been suggested that this variant may have a dominant negative impact functionally as well though this hasn't really been supported in human cases. PMIDs: 16849369, 12189493, 10556284, 16300957, 15033936, 12189493. This criteria was not counted however because in de Wolf et al. 2016 there was residual function of the p.M34T Cx26 protein, therefore we decided to be conservative and not score this criterion. However, c.101T>C transfected HeLa cells were able to load the dye in response to nonphysiological zero extracellular Ca2+ stimulus, suggesting that p.Met34Thr variant connexin hemichannels may retain some residual function under unusual circumstances.","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,PS3,not_met,PubMed:26088551,Propidium iodide dye transfer was impaired in GJB2 c.109G>A transfected HEK293T cells.,"Conduction experiments in Xenopus oocytes transfected with V37I demonstrate reduced conduction. There is a homozygous c.109G>A knock-in mouse model that demonstrates mild hearing loss that is more profound at high  frequencies. However, the codon used in mice, when transferred to humans, is p.Val37Met, so it was not counted as strong functional evidence. Dye transfer was impaired in HEK293T cells transfected with the p.V37I variant.","Conduction experiments in Xenopus oocytes transfected with V37I demonstrate reduced conduction. There is a homozygous c.109G>A knock-in mouse model that demonstrates mild hearing loss that is more profound at high  frequencies. However, the codon used in mice, when transferred to humans, is p.Val37Met, so it was not counted as strong functional evidence. Dye transfer was impaired in HEK293T cells transfected with the p.V37I variant. Propidium iodide dye transfer was impaired in GJB2 c.109G>A transfected HEK293T cells.","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"
1748,NM_206933.2(USH2A):c.2522C>A (p.Ser841Tyr),USH2A,Usher syndrome,MONDO:0019501,Benign,Autosomal recessive inheritance,Hearing Loss,2020-12-24,PS3,not_met,PubMed:22004887,conclude the p.S841Y variant is non-pathogenic. No functional studies performed.,, conclude the p.S841Y variant is non-pathogenic. No functional studies performed.,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
1963,NM_206933.3(USH2A):c.9433C>T (p.Leu3145Phe),USH2A,Usher syndrome,MONDO:0019501,Uncertain Significance,Autosomal recessive inheritance,Hearing Loss,2020-07-28,PM3-Supporting,not_met,PubMed:26806561,,Proband from Perez-Carro 2016 given 0.5 PM3 points to meet this criteria code at the supporting level.,Proband from Perez-Carro 2016 given 0.5 PM3 points to meet this criteria code at the supporting level. ,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
1963,NM_206933.3(USH2A):c.9433C>T (p.Leu3145Phe),USH2A,Usher syndrome,MONDO:0019501,Uncertain Significance,Autosomal recessive inheritance,Hearing Loss,2020-07-28,PM3-Supporting,not_met,PubMed:26667666,,Proband from Perez-Carro 2016 given 0.5 PM3 points to meet this criteria code at the supporting level.,Proband from Perez-Carro 2016 given 0.5 PM3 points to meet this criteria code at the supporting level. ,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
854,NM_206933.2(USH2A):c.2276G>T (p.Cys759Phe),USH2A,Usher syndrome,MONDO:0019501,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-08-16,BS1,met,PubMed:25261458,Found on 0.78% (4/504) of health Spanish control chromosomes.,Found at an allele frequency of 0.33% (21/4278 with a 95% CI) in meta-cohort of healthy individuals. It has also been observed at 0.43% (95% CI of 17/2536) of across several Spanish or Latino populations published in the literature. GnomAD Latino = 0.17% (95% CI of 72/35410).,Found at an allele frequency of 0.33% (21/4278 with a 95% CI) in meta-cohort of healthy individuals. It has also been observed at 0.43% (95% CI of 17/2536) of across several Spanish or Latino populations published in the literature. GnomAD Latino = 0.17% (95% CI of 72/35410). Found on 0.78% (4/504) of health Spanish control chromosomes.,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
854,NM_206933.2(USH2A):c.2276G>T (p.Cys759Phe),USH2A,Usher syndrome,MONDO:0019501,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-08-16,BS1,met,PubMed:26764160,Found on 0.72% (4/552) of Spanish chromosomes with no known diseases.,Found at an allele frequency of 0.33% (21/4278 with a 95% CI) in meta-cohort of healthy individuals. It has also been observed at 0.43% (95% CI of 17/2536) of across several Spanish or Latino populations published in the literature. GnomAD Latino = 0.17% (95% CI of 72/35410).,Found at an allele frequency of 0.33% (21/4278 with a 95% CI) in meta-cohort of healthy individuals. It has also been observed at 0.43% (95% CI of 17/2536) of across several Spanish or Latino populations published in the literature. GnomAD Latino = 0.17% (95% CI of 72/35410). Found on 0.72% (4/552) of Spanish chromosomes with no known diseases.,"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"
651,NM_206933.2(USH2A):c.1036A>C (p.Asn346His),USH2A,Usher syndrome,MONDO:0019501,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PP4,met,PubMed:22135276,Usher syndrome type II,"The patiens of compound heterozygotes or homozygotes with the mutation showed retinitis pigmentosa with hearing loss.

Enough patients were also tested for the other Usher syndrome genes and found to be negative for changes in them.  I also agree.
-MD","The patiens of compound heterozygotes or homozygotes with the mutation showed retinitis pigmentosa with hearing loss.

Enough patients were also tested for the other Usher syndrome genes and found to be negative for changes in them.  I also agree.
-MD Usher syndrome type II","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"
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,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"
743,NM_004004.5(GJB2):c.571T>C (p.Phe191Leu),GJB2,nonsyndromic genetic deafness,MONDO:0019497,Uncertain Significance,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PS3-Supporting,not_met,PubMed:23967136,"When expressed in HeLa cells, F191L showed intracellular fluorescence with patterns indicating ER retention or cytoplasmic aggregation.
F191L mutant formed large aggregates with possible plasma membrane locations, but closer inspection of the images showed that the fluorescence patterns did not have appearance of gap junctions, since apposing plasma membranes did not appear close enough together to make a gap junction.
Computational modeling: Phe191 side chain is buried in the 4-helix bundle and makes hydrophobic interactions with Arg75 (alpha-helix transmembrane domain 2, TM2), Leu79 (TM2) from an adjacent monomer as well as amino acids Val38 (TM1), Ala39 (TM1) and Val190 (TM4) from the same monomer. Possible effect: substitution of Leu would destabilize structure by causing formation of hydrophobic cavity.","2 studies performed in HeLa cells revealed that F191L mutants were not properly trafficked to the plasma membrane, with immunocytochemsistyr / fluorescence showing retention in the ER and aggregation in the cytoplasm.","2 studies performed in HeLa cells revealed that F191L mutants were not properly trafficked to the plasma membrane, with immunocytochemsistyr / fluorescence showing retention in the ER and aggregation in the cytoplasm. When expressed in HeLa cells, F191L showed intracellular fluorescence with patterns indicating ER retention or cytoplasmic aggregation.
F191L mutant formed large aggregates with possible plasma membrane locations, but closer inspection of the images showed that the fluorescence patterns did not have appearance of gap junctions, since apposing plasma membranes did not appear close enough together to make a gap junction.
Computational modeling: Phe191 side chain is buried in the 4-helix bundle and makes hydrophobic interactions with Arg75 (alpha-helix transmembrane domain 2, TM2), Leu79 (TM2) from an adjacent monomer as well as amino acids Val38 (TM1), Ala39 (TM1) and Val190 (TM4) from the same monomer. Possible effect: substitution of Leu would destabilize structure by causing formation of hydrophobic cavity.","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"
546,NM_000314.6(PTEN):c.392C>T (p.Thr131Ile),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2018-12-10,PS3,met,PubMed:29785012,"Variant categorized as ""WT-like"" on VAMPseq high throughput assay assessing protein abundance as a measure of stability.",," Variant categorized as ""WT-like"" on VAMPseq high throughput assay assessing protein abundance as a measure of stability.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
749,NM_000314.6(PTEN):c.388C>G (p.Arg130Gly),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2019-07-23,PS3,met,PubMed:29785012,Matreyek et al. classified this variant as abundance class - WT-like with an a G-score of 1.085198.,"Escudero et al (2011) demonstrated loss of function and inactive protein using a yeast functional analysis using drop growth assays of tumor associated PTEN.  Revealed no protein activity in figure 4.  This variant is in the PTEN catalytic loop.  He X et al (2011) measured PTEN levels in lymphoblastoid cell lines isolated from two CS patients, one with this variant.  Figure 5C demonstrates significant decrease in PTEN levels suggesting that some ATP-binding mutant proteins are unstable.  Lobo G et al. (2009) also demonstrated in figure 5 altered PTEN localization using western blot.  Patient likely the same as patient analyzed in Xin He et al. paper.
The cumulative score generated by Miguell et al. is -2.13842062 which is slightly less than cut-off of -2.13 for PS3, truncation-like classification.  In contrast, Matreyek et al. classified this variant as abundance class - WT-like with an a G-score of 1.085198. (MP submitted). KS agrees.","Escudero et al (2011) demonstrated loss of function and inactive protein using a yeast functional analysis using drop growth assays of tumor associated PTEN.  Revealed no protein activity in figure 4.  This variant is in the PTEN catalytic loop.  He X et al (2011) measured PTEN levels in lymphoblastoid cell lines isolated from two CS patients, one with this variant.  Figure 5C demonstrates significant decrease in PTEN levels suggesting that some ATP-binding mutant proteins are unstable.  Lobo G et al. (2009) also demonstrated in figure 5 altered PTEN localization using western blot.  Patient likely the same as patient analyzed in Xin He et al. paper.
The cumulative score generated by Miguell et al. is -2.13842062 which is slightly less than cut-off of -2.13 for PS3, truncation-like classification.  In contrast, Matreyek et al. classified this variant as abundance class - WT-like with an a G-score of 1.085198. (MP submitted). KS agrees. Matreyek et al. classified this variant as abundance class - WT-like with an a G-score of 1.085198.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
749,NM_000314.6(PTEN):c.388C>G (p.Arg130Gly),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2019-07-23,PS3,met,PubMed:20926450,"He X et al (2011) measured PTEN levels in lymphoblastoid cell lines isolated from two CS patients, one with this variant.  Figure 5C demonstrates significant decrease in PTEN levels suggesting that some ATP-binding mutant proteins are unstable.","Escudero et al (2011) demonstrated loss of function and inactive protein using a yeast functional analysis using drop growth assays of tumor associated PTEN.  Revealed no protein activity in figure 4.  This variant is in the PTEN catalytic loop.  He X et al (2011) measured PTEN levels in lymphoblastoid cell lines isolated from two CS patients, one with this variant.  Figure 5C demonstrates significant decrease in PTEN levels suggesting that some ATP-binding mutant proteins are unstable.  Lobo G et al. (2009) also demonstrated in figure 5 altered PTEN localization using western blot.  Patient likely the same as patient analyzed in Xin He et al. paper.
The cumulative score generated by Miguell et al. is -2.13842062 which is slightly less than cut-off of -2.13 for PS3, truncation-like classification.  In contrast, Matreyek et al. classified this variant as abundance class - WT-like with an a G-score of 1.085198. (MP submitted). KS agrees.","Escudero et al (2011) demonstrated loss of function and inactive protein using a yeast functional analysis using drop growth assays of tumor associated PTEN.  Revealed no protein activity in figure 4.  This variant is in the PTEN catalytic loop.  He X et al (2011) measured PTEN levels in lymphoblastoid cell lines isolated from two CS patients, one with this variant.  Figure 5C demonstrates significant decrease in PTEN levels suggesting that some ATP-binding mutant proteins are unstable.  Lobo G et al. (2009) also demonstrated in figure 5 altered PTEN localization using western blot.  Patient likely the same as patient analyzed in Xin He et al. paper.
The cumulative score generated by Miguell et al. is -2.13842062 which is slightly less than cut-off of -2.13 for PS3, truncation-like classification.  In contrast, Matreyek et al. classified this variant as abundance class - WT-like with an a G-score of 1.085198. (MP submitted). KS agrees. He X et al (2011) measured PTEN levels in lymphoblastoid cell lines isolated from two CS patients, one with this variant.  Figure 5C demonstrates significant decrease in PTEN levels suggesting that some ATP-binding mutant proteins are unstable.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
750,NM_000314.6(PTEN):c.477G>T (p.Arg159Ser),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Likely Pathogenic,Autosomal dominant inheritance,PTEN,2019-07-23,PS3,met,PubMed:29617666,"Article studied variant for splicing impact.  Identified in TCGA tumor; RT-PCR showed 21bp deletion.  However, fig. 5 mini-gene appears same as WT?  No apparent impact on native site, but possible strengthening of alternative SDS.",," Article studied variant for splicing impact.  Identified in TCGA tumor; RT-PCR showed 21bp deletion.  However, fig. 5 mini-gene appears same as WT?  No apparent impact on native site, but possible strengthening of alternative SDS.",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
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
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,PS3,met,PubMed:29785012,"Variant showed low protein abundance (score 0.17), PS3 already applied to phosphatase data.",KS agrees.,"KS agrees. Variant showed low protein abundance (score 0.17), PS3 already applied to phosphatase data.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
771,NM_000314.6(PTEN):c.104T>G (p.Met35Arg),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2019-07-23,PS3,met,PubMed:25875300,"Figure 2: functional analysis of PTEN tumor suppressor function in vivo on a panel of N-terminal PTEN mutations including M35R. Shown in 2B, 2C and table 1, there is increased nuclear localization on a PTEN WT background when tested on mammalian COS-7 cells.  A partial inhibition of nuclear accumulation was observed on a PTEN 1-375 background. PIP3 phosphatase activity was assessed next using S. cerevisiae heterologous reconstitution system. Fig 2D, 2E, Table 2, M35R totally abrogated PTEN activity in the yeast model.  Figure 2D shows no galactose activity indicating non-functioning PTEN.",I agree (FH),"I agree (FH) Figure 2: functional analysis of PTEN tumor suppressor function in vivo on a panel of N-terminal PTEN mutations including M35R. Shown in 2B, 2C and table 1, there is increased nuclear localization on a PTEN WT background when tested on mammalian COS-7 cells.  A partial inhibition of nuclear accumulation was observed on a PTEN 1-375 background. PIP3 phosphatase activity was assessed next using S. cerevisiae heterologous reconstitution system. Fig 2D, 2E, Table 2, M35R totally abrogated PTEN activity in the yeast model.  Figure 2D shows no galactose activity indicating non-functioning PTEN.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
774,NM_000314.6(PTEN):c.701G>A (p.Arg234Gln),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Uncertain Significance,Autosomal dominant inheritance,PTEN,2023-10-19,PS3,not_met,PubMed:12085208,Variant transfected into U87MG glioma cell line (PTEN-null).  Cells with mutant had 5x higher proliferation rate than WT over 2 week period and demonstrated apoptosis rate comparable to empty vector (WT had 2x rate).  Mutant also had increased PKB phosphorylation.,"Need to discuss PS3_supporting with group, may not apply?
Matreyek et al (no PMID yet) also describe variant as PATH in ClinVar (is actually conflicting) but with normal protein abundance.
Eng lab papers also describe M3/M4 mouse with this plus 4 other PTEN missense variants; can't use for analyzing function of this variant separately.

I agree with PS3_supporting for Staal et al. (FH)

Following expert panel discussion, group decided to apply no criteria based on conflicting nature of functional results.","Need to discuss PS3_supporting with group, may not apply?
Matreyek et al (no PMID yet) also describe variant as PATH in ClinVar (is actually conflicting) but with normal protein abundance.
Eng lab papers also describe M3/M4 mouse with this plus 4 other PTEN missense variants; can't use for analyzing function of this variant separately.

I agree with PS3_supporting for Staal et al. (FH)

Following expert panel discussion, group decided to apply no criteria based on conflicting nature of functional results. Variant transfected into U87MG glioma cell line (PTEN-null).  Cells with mutant had 5x higher proliferation rate than WT over 2 week period and demonstrated apoptosis rate comparable to empty vector (WT had 2x rate).  Mutant also had increased PKB phosphorylation.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
774,NM_000314.6(PTEN):c.701G>A (p.Arg234Gln),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Uncertain Significance,Autosomal dominant inheritance,PTEN,2023-10-19,PS3,not_met,PubMed:29785012,“WT-like” protein abundance on high throughput assay,"Need to discuss PS3_supporting with group, may not apply?
Matreyek et al (no PMID yet) also describe variant as PATH in ClinVar (is actually conflicting) but with normal protein abundance.
Eng lab papers also describe M3/M4 mouse with this plus 4 other PTEN missense variants; can't use for analyzing function of this variant separately.

I agree with PS3_supporting for Staal et al. (FH)

Following expert panel discussion, group decided to apply no criteria based on conflicting nature of functional results.","Need to discuss PS3_supporting with group, may not apply?
Matreyek et al (no PMID yet) also describe variant as PATH in ClinVar (is actually conflicting) but with normal protein abundance.
Eng lab papers also describe M3/M4 mouse with this plus 4 other PTEN missense variants; can't use for analyzing function of this variant separately.

I agree with PS3_supporting for Staal et al. (FH)

Following expert panel discussion, group decided to apply no criteria based on conflicting nature of functional results. “WT-like” protein abundance on high throughput assay",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
1048,NM_000314.7(PTEN):c.464A>G (p.Tyr155Cys),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2019-12-11,PS3,met,PubMed:27829222,Phadngam S et al. evaluated ovarian cancer cells and PTEN protein expression.  Figure 4C shows a theoretical 3D structure of Y155C and concluded that the presence of this mutation does not alter the structure of PTEN including the phosphatase domain (*discuss with group whether this is negates criteria).,"Miguell et al. table shows G score of -2.26881194 which is in the truncation-like range 
(< -2.13). Han et al. paper demonstrated variant as having no phosphatase activity compared to WT in Figure 2G.  Rodriguez-Escudero et al completed a functional assessment of PTEN mutations related to PHTS.  They demonstrated  in Figure 6A that this variant had PIP3 (+) cells with activity of 100% which was similar to the vector activity.  WT showed negligible activity.  Phadngam S et al. evaluated ovarian cancer cells and PTEN protein expression.  Figure 4C shows a theoretical 3D structure of Y155C and concluded that the presence of this mutation does not alter the structure of PTEN including the phosphatase domain (*discuss with group whether this is negates criteria). Smith et al. evaluated mutational effects that lead to PTEN-ASD and PTEN-cancer phenotypes.  Using protein-dynamic structural-network analysis.  They assessed the difference in closeness centrality at the network level and identified significant differences compared to WT (figures S5A and S5B). This variant is found in the central core of the protein. *Discuss figure 3 (residue-based betweenness centrality estimation plot) with group. Andres-Pons et al. identified a patient described to meet criteria of PHTS/Cowden with this variant. Yeast functional analysis (table 1) was conducted on this variant and found no reconstitution and low yeast protein expression level.  Clinical features of patient could not be located in this paper or referenced papers by the authors.","Miguell et al. table shows G score of -2.26881194 which is in the truncation-like range 
(< -2.13). Han et al. paper demonstrated variant as having no phosphatase activity compared to WT in Figure 2G.  Rodriguez-Escudero et al completed a functional assessment of PTEN mutations related to PHTS.  They demonstrated  in Figure 6A that this variant had PIP3 (+) cells with activity of 100% which was similar to the vector activity.  WT showed negligible activity.  Phadngam S et al. evaluated ovarian cancer cells and PTEN protein expression.  Figure 4C shows a theoretical 3D structure of Y155C and concluded that the presence of this mutation does not alter the structure of PTEN including the phosphatase domain (*discuss with group whether this is negates criteria). Smith et al. evaluated mutational effects that lead to PTEN-ASD and PTEN-cancer phenotypes.  Using protein-dynamic structural-network analysis.  They assessed the difference in closeness centrality at the network level and identified significant differences compared to WT (figures S5A and S5B). This variant is found in the central core of the protein. *Discuss figure 3 (residue-based betweenness centrality estimation plot) with group. Andres-Pons et al. identified a patient described to meet criteria of PHTS/Cowden with this variant. Yeast functional analysis (table 1) was conducted on this variant and found no reconstitution and low yeast protein expression level.  Clinical features of patient could not be located in this paper or referenced papers by the authors. Phadngam S et al. evaluated ovarian cancer cells and PTEN protein expression.  Figure 4C shows a theoretical 3D structure of Y155C and concluded that the presence of this mutation does not alter the structure of PTEN including the phosphatase domain (*discuss with group whether this is negates criteria).",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
5694,NM_000314.8(PTEN):c.35A>G (p.Asn12Ser),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Uncertain Significance,Autosomal dominant inheritance,PTEN,2023-10-19,PS3,not_met,PubMed:29785012,WT-like protein abundance; no criteria for this study,, WT-like protein abundance; no criteria for this study,ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
88,NM_000314.6(PTEN):c.1171C>T (p.Pro391Ser),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Uncertain Significance,Autosomal dominant inheritance,PTEN,2020-03-26,BS3,met,PubMed:30993208,phosphorylated AKT and subcellular localization similar to WT,"Phosphatase activity, stability, pAKT, and subcellular localization similar to WT","Phosphatase activity, stability, pAKT, and subcellular localization similar to WT phosphorylated AKT and subcellular localization similar to WT",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_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
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,BS3,not_met,PubMed:29785012,Variant showed WT-like protein stability (score = 1.37) but only 2 experimental replicates.,"Mighell et al. 2018 PMID: 29706350: Lipid phosphatase activity score, -1.03673832 (FALSE)
Matreyek et al. 2018 PMID: 29785012: abundance_class is WT-like.
","Mighell et al. 2018 PMID: 29706350: Lipid phosphatase activity score, -1.03673832 (FALSE)
Matreyek et al. 2018 PMID: 29785012: abundance_class is WT-like.
 Variant showed WT-like protein stability (score = 1.37) but only 2 experimental replicates.",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,BS3,not_met,PubMed:22171747,,, ,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
766,NM_000314.6(PTEN):c.195C>G (p.Tyr65Ter),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2019-07-23,BS3,not_met,PubMed:29785012,,, ,ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
774,NM_000314.6(PTEN):c.701G>A (p.Arg234Gln),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Uncertain Significance,Autosomal dominant inheritance,PTEN,2023-10-19,BS3,not_met,PubMed:12085208,Variant transfected into U87MG glioma cell line (PTEN-null).  Cells with mutant had 5x higher proliferation rate than WT over 2 week period and demonstrated apoptosis rate comparable to empty vector (WT had 2x rate).  Mutant also had increased PKB phosphorylation.,"Need to discuss PS3_supporting with group, may not apply?
Matreyek et al (no PMID yet) also describe variant as PATH in ClinVar (is actually conflicting) but with normal protein abundance.
Eng lab papers also describe M3/M4 mouse with this plus 4 other PTEN missense variants; can't use for analyzing function of this variant separately.

I agree with PS3_supporting for Staal et al. (FH)","Need to discuss PS3_supporting with group, may not apply?
Matreyek et al (no PMID yet) also describe variant as PATH in ClinVar (is actually conflicting) but with normal protein abundance.
Eng lab papers also describe M3/M4 mouse with this plus 4 other PTEN missense variants; can't use for analyzing function of this variant separately.

I agree with PS3_supporting for Staal et al. (FH) Variant transfected into U87MG glioma cell line (PTEN-null).  Cells with mutant had 5x higher proliferation rate than WT over 2 week period and demonstrated apoptosis rate comparable to empty vector (WT had 2x rate).  Mutant also had increased PKB phosphorylation.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
774,NM_000314.6(PTEN):c.701G>A (p.Arg234Gln),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Uncertain Significance,Autosomal dominant inheritance,PTEN,2023-10-19,BS3,not_met,PubMed:29785012,“WT-like” protein abundance on high throughput assay,"Need to discuss PS3_supporting with group, may not apply?
Matreyek et al (no PMID yet) also describe variant as PATH in ClinVar (is actually conflicting) but with normal protein abundance.
Eng lab papers also describe M3/M4 mouse with this plus 4 other PTEN missense variants; can't use for analyzing function of this variant separately.

I agree with PS3_supporting for Staal et al. (FH)","Need to discuss PS3_supporting with group, may not apply?
Matreyek et al (no PMID yet) also describe variant as PATH in ClinVar (is actually conflicting) but with normal protein abundance.
Eng lab papers also describe M3/M4 mouse with this plus 4 other PTEN missense variants; can't use for analyzing function of this variant separately.

I agree with PS3_supporting for Staal et al. (FH) “WT-like” protein abundance on high throughput assay",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
5694,NM_000314.8(PTEN):c.35A>G (p.Asn12Ser),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Uncertain Significance,Autosomal dominant inheritance,PTEN,2023-10-19,BS3,not_met,PubMed:29785012,WT-like protein abundance; no criteria for this study,, WT-like protein abundance; no criteria for this study,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
749,NM_000314.6(PTEN):c.388C>G (p.Arg130Gly),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2019-07-23,PS4,not_met,PubMed:19457929,"Author and institution overlap. Likely same patient as Ngeow et al., 2014.","KS: Lots of somatic papers for this variant! Agree MP.
GeneDx internal data: 7yo female with macrocephaly (5-6SD), lipoma, lip discoloration, facial telangiectasias, constipation, macrosomia (ht/wt+2.5-3SD).  Does not meet PP4 since pediatric proband specificity score is 4. PTEN study data: Female, OFC = 58.5 cm, goiter, thyroid gland follicular adenoma, hashimoto disease, bilateral breast cancer dx 44, FCBD, intraductal papilloma of breast, uterine fibroids, lipoma, papilloma, skin tag, acral keratoses, CC score = 16.","KS: Lots of somatic papers for this variant! Agree MP.
GeneDx internal data: 7yo female with macrocephaly (5-6SD), lipoma, lip discoloration, facial telangiectasias, constipation, macrosomia (ht/wt+2.5-3SD).  Does not meet PP4 since pediatric proband specificity score is 4. PTEN study data: Female, OFC = 58.5 cm, goiter, thyroid gland follicular adenoma, hashimoto disease, bilateral breast cancer dx 44, FCBD, intraductal papilloma of breast, uterine fibroids, lipoma, papilloma, skin tag, acral keratoses, CC score = 16. Author and institution overlap. Likely same patient as Ngeow et al., 2014.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
749,NM_000314.6(PTEN):c.388C>G (p.Arg130Gly),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2019-07-23,PS4,not_met,PubMed:25669429,"Author and institution overlap. Likely is the same patient as Ngeow et al., 2014.","KS: Lots of somatic papers for this variant! Agree MP.
GeneDx internal data: 7yo female with macrocephaly (5-6SD), lipoma, lip discoloration, facial telangiectasias, constipation, macrosomia (ht/wt+2.5-3SD).  Does not meet PP4 since pediatric proband specificity score is 4. PTEN study data: Female, OFC = 58.5 cm, goiter, thyroid gland follicular adenoma, hashimoto disease, bilateral breast cancer dx 44, FCBD, intraductal papilloma of breast, uterine fibroids, lipoma, papilloma, skin tag, acral keratoses, CC score = 16.","KS: Lots of somatic papers for this variant! Agree MP.
GeneDx internal data: 7yo female with macrocephaly (5-6SD), lipoma, lip discoloration, facial telangiectasias, constipation, macrosomia (ht/wt+2.5-3SD).  Does not meet PP4 since pediatric proband specificity score is 4. PTEN study data: Female, OFC = 58.5 cm, goiter, thyroid gland follicular adenoma, hashimoto disease, bilateral breast cancer dx 44, FCBD, intraductal papilloma of breast, uterine fibroids, lipoma, papilloma, skin tag, acral keratoses, CC score = 16. Author and institution overlap. Likely is the same patient as Ngeow et al., 2014.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
749,NM_000314.6(PTEN):c.388C>G (p.Arg130Gly),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2019-07-23,PS4,not_met,PubMed:20926450,"Author and institution overlap. Likely is the same patient as Ngeow et al., 2014.","KS: Lots of somatic papers for this variant! Agree MP.
GeneDx internal data: 7yo female with macrocephaly (5-6SD), lipoma, lip discoloration, facial telangiectasias, constipation, macrosomia (ht/wt+2.5-3SD).  Does not meet PP4 since pediatric proband specificity score is 4. PTEN study data: Female, OFC = 58.5 cm, goiter, thyroid gland follicular adenoma, hashimoto disease, bilateral breast cancer dx 44, FCBD, intraductal papilloma of breast, uterine fibroids, lipoma, papilloma, skin tag, acral keratoses, CC score = 16.","KS: Lots of somatic papers for this variant! Agree MP.
GeneDx internal data: 7yo female with macrocephaly (5-6SD), lipoma, lip discoloration, facial telangiectasias, constipation, macrosomia (ht/wt+2.5-3SD).  Does not meet PP4 since pediatric proband specificity score is 4. PTEN study data: Female, OFC = 58.5 cm, goiter, thyroid gland follicular adenoma, hashimoto disease, bilateral breast cancer dx 44, FCBD, intraductal papilloma of breast, uterine fibroids, lipoma, papilloma, skin tag, acral keratoses, CC score = 16. Author and institution overlap. Likely is the same patient as Ngeow et al., 2014.",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
760,NM_000314.6(PTEN):c.1027-1G>A,PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2019-07-23,PS4,not_met,PubMed:27477328,"variant reported in 41yo M with ""CS"" - pts from CCF cohort. no other phenotype provided.",," variant reported in 41yo M with ""CS"" - pts from CCF cohort. no other phenotype provided.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
762,NM_000314.6(PTEN):c.-1195_-1184delAAGCCGCAGCAA,PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Likely Benign,Autosomal dominant inheritance,PTEN,2019-07-23,PS4,not_met,PubMed:25669429,Variant listed as identified in this study in Supplementary Table 4. No additional patient specific information reported. Patients met full or relaxed criteria for Cowden syndrome per methods section.,, Variant listed as identified in this study in Supplementary Table 4. No additional patient specific information reported. Patients met full or relaxed criteria for Cowden syndrome per methods section.,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,PS4,not_met,PubMed:28677221,"Variant present in 11 pts from CCF PTEN study (probands or relatives).  3 with CC score and/or box checked for ""negative for phenotypes of interest"".  One with CC score = 42 (macrocephaly, BrCA, benign thyroid, hamartomas, GU tumor, AK, papillomas) but given BS1 applies, can't apply PS4/PP4 criteria anyways.","If BS1 met, PS4/PP4 cannot apply","If BS1 met, PS4/PP4 cannot apply Variant present in 11 pts from CCF PTEN study (probands or relatives).  3 with CC score and/or box checked for ""negative for phenotypes of interest"".  One with CC score = 42 (macrocephaly, BrCA, benign thyroid, hamartomas, GU tumor, AK, papillomas) but given BS1 applies, can't apply PS4/PP4 criteria anyways.",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,PS4,not_met,PubMed:28677221,,"Patients with our variant, however CC scores too low.","Patients with our variant, however CC scores too low. ",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
90,NM_000314.6(PTEN):c.44G>A (p.Arg15Lys),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Likely Pathogenic,Autosomal dominant inheritance,PTEN,2024-04-10,PS3-Moderate,not_met,PubMed:29785012,wt-like stability score 1.2,"Functional studies supportive of a damaging effect on the gene or gene product. Score of this variant = -1.65 (≤ -1.11) on a high throughput phosphatase assay (PMID:29706350). 
","Functional studies supportive of a damaging effect on the gene or gene product. Score of this variant = -1.65 (≤ -1.11) on a high throughput phosphatase assay (PMID:29706350). 
 wt-like stability score 1.2",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
555,NM_000314.6(PTEN):c.722T>C (p.Phe241Ser),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Likely Pathogenic,Autosomal dominant inheritance,PTEN,2023-10-19,PS3-Moderate,not_met,PubMed:25527629,"Variant demonstrated decreased protein stability and PTEN expression.  No significant increase in pAKT or neuronal cells, but authors posit this is due to lack of protein stability.",Functional studies supportive of a damaging effect on the gene or gene product. This variant: score of -2.39943 (≤ -1.11) on a high throughput phosphatase assay (PMID:29706350). ,"Functional studies supportive of a damaging effect on the gene or gene product. This variant: score of -2.39943 (≤ -1.11) on a high throughput phosphatase assay (PMID:29706350).  Variant demonstrated decreased protein stability and PTEN expression.  No significant increase in pAKT or neuronal cells, but authors posit this is due to lack of protein stability.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
555,NM_000314.6(PTEN):c.722T>C (p.Phe241Ser),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Likely Pathogenic,Autosomal dominant inheritance,PTEN,2023-10-19,PS3-Moderate,not_met,PubMed:29785012,"low (lowest) range protein abundance (score 0.17, range 0-1)",Functional studies supportive of a damaging effect on the gene or gene product. This variant: score of -2.39943 (≤ -1.11) on a high throughput phosphatase assay (PMID:29706350). ,"Functional studies supportive of a damaging effect on the gene or gene product. This variant: score of -2.39943 (≤ -1.11) on a high throughput phosphatase assay (PMID:29706350).  low (lowest) range protein abundance (score 0.17, range 0-1)",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
555,NM_000314.6(PTEN):c.722T>C (p.Phe241Ser),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Likely Pathogenic,Autosomal dominant inheritance,PTEN,2023-10-19,PS3-Moderate,not_met,PubMed:26579216,Variant resulted in decreased protein stability. Also appeared to be unable to suppress tyrosine hydroxylase similar to other mutants.,Functional studies supportive of a damaging effect on the gene or gene product. This variant: score of -2.39943 (≤ -1.11) on a high throughput phosphatase assay (PMID:29706350). ,Functional studies supportive of a damaging effect on the gene or gene product. This variant: score of -2.39943 (≤ -1.11) on a high throughput phosphatase assay (PMID:29706350).  Variant resulted in decreased protein stability. Also appeared to be unable to suppress tyrosine hydroxylase similar to other mutants.,ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
1060,NM_000314.7(PTEN):c.610C>G (p.Pro204Ala),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2023-10-18,PS3-Moderate,not_met,PubMed:29785012,"Protein abundance score 0.52, ""possibly low"" range.",Mighell score hypomorphic,"Mighell score hypomorphic Protein abundance score 0.52, ""possibly low"" range.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
1061,NM_000314.8(PTEN):c.80A>G (p.Tyr27Cys),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Likely Pathogenic,Autosomal dominant inheritance,PTEN,2023-10-18,PS3-Moderate,not_met,PubMed:29785012,Low (score 0.35) protein abundance,"Functional studies supportive of a damaging effect on the gene or gene product. Score of this variant = -1.648 (≤ -1.11) on a high throughput phosphatase assay (PMID:29706350). 

Note: discussed with team, decided to not apply criteria to Mingo given lack of positive control.
Mighell et al (2018): High confidence variant, cum_score = -1.648","Functional studies supportive of a damaging effect on the gene or gene product. Score of this variant = -1.648 (≤ -1.11) on a high throughput phosphatase assay (PMID:29706350). 

Note: discussed with team, decided to not apply criteria to Mingo given lack of positive control.
Mighell et al (2018): High confidence variant, cum_score = -1.648 Low (score 0.35) protein abundance",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,PS4-Supporting,not_met,PubMed:28677221,"Found in pt 37, 45yo with CC score = 68. Pers hx macrocephaly, thyroid cancer, LDD, benign thyroid disease, hamartomatous polyps, lipomas, fibromas, acral keratoses, mucosal lesions. Recalculation CC score without more details score still >30, 1 phenotype point.","Proband specificity score is 1-1.5 (PMID 2867721). 

","Proband specificity score is 1-1.5 (PMID 2867721). 

 Found in pt 37, 45yo with CC score = 68. Pers hx macrocephaly, thyroid cancer, LDD, benign thyroid disease, hamartomatous polyps, lipomas, fibromas, acral keratoses, mucosal lesions. Recalculation CC score without more details score still >30, 1 phenotype point.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
770,NM_000314.6(PTEN):c.512dup (p.Arg172Glufs),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2019-07-23,PS4-Supporting,not_met,PubMed:25669429,"Author overlap and likely patient overlap with PMIDs 21194675, 20600018, 21956414, 22261759. Variant listed identified in this study in Supplementary Table 4.","Per K. Sesock: At least 2 patients (please see notes below). A patient with CC score = at least 10, and a pediatric patient with a peds score = 11.

Per J. Mester: agree PS4_supporting; strongly suspect pt reported in CCF and Boston publications is the same individual.","Per K. Sesock: At least 2 patients (please see notes below). A patient with CC score = at least 10, and a pediatric patient with a peds score = 11.

Per J. Mester: agree PS4_supporting; strongly suspect pt reported in CCF and Boston publications is the same individual. Author overlap and likely patient overlap with PMIDs 21194675, 20600018, 21956414, 22261759. Variant listed identified in this study in Supplementary Table 4.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
770,NM_000314.6(PTEN):c.512dup (p.Arg172Glufs),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2019-07-23,PS4-Supporting,not_met,PubMed:27477328,"Author overlap and possible patient overlap with PMIDs 21194675, 20600018, 21956414, 22261759, 25669429. This study reports a 21-year-old female with Cowden syndrome and lymphoid hyperplasia. This could be the same patient as the 19.4-year-old patient reported in PMID 21194675, however there is limited information to confirm if this is the same patient or not.","Per K. Sesock: At least 2 patients (please see notes below). A patient with CC score = at least 10, and a pediatric patient with a peds score = 11.

Per J. Mester: agree PS4_supporting; strongly suspect pt reported in CCF and Boston publications is the same individual.","Per K. Sesock: At least 2 patients (please see notes below). A patient with CC score = at least 10, and a pediatric patient with a peds score = 11.

Per J. Mester: agree PS4_supporting; strongly suspect pt reported in CCF and Boston publications is the same individual. Author overlap and possible patient overlap with PMIDs 21194675, 20600018, 21956414, 22261759, 25669429. This study reports a 21-year-old female with Cowden syndrome and lymphoid hyperplasia. This could be the same patient as the 19.4-year-old patient reported in PMID 21194675, however there is limited information to confirm if this is the same patient or not.",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,PS4-Supporting,not_met,PubMed:28677221,"Identified in pt 15: 49yrs old, CC score = 42 per article. Macrocephaly, breast cancer, thyroid disease, hamartomatous polyps, GU tumor, acral keratoses, papillomas, and mucosal lesions.",1 pt from Eng lab articles,"1 pt from Eng lab articles Identified in pt 15: 49yrs old, CC score = 42 per article. Macrocephaly, breast cancer, thyroid disease, hamartomatous polyps, GU tumor, acral keratoses, papillomas, and mucosal lesions.",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
768,NM_000314.8(PTEN):c.441_442delinsA (p.Ala148fs),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Likely Pathogenic,Autosomal dominant inheritance,PTEN,2023-10-19,PP4,not_met,PubMed:27477328,"Identified in a Male 43 (patient 21) with CS/BRRS, but no specifics on clinical features were given.",," Identified in a Male 43 (patient 21) with CS/BRRS, but no specifics on clinical features were given.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
768,NM_000314.8(PTEN):c.441_442delinsA (p.Ala148fs),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Likely Pathogenic,Autosomal dominant inheritance,PTEN,2023-10-19,PP4,not_met,PubMed:25669429,"Detected in a cohort of patients who met clinical diagnostic criteria for Cowden syndrome (CS) or relaxed clinical diagnostic criteria for CS-like, but no specifics on clinical features were given.",," Detected in a cohort of patients who met clinical diagnostic criteria for Cowden syndrome (CS) or relaxed clinical diagnostic criteria for CS-like, but no specifics on clinical features were given.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
774,NM_000314.6(PTEN):c.701G>A (p.Arg234Gln),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Uncertain Significance,Autosomal dominant inheritance,PTEN,2023-10-19,PP4,not_met,PubMed:12085208,"Germline finding in a male pt with R frontal meningioma dx 42, L frontal low-grade glioma dx 47, this tumor turned into an  anaplastic oligodendroglioma when resected at 50 yrs. This tumor recurred a few yrs later.  Pt had no prev unusual med hx. Tumors also had variant and no LOH at 10q.","No GDx internal cases with phenotype specificity.

No Ambry internal cases with phenotype specificity (FH).","No GDx internal cases with phenotype specificity.

No Ambry internal cases with phenotype specificity (FH). Germline finding in a male pt with R frontal meningioma dx 42, L frontal low-grade glioma dx 47, this tumor turned into an  anaplastic oligodendroglioma when resected at 50 yrs. This tumor recurred a few yrs later.  Pt had no prev unusual med hx. Tumors also had variant and no LOH at 10q.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
556,NM_000314.6(PTEN):c.278A>G (p.His93Arg),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2018-12-10,PS3-Supporting,not_met,PubMed:22505997,H93R prefers to bind Phosphatidylserine (PS) ?over PIP3 and has high affinity for plasma membrane; similar to Redfern results.,PS3_supporting applied following functional subgroup discussion.,PS3_supporting applied following functional subgroup discussion. H93R prefers to bind Phosphatidylserine (PS) ?over PIP3 and has high affinity for plasma membrane; similar to Redfern results.,ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
556,NM_000314.6(PTEN):c.278A>G (p.His93Arg),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2018-12-10,PS3-Supporting,not_met,PubMed:26579216,H93R unable to suppress expression of tyrosine hydroxylase.  Variant also led to unstable protein; 80% degraded after 8 hours of cycloheximide tx (WT unchanged).,PS3_supporting applied following functional subgroup discussion.,PS3_supporting applied following functional subgroup discussion. H93R unable to suppress expression of tyrosine hydroxylase.  Variant also led to unstable protein; 80% degraded after 8 hours of cycloheximide tx (WT unchanged).,ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
4163,NM_000314.8(PTEN):c.16A>G (p.Lys6Glu),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2022-09-30,PS3-Supporting,not_met,PubMed:32350270,"no impact on stability, but LOF with respect to lipid phosphatase and some additional studies ","VCEP approved criteria based on combined published evidence suggesting some functional impact, but not strong enough for full PS3","VCEP approved criteria based on combined published evidence suggesting some functional impact, but not strong enough for full PS3 no impact on stability, but LOF with respect to lipid phosphatase and some additional studies ",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
4163,NM_000314.8(PTEN):c.16A>G (p.Lys6Glu),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2022-09-30,PS3-Supporting,not_met,PubMed:29785012,"WT-like abundance, indicating protein stability","VCEP approved criteria based on combined published evidence suggesting some functional impact, but not strong enough for full PS3","VCEP approved criteria based on combined published evidence suggesting some functional impact, but not strong enough for full PS3 WT-like abundance, indicating protein stability",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
550,NM_000314.8(PTEN):c.1061C>A (p.Pro354Gln),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Likely Benign,Autosomal dominant inheritance,PTEN,2023-10-19,BS3-Supporting,not_met,PubMed:29785012,"WT-like abundance on high-throughput VAMP-seq assay, indicating stable protein",In vitro or in vivo functional study or studies showing no damaging effect on protein function. Score of 0.09 (WT-like range) on high throughput phosphatase assay (PMID:29706350).,"In vitro or in vivo functional study or studies showing no damaging effect on protein function. Score of 0.09 (WT-like range) on high throughput phosphatase assay (PMID:29706350). WT-like abundance on high-throughput VAMP-seq assay, indicating stable protein",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,PS4-Moderate,not_met,PubMed:23886400,"Proband had glycogenic acanthosis of the esophagus, keratosis of the hands and of the feet and juvenile polyps. He later developed a metastatic and locally advanced rectal cancer and hamartomatous small stomach polyps. minimum CC score = 27, 0.5 phenotype points.  Daughter also positive for variant (but age unknown), her hx includes hamartomatous colon polyps since the age of 10. She was also affected by Hashimoto disease and arteriovenous malformation and showed small facial keratosis.","1 GDx internal case with peds score = 6, 1 phenotype point; in addition to other lit reports, 2.5 points total, moderate evidence. KS agrees.","1 GDx internal case with peds score = 6, 1 phenotype point; in addition to other lit reports, 2.5 points total, moderate evidence. KS agrees. Proband had glycogenic acanthosis of the esophagus, keratosis of the hands and of the feet and juvenile polyps. He later developed a metastatic and locally advanced rectal cancer and hamartomatous small stomach polyps. minimum CC score = 27, 0.5 phenotype points.  Daughter also positive for variant (but age unknown), her hx includes hamartomatous colon polyps since the age of 10. She was also affected by Hashimoto disease and arteriovenous malformation and showed small facial keratosis.",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,BS4,not_met,PubMed:23886400,"Variant identified in proband described in PS4 section, variant also present in his daughter with hamartomatous colon polyps since the age of 10. She was also affected by Hashimoto disease and arteriovenous malformation and showed small facial keratosis. 1 meiosis.",," Variant identified in proband described in PS4 section, variant also present in his daughter with hamartomatous colon polyps since the age of 10. She was also affected by Hashimoto disease and arteriovenous malformation and showed small facial keratosis. 1 meiosis.",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,PP1,met,PubMed:23886400,"Variant identified in proband described in PS4 section, variant also present in his daughter with hamartomatous colon polyps since the age of 10. She was also affected by Hashimoto disease and arteriovenous malformation and showed small facial keratosis. 1 meiosis.","3 meioses total (1 Paparo, 1 Hansen-Kiss, 1 GDx internal family)","3 meioses total (1 Paparo, 1 Hansen-Kiss, 1 GDx internal family) Variant identified in proband described in PS4 section, variant also present in his daughter with hamartomatous colon polyps since the age of 10. She was also affected by Hashimoto disease and arteriovenous malformation and showed small facial keratosis. 1 meiosis.",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
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,PM3,met,PubMed:27417441,,"At least 6 patients have been reported with this variant and deficiency of GAA activity meeting the ClinGen LSD VCEP’s PP4 specifications. One of these individuals is compound heterozygous for the variant and c.-32-13T>G, phase unknown (PMID 16531044; 0.5 points), and another is homozygous for the variant (PMID 17723315; 0.5 points). A total of one point was given, meeting PM3. Other individuals meeting PP4 specifications are compound heterozygous for the variant and either c.1574T>A (p.Phe525Tyr) (PMID 21232767), c.1935C>A (p.Asp645Glu) (PMID 18458862), or c.2238G>C (p.Trp746Cys) (PMID 25526786). However in each case, the in trans data from these patients will be used in the assessment of the other variant and was not used here in order to avoid a circular argument. Additional cases with the variant have been reported but were not included because the residual GAA activity was not provided, and therefore PP4 cannot be assessed (PMIDs 24269976, 25455803, 25626711, 27417441, 28394184, 31743840), or the patient carried a pseudodeficiency allele (PMID 21232767).","At least 6 patients have been reported with this variant and deficiency of GAA activity meeting the ClinGen LSD VCEP’s PP4 specifications. One of these individuals is compound heterozygous for the variant and c.-32-13T>G, phase unknown (PMID 16531044; 0.5 points), and another is homozygous for the variant (PMID 17723315; 0.5 points). A total of one point was given, meeting PM3. Other individuals meeting PP4 specifications are compound heterozygous for the variant and either c.1574T>A (p.Phe525Tyr) (PMID 21232767), c.1935C>A (p.Asp645Glu) (PMID 18458862), or c.2238G>C (p.Trp746Cys) (PMID 25526786). However in each case, the in trans data from these patients will be used in the assessment of the other variant and was not used here in order to avoid a circular argument. Additional cases with the variant have been reported but were not included because the residual GAA activity was not provided, and therefore PP4 cannot be assessed (PMIDs 24269976, 25455803, 25626711, 27417441, 28394184, 31743840), or the patient carried a pseudodeficiency allele (PMID 21232767). ",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
1337,NM_000152.4(GAA):c.2269C>T (p.Gln757Ter),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-05-28,PM3,not_met,PubMed:29149851,"Patient 7 is a compound heterozygote for p.Gln757Ter and c.-32-13T>G in GAA, a known pathogenic variant. However, the phase of the variants was not confirmed and the patient does not meet PP4 (0 points).",One patient meeting the ClinGen LSD VCEP’s specifications for PP4 and compound heterozygous for this variant and c.925G>A (p.Gly309Arg) in GAA has been reported (PMID 24337590). The phase of the variants was not confirmed. In trans data from this patient was used in the assessment of p.Gly309Arg and was not included here in order to avoid circular logic.,"One patient meeting the ClinGen LSD VCEP’s specifications for PP4 and compound heterozygous for this variant and c.925G>A (p.Gly309Arg) in GAA has been reported (PMID 24337590). The phase of the variants was not confirmed. In trans data from this patient was used in the assessment of p.Gly309Arg and was not included here in order to avoid circular logic. Patient 7 is a compound heterozygote for p.Gln757Ter and c.-32-13T>G in GAA, a known pathogenic variant. However, the phase of the variants was not confirmed and the patient does not meet PP4 (0 points).",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1356,NM_000152.4(GAA):c.1438-1G>C,GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-05-28,PM3,met,PubMed:27896092,,"Two patients with Pompe disease and meeting the ClinGen LSD VCEP’s specifications for PP4 have been identified. One patient is compound heterozygous for the variant and c.1655T>C, phase unknown (p.Leu552Pro)(PMIDs 22538254)(0.5 points). The second patient was identified in a clinical laboratory and is compound heterozygous for the variant and c.-32-13T>G. The phase is unknown (0.5 points). A total of 1 point was given, meeting PM3. Additional cases have been reported but were not included because the residual GAA activity was not provided and therefore PP4 cannot be assessed (PMIDs 27896092, 25455803), or HGVS nomenclature was not used (PMID 24495340).","Two patients with Pompe disease and meeting the ClinGen LSD VCEP’s specifications for PP4 have been identified. One patient is compound heterozygous for the variant and c.1655T>C, phase unknown (p.Leu552Pro)(PMIDs 22538254)(0.5 points). The second patient was identified in a clinical laboratory and is compound heterozygous for the variant and c.-32-13T>G. The phase is unknown (0.5 points). A total of 1 point was given, meeting PM3. Additional cases have been reported but were not included because the residual GAA activity was not provided and therefore PP4 cannot be assessed (PMIDs 27896092, 25455803), or HGVS nomenclature was not used (PMID 24495340). ",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1356,NM_000152.4(GAA):c.1438-1G>C,GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-05-28,PM3,met,PubMed:24495340,,"Two patients with Pompe disease and meeting the ClinGen LSD VCEP’s specifications for PP4 have been identified. One patient is compound heterozygous for the variant and c.1655T>C, phase unknown (p.Leu552Pro)(PMIDs 22538254)(0.5 points). The second patient was identified in a clinical laboratory and is compound heterozygous for the variant and c.-32-13T>G. The phase is unknown (0.5 points). A total of 1 point was given, meeting PM3. Additional cases have been reported but were not included because the residual GAA activity was not provided and therefore PP4 cannot be assessed (PMIDs 27896092, 25455803), or HGVS nomenclature was not used (PMID 24495340).","Two patients with Pompe disease and meeting the ClinGen LSD VCEP’s specifications for PP4 have been identified. One patient is compound heterozygous for the variant and c.1655T>C, phase unknown (p.Leu552Pro)(PMIDs 22538254)(0.5 points). The second patient was identified in a clinical laboratory and is compound heterozygous for the variant and c.-32-13T>G. The phase is unknown (0.5 points). A total of 1 point was given, meeting PM3. Additional cases have been reported but were not included because the residual GAA activity was not provided and therefore PP4 cannot be assessed (PMIDs 27896092, 25455803), or HGVS nomenclature was not used (PMID 24495340). ",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1584,NM_000152.4(GAA):c.1128_1129delGGinsC (p.Trp376Cysfs),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-05-26,PM3,met,PubMed:29523196,"c.1128_1129delGGinsC was found in compound heterozygosity with a pathogenic variant, -32-13T>G, in an individual with late onset Pompe disease. The phase is unknown. No GAA activity data is available,and therefore this data will not be included. The patient is on ERT.","Two individuals have been reported who meet the ClinGen LSD VCEP’s specifications for PP4 and who are compound heterozygous for c.1128_1129delGGinsC (p.Trp376Cysfs) and a unique pathogenic variant in GAA; one individual has infantile-onset Pompe disease and is compound heterozygous for the variant and c.2237G>A (p.Trp746Ter), phase unknown (PMID: 22237443), the second individual has late onset Pompe disease and is compound heterozygous for the variant and c.-32-13T>G, phase unknown (PMID  26873529). Based on this data, PM3 can be applied. Additional cases have been reported but were not included for PM3 because the residual GAA activity was not reported and therefore PP4 cannot be assessed (PMIDs 29523196, 27408821), full HGVS nomenclature was not provided (PMID 20033296), or the second variant is a variant of unknown significance (PMID 18607768).","Two individuals have been reported who meet the ClinGen LSD VCEP’s specifications for PP4 and who are compound heterozygous for c.1128_1129delGGinsC (p.Trp376Cysfs) and a unique pathogenic variant in GAA; one individual has infantile-onset Pompe disease and is compound heterozygous for the variant and c.2237G>A (p.Trp746Ter), phase unknown (PMID: 22237443), the second individual has late onset Pompe disease and is compound heterozygous for the variant and c.-32-13T>G, phase unknown (PMID  26873529). Based on this data, PM3 can be applied. Additional cases have been reported but were not included for PM3 because the residual GAA activity was not reported and therefore PP4 cannot be assessed (PMIDs 29523196, 27408821), full HGVS nomenclature was not provided (PMID 20033296), or the second variant is a variant of unknown significance (PMID 18607768). c.1128_1129delGGinsC was found in compound heterozygosity with a pathogenic variant, -32-13T>G, in an individual with late onset Pompe disease. The phase is unknown. No GAA activity data is available,and therefore this data will not be included. The patient is on ERT.",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1585,NM_000152.4(GAA):c.1841C>A (p.Thr614Lys),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-05-28,PM3,met,PubMed:30564623,"Patient AOP13, with a prior clinical diagnosis of limb girdle muscular dystrophy, is compound heterozygous for c.1841C>A (p.Thr614Lys) and c.-32-13T>G. No individual GAA activity is provided, therefore this data will not be included.","The variant was found in compound heterozygosity in two patients published in the literature who meet the specifications for PP4. In one patient, the variant is in compound heterozygosity with c.1076–22T>G, phase unknown (PMID 21484825) (in trans data will be used for classification of c.1076–22T>G and is therefore not used here in order to avoid a circular argument), and in the other patient, the variant is in compound heterozygosity with c.-32-13T>G, phase unknown (PMID 24590251) (0.5 points). In addition, in a clinical laboratory, the variant was found in two patients with c.-32-13T>G (not counted because another patient with the same genotype, phase unknown, has already been included), one patient with c.2481+102_2646+31del (0.5 points), and one patient with c.1402A>T (p.Ile468Phe) (in trans data will be used for classification of p.Ile468Phe and is therefore not used here in order to avoid a circular argument), with all patients meeting PP4_Moderate and phase unknown. This data was given a total of 1 point, meeting PM3. Additional cases have been reported but were not included because the residual GAA activity was not reported and therefore PP4 cannot be assessed (PMIDs 25544546, 27708273, 30564623).","The variant was found in compound heterozygosity in two patients published in the literature who meet the specifications for PP4. In one patient, the variant is in compound heterozygosity with c.1076–22T>G, phase unknown (PMID 21484825) (in trans data will be used for classification of c.1076–22T>G and is therefore not used here in order to avoid a circular argument), and in the other patient, the variant is in compound heterozygosity with c.-32-13T>G, phase unknown (PMID 24590251) (0.5 points). In addition, in a clinical laboratory, the variant was found in two patients with c.-32-13T>G (not counted because another patient with the same genotype, phase unknown, has already been included), one patient with c.2481+102_2646+31del (0.5 points), and one patient with c.1402A>T (p.Ile468Phe) (in trans data will be used for classification of p.Ile468Phe and is therefore not used here in order to avoid a circular argument), with all patients meeting PP4_Moderate and phase unknown. This data was given a total of 1 point, meeting PM3. Additional cases have been reported but were not included because the residual GAA activity was not reported and therefore PP4 cannot be assessed (PMIDs 25544546, 27708273, 30564623). Patient AOP13, with a prior clinical diagnosis of limb girdle muscular dystrophy, is compound heterozygous for c.1841C>A (p.Thr614Lys) and c.-32-13T>G. No individual GAA activity is provided, therefore this data will not be included.",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1705,NM_000152.5(GAA):c.236_246del (p.Pro79fs),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-11-11,PM3,met,PubMed:23825616,,"This variant was found in compound heterozygosity with a unique pathogenic  variant in GAA in 2 patients with Pompe disease who also meet the ClinGen LSD VCEP's PP4 specifications, with either c.377G>A (p.Trp126Ter), in trans (PMID 17056254), or c.1655T>C (p.Leu552Pro), phase unknown (PMID 30778879). Based on the ClinGen LSD VCEP's specifications, this data was given a total of 1.5 points which meets PM3. Additional cases, both homozygous and compound heterozygous, have been reported but were not included because the residual GAA activity was not provided, and therefore PP4 cannot be assessed (PMIDs, 19588081, 22194990, 22980766, 23825616, 25998610, 26913919, 29143201, 30022036, 32125626).","This variant was found in compound heterozygosity with a unique pathogenic  variant in GAA in 2 patients with Pompe disease who also meet the ClinGen LSD VCEP's PP4 specifications, with either c.377G>A (p.Trp126Ter), in trans (PMID 17056254), or c.1655T>C (p.Leu552Pro), phase unknown (PMID 30778879). Based on the ClinGen LSD VCEP's specifications, this data was given a total of 1.5 points which meets PM3. Additional cases, both homozygous and compound heterozygous, have been reported but were not included because the residual GAA activity was not provided, and therefore PP4 cannot be assessed (PMIDs, 19588081, 22194990, 22980766, 23825616, 25998610, 26913919, 29143201, 30022036, 32125626). ",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1705,NM_000152.5(GAA):c.236_246del (p.Pro79fs),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-11-11,PM3,met,PubMed:30371346,,"This variant was found in compound heterozygosity with a unique pathogenic  variant in GAA in 2 patients with Pompe disease who also meet the ClinGen LSD VCEP's PP4 specifications, with either c.377G>A (p.Trp126Ter), in trans (PMID 17056254), or c.1655T>C (p.Leu552Pro), phase unknown (PMID 30778879). Based on the ClinGen LSD VCEP's specifications, this data was given a total of 1.5 points which meets PM3. Additional cases, both homozygous and compound heterozygous, have been reported but were not included because the residual GAA activity was not provided, and therefore PP4 cannot be assessed (PMIDs, 19588081, 22194990, 22980766, 23825616, 25998610, 26913919, 29143201, 30022036, 32125626).","This variant was found in compound heterozygosity with a unique pathogenic  variant in GAA in 2 patients with Pompe disease who also meet the ClinGen LSD VCEP's PP4 specifications, with either c.377G>A (p.Trp126Ter), in trans (PMID 17056254), or c.1655T>C (p.Leu552Pro), phase unknown (PMID 30778879). Based on the ClinGen LSD VCEP's specifications, this data was given a total of 1.5 points which meets PM3. Additional cases, both homozygous and compound heterozygous, have been reported but were not included because the residual GAA activity was not provided, and therefore PP4 cannot be assessed (PMIDs, 19588081, 22194990, 22980766, 23825616, 25998610, 26913919, 29143201, 30022036, 32125626). ",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1705,NM_000152.5(GAA):c.236_246del (p.Pro79fs),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-11-11,PM3,met,PubMed:22194990,,"This variant was found in compound heterozygosity with a unique pathogenic  variant in GAA in 2 patients with Pompe disease who also meet the ClinGen LSD VCEP's PP4 specifications, with either c.377G>A (p.Trp126Ter), in trans (PMID 17056254), or c.1655T>C (p.Leu552Pro), phase unknown (PMID 30778879). Based on the ClinGen LSD VCEP's specifications, this data was given a total of 1.5 points which meets PM3. Additional cases, both homozygous and compound heterozygous, have been reported but were not included because the residual GAA activity was not provided, and therefore PP4 cannot be assessed (PMIDs, 19588081, 22194990, 22980766, 23825616, 25998610, 26913919, 29143201, 30022036, 32125626).","This variant was found in compound heterozygosity with a unique pathogenic  variant in GAA in 2 patients with Pompe disease who also meet the ClinGen LSD VCEP's PP4 specifications, with either c.377G>A (p.Trp126Ter), in trans (PMID 17056254), or c.1655T>C (p.Leu552Pro), phase unknown (PMID 30778879). Based on the ClinGen LSD VCEP's specifications, this data was given a total of 1.5 points which meets PM3. Additional cases, both homozygous and compound heterozygous, have been reported but were not included because the residual GAA activity was not provided, and therefore PP4 cannot be assessed (PMIDs, 19588081, 22194990, 22980766, 23825616, 25998610, 26913919, 29143201, 30022036, 32125626). ",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1718,NM_000152.5(GAA):c.482_483del (p.Pro161fs),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-11-11,PM3,met,PubMed:32248831,,"Four individuals have been reported with Pompe disease who meet the ClinGen LSD VCEP's specifications for PP4. Of these individuals, two are compound heterozygous for c.-32-13T>G (PMID 9196050; 0.5 points given for PM3), and one is compound heterozygous for c.-32-3C>A (PMID 21550241, probably the same patient is also reported in PMIDs 30155607, 21803581). The phase is unknown in these cases. The in trans data for the latter patient, who is compound heterozygous for c.-32-3C>A, will be used in the assessment of that variant and was not included here in order to avoid a circular argument. Therefore, a total of 0.5 points was given, meeting PM3_Supporting. Additional patients have been reported but were not included because the residual GAA activity was not provided (and therefore PP4 cannot be assessed) or full HGVS nomenclature was not provided (PMIDs 11071489, 28648663, 32248831).","Four individuals have been reported with Pompe disease who meet the ClinGen LSD VCEP's specifications for PP4. Of these individuals, two are compound heterozygous for c.-32-13T>G (PMID 9196050; 0.5 points given for PM3), and one is compound heterozygous for c.-32-3C>A (PMID 21550241, probably the same patient is also reported in PMIDs 30155607, 21803581). The phase is unknown in these cases. The in trans data for the latter patient, who is compound heterozygous for c.-32-3C>A, will be used in the assessment of that variant and was not included here in order to avoid a circular argument. Therefore, a total of 0.5 points was given, meeting PM3_Supporting. Additional patients have been reported but were not included because the residual GAA activity was not provided (and therefore PP4 cannot be assessed) or full HGVS nomenclature was not provided (PMIDs 11071489, 28648663, 32248831). ",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
1739,NM_000152.5(GAA):c.1411_1414del (p.Glu471fs),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-11-12,PM3,not_met,PubMed:31510962,,"This variant has been reported multiple times in Asian patients with Pompe disease, either presenting clinically or identified by newborn screening. At least eight patients with Pompe disease and meeting the ClinGen LSD VCEP’s specifications for PP4 have been reported as compound heterozygous with either c.214C>A (p.Leu141Met), c.872T>C, (p.Leu291Pro), c.1933G>C (p.Asp645His), or c.1935C>A (p.Asp645Glu)  (PMIDs 8604985, 18458862, 24243590, 31510962). The in trans data for these patients will be used in the assessment of the missense variants and, therefore, was not included here in order to avoid circular logic. Additional patients with this variant have been reported but were not included because no residual GAA activity provided and, therefore, PP4 could not be assessed (PMIDs 10338092, 25466677, 27183828, 27692865, 28394184, 29122469), or pseudodeficiency alleles are present (PMID 19948615, 21232767, 23632029, 27183828). Of note, the variant has been reported to be in cis with two missense changes, c.[752C>T; 761C>T] (p.[Ser251Leu; Ser254Leu]) (PMIDs 20080426, 25466677, 27183828, 29122469). Based on this data, PM3 is not currently met.","This variant has been reported multiple times in Asian patients with Pompe disease, either presenting clinically or identified by newborn screening. At least eight patients with Pompe disease and meeting the ClinGen LSD VCEP’s specifications for PP4 have been reported as compound heterozygous with either c.214C>A (p.Leu141Met), c.872T>C, (p.Leu291Pro), c.1933G>C (p.Asp645His), or c.1935C>A (p.Asp645Glu)  (PMIDs 8604985, 18458862, 24243590, 31510962). The in trans data for these patients will be used in the assessment of the missense variants and, therefore, was not included here in order to avoid circular logic. Additional patients with this variant have been reported but were not included because no residual GAA activity provided and, therefore, PP4 could not be assessed (PMIDs 10338092, 25466677, 27183828, 27692865, 28394184, 29122469), or pseudodeficiency alleles are present (PMID 19948615, 21232767, 23632029, 27183828). Of note, the variant has been reported to be in cis with two missense changes, c.[752C>T; 761C>T] (p.[Ser251Leu; Ser254Leu]) (PMIDs 20080426, 25466677, 27183828, 29122469). Based on this data, PM3 is not currently met. ",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1739,NM_000152.5(GAA):c.1411_1414del (p.Glu471fs),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-11-12,PM3,not_met,PubMed:27183828,,"This variant has been reported multiple times in Asian patients with Pompe disease, either presenting clinically or identified by newborn screening. At least eight patients with Pompe disease and meeting the ClinGen LSD VCEP’s specifications for PP4 have been reported as compound heterozygous with either c.214C>A (p.Leu141Met), c.872T>C, (p.Leu291Pro), c.1933G>C (p.Asp645His), or c.1935C>A (p.Asp645Glu)  (PMIDs 8604985, 18458862, 24243590, 31510962). The in trans data for these patients will be used in the assessment of the missense variants and, therefore, was not included here in order to avoid circular logic. Additional patients with this variant have been reported but were not included because no residual GAA activity provided and, therefore, PP4 could not be assessed (PMIDs 10338092, 25466677, 27183828, 27692865, 28394184, 29122469), or pseudodeficiency alleles are present (PMID 19948615, 21232767, 23632029, 27183828). Of note, the variant has been reported to be in cis with two missense changes, c.[752C>T; 761C>T] (p.[Ser251Leu; Ser254Leu]) (PMIDs 20080426, 25466677, 27183828, 29122469). Based on this data, PM3 is not currently met.","This variant has been reported multiple times in Asian patients with Pompe disease, either presenting clinically or identified by newborn screening. At least eight patients with Pompe disease and meeting the ClinGen LSD VCEP’s specifications for PP4 have been reported as compound heterozygous with either c.214C>A (p.Leu141Met), c.872T>C, (p.Leu291Pro), c.1933G>C (p.Asp645His), or c.1935C>A (p.Asp645Glu)  (PMIDs 8604985, 18458862, 24243590, 31510962). The in trans data for these patients will be used in the assessment of the missense variants and, therefore, was not included here in order to avoid circular logic. Additional patients with this variant have been reported but were not included because no residual GAA activity provided and, therefore, PP4 could not be assessed (PMIDs 10338092, 25466677, 27183828, 27692865, 28394184, 29122469), or pseudodeficiency alleles are present (PMID 19948615, 21232767, 23632029, 27183828). Of note, the variant has been reported to be in cis with two missense changes, c.[752C>T; 761C>T] (p.[Ser251Leu; Ser254Leu]) (PMIDs 20080426, 25466677, 27183828, 29122469). Based on this data, PM3 is not currently met. ",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1344,NM_000152.3(GAA):c.118C>T (p.Arg40Ter),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-05-28,PM3-Supporting,not_met,PubMed:24107549,"Report of a family with 10 out of 13 siblings affected by late-onset Pompe disease. Three variants segregated in the family. One sibling, with a progressive undefined myopathy, was deceased. Seven siblings were compound heterozygous for c.118C>T (p.Arg40X) and c.2647-7G>A [p.Asn882fs] (VOUS based on the guidelines of the ClinGen LSD VCEP) in GAA. Of note, two other siblings are compound heterozygous for c.2276G>A (p.Gly759Arg) and c.2647-7G>A, and one unaffected sibling is heterozygous for c.2276G>C. While it is highly likely that the variants are in trans, parental testing results are unavailable. Six siblings with the p.Arg40X/c.2647-7G>A genotype had muscle GAA activity <10% the lower limit of normal.","The variant was found in compound heterozygosity with c.-32-13T>G, phase unknown, in two patients with Pompe disease who also meet the ClinGen LSD VCEP's PP4 criterion (PMID 22676651, 22958975). Additional compound heterozygous cases have been reported but were not included because the residual GAA activity was not provided and therefore PP4 cannot be assessed. In addition, a large sibship is reported with 7 affected siblings who are compound heterozygous for the variant and a variant of unknown significance, c.2647-7G>A (PMID 24107549). Based on the ClinGen LSD VCEP's specifications, this data was given a total of 0.5 points which meets PM3_Supporting.","The variant was found in compound heterozygosity with c.-32-13T>G, phase unknown, in two patients with Pompe disease who also meet the ClinGen LSD VCEP's PP4 criterion (PMID 22676651, 22958975). Additional compound heterozygous cases have been reported but were not included because the residual GAA activity was not provided and therefore PP4 cannot be assessed. In addition, a large sibship is reported with 7 affected siblings who are compound heterozygous for the variant and a variant of unknown significance, c.2647-7G>A (PMID 24107549). Based on the ClinGen LSD VCEP's specifications, this data was given a total of 0.5 points which meets PM3_Supporting. Report of a family with 10 out of 13 siblings affected by late-onset Pompe disease. Three variants segregated in the family. One sibling, with a progressive undefined myopathy, was deceased. Seven siblings were compound heterozygous for c.118C>T (p.Arg40X) and c.2647-7G>A [p.Asn882fs] (VOUS based on the guidelines of the ClinGen LSD VCEP) in GAA. Of note, two other siblings are compound heterozygous for c.2276G>A (p.Gly759Arg) and c.2647-7G>A, and one unaffected sibling is heterozygous for c.2276G>C. While it is highly likely that the variants are in trans, parental testing results are unavailable. Six siblings with the p.Arg40X/c.2647-7G>A genotype had muscle GAA activity <10% the lower limit of normal.",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1344,NM_000152.3(GAA):c.118C>T (p.Arg40Ter),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-05-28,PM3-Supporting,not_met,PubMed:29869463,"Patient CD_7 is compound heterozygous for c.188C>T and c.2015G>A, p.(Arg672Gln). The phase of the variants is unknown. The patient has reduced GAA activity but the level is not available.","The variant was found in compound heterozygosity with c.-32-13T>G, phase unknown, in two patients with Pompe disease who also meet the ClinGen LSD VCEP's PP4 criterion (PMID 22676651, 22958975). Additional compound heterozygous cases have been reported but were not included because the residual GAA activity was not provided and therefore PP4 cannot be assessed. In addition, a large sibship is reported with 7 affected siblings who are compound heterozygous for the variant and a variant of unknown significance, c.2647-7G>A (PMID 24107549). Based on the ClinGen LSD VCEP's specifications, this data was given a total of 0.5 points which meets PM3_Supporting.","The variant was found in compound heterozygosity with c.-32-13T>G, phase unknown, in two patients with Pompe disease who also meet the ClinGen LSD VCEP's PP4 criterion (PMID 22676651, 22958975). Additional compound heterozygous cases have been reported but were not included because the residual GAA activity was not provided and therefore PP4 cannot be assessed. In addition, a large sibship is reported with 7 affected siblings who are compound heterozygous for the variant and a variant of unknown significance, c.2647-7G>A (PMID 24107549). Based on the ClinGen LSD VCEP's specifications, this data was given a total of 0.5 points which meets PM3_Supporting. Patient CD_7 is compound heterozygous for c.188C>T and c.2015G>A, p.(Arg672Gln). The phase of the variants is unknown. The patient has reduced GAA activity but the level is not available.",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1344,NM_000152.3(GAA):c.118C>T (p.Arg40Ter),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-05-28,PM3-Supporting,not_met,PubMed:22676651,Patient 12 is compound heterozygous for c.118C>T (p.Arg40Ter) and c.-32-13T>G. The phase of the variants is unknown. GAA activity in lymphocytes is 0.5 (normal range of 9-42 nmole/mg/hr). (0.5 points),"The variant was found in compound heterozygosity with c.-32-13T>G, phase unknown, in two patients with Pompe disease who also meet the ClinGen LSD VCEP's PP4 criterion (PMID 22676651, 22958975). Additional compound heterozygous cases have been reported but were not included because the residual GAA activity was not provided and therefore PP4 cannot be assessed. In addition, a large sibship is reported with 7 affected siblings who are compound heterozygous for the variant and a variant of unknown significance, c.2647-7G>A (PMID 24107549). Based on the ClinGen LSD VCEP's specifications, this data was given a total of 0.5 points which meets PM3_Supporting.","The variant was found in compound heterozygosity with c.-32-13T>G, phase unknown, in two patients with Pompe disease who also meet the ClinGen LSD VCEP's PP4 criterion (PMID 22676651, 22958975). Additional compound heterozygous cases have been reported but were not included because the residual GAA activity was not provided and therefore PP4 cannot be assessed. In addition, a large sibship is reported with 7 affected siblings who are compound heterozygous for the variant and a variant of unknown significance, c.2647-7G>A (PMID 24107549). Based on the ClinGen LSD VCEP's specifications, this data was given a total of 0.5 points which meets PM3_Supporting. Patient 12 is compound heterozygous for c.118C>T (p.Arg40Ter) and c.-32-13T>G. The phase of the variants is unknown. GAA activity in lymphocytes is 0.5 (normal range of 9-42 nmole/mg/hr). (0.5 points)",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
1729,NM_000152.5(GAA):c.1143del (p.Ala382fs),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-11-12,PM3-Supporting,not_met,PubMed:30564623,,"At least five individuals with late onset Pompe disease (believed to be different individuals based on age of onset and age at report) who are compound heterozygous for the variant and c.-32-13T>G have been reported (PMIDs 22676651, 24383498, 25155446, 29122469, 29315315, 30564623), and three of them meet the ClinGen LSD VCEP’s specifications for PP4 (PMID 22676651, 29122469). The phase of the variants is unknown for all of these patients. PM3_Supporting (0.5 points) is met based on counting no more than one individual with the same genotype if not confirmed in trans.","At least five individuals with late onset Pompe disease (believed to be different individuals based on age of onset and age at report) who are compound heterozygous for the variant and c.-32-13T>G have been reported (PMIDs 22676651, 24383498, 25155446, 29122469, 29315315, 30564623), and three of them meet the ClinGen LSD VCEP’s specifications for PP4 (PMID 22676651, 29122469). The phase of the variants is unknown for all of these patients. PM3_Supporting (0.5 points) is met based on counting no more than one individual with the same genotype if not confirmed in trans. ",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1729,NM_000152.5(GAA):c.1143del (p.Ala382fs),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-11-12,PM3-Supporting,not_met,PubMed:29315315,,"At least five individuals with late onset Pompe disease (believed to be different individuals based on age of onset and age at report) who are compound heterozygous for the variant and c.-32-13T>G have been reported (PMIDs 22676651, 24383498, 25155446, 29122469, 29315315, 30564623), and three of them meet the ClinGen LSD VCEP’s specifications for PP4 (PMID 22676651, 29122469). The phase of the variants is unknown for all of these patients. PM3_Supporting (0.5 points) is met based on counting no more than one individual with the same genotype if not confirmed in trans.","At least five individuals with late onset Pompe disease (believed to be different individuals based on age of onset and age at report) who are compound heterozygous for the variant and c.-32-13T>G have been reported (PMIDs 22676651, 24383498, 25155446, 29122469, 29315315, 30564623), and three of them meet the ClinGen LSD VCEP’s specifications for PP4 (PMID 22676651, 29122469). The phase of the variants is unknown for all of these patients. PM3_Supporting (0.5 points) is met based on counting no more than one individual with the same genotype if not confirmed in trans. ",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1729,NM_000152.5(GAA):c.1143del (p.Ala382fs),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-11-12,PM3-Supporting,not_met,PubMed:22676651,,"At least five individuals with late onset Pompe disease (believed to be different individuals based on age of onset and age at report) who are compound heterozygous for the variant and c.-32-13T>G have been reported (PMIDs 22676651, 24383498, 25155446, 29122469, 29315315, 30564623), and three of them meet the ClinGen LSD VCEP’s specifications for PP4 (PMID 22676651, 29122469). The phase of the variants is unknown for all of these patients. PM3_Supporting (0.5 points) is met based on counting no more than one individual with the same genotype if not confirmed in trans.","At least five individuals with late onset Pompe disease (believed to be different individuals based on age of onset and age at report) who are compound heterozygous for the variant and c.-32-13T>G have been reported (PMIDs 22676651, 24383498, 25155446, 29122469, 29315315, 30564623), and three of them meet the ClinGen LSD VCEP’s specifications for PP4 (PMID 22676651, 29122469). The phase of the variants is unknown for all of these patients. PM3_Supporting (0.5 points) is met based on counting no more than one individual with the same genotype if not confirmed in trans. ",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1732,NM_000152.5(GAA):c.1192dup (p.Leu398fs),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-11-12,PM3-Supporting,not_met,PubMed:27711114,,"One patient meeting the ClinGen LSD VCEP's PP4 specifications is compound heterozygous for the variant and c.-32-13T>G pathogenic variant, phase unknown (PMID 17616415), meeting PM3_Supporting. Additional patients have been reported but were not included because the GAA activity was not provided and therefore PP4 cannot be assessed (PMIDs 22980766, 27711114).","One patient meeting the ClinGen LSD VCEP's PP4 specifications is compound heterozygous for the variant and c.-32-13T>G pathogenic variant, phase unknown (PMID 17616415), meeting PM3_Supporting. Additional patients have been reported but were not included because the GAA activity was not provided and therefore PP4 cannot be assessed (PMIDs 22980766, 27711114). ",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1734,NM_000152.5(GAA):c.1292_1295dup (p.Gln433fs),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-11-12,PM3-Supporting,not_met,PubMed:30214072,,"Three patients with Pompe disease and meeting the ClinGen LSD VCEP's specifications have been reported, including two patients with <1% GAA activity in skin fibroblasts (PMIDs 28814660, 29122469, 30214072, personal communication), and one patient with deficient activity on dried blood spot (PMID  32802993). One patient is compound heterozygous for the variant and c.2560C>T (p.Arg854Ter), a known pathogenic variant. The phase is unknown (PMIDs 28814660, 29122469, personal communication). The other two patients are compound heterozygous for the variant and a missense variant, either c.1019A>G (p.Tyr340Cys) (PMID 32802993) or c.953T>C (p.Met318Thr) (PMID 30214072). The phase is unknown. The in trans data from these latter two patients may be used in the assessment of the missense variants and was not included here in order to avoid circular logic. In total, 0.5 points was given towards PM3, meeting PM3_Supporting.","Three patients with Pompe disease and meeting the ClinGen LSD VCEP's specifications have been reported, including two patients with <1% GAA activity in skin fibroblasts (PMIDs 28814660, 29122469, 30214072, personal communication), and one patient with deficient activity on dried blood spot (PMID  32802993). One patient is compound heterozygous for the variant and c.2560C>T (p.Arg854Ter), a known pathogenic variant. The phase is unknown (PMIDs 28814660, 29122469, personal communication). The other two patients are compound heterozygous for the variant and a missense variant, either c.1019A>G (p.Tyr340Cys) (PMID 32802993) or c.953T>C (p.Met318Thr) (PMID 30214072). The phase is unknown. The in trans data from these latter two patients may be used in the assessment of the missense variants and was not included here in order to avoid circular logic. In total, 0.5 points was given towards PM3, meeting PM3_Supporting. ",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,PM3-Supporting,not_met,PubMed:29523196,,"An individual with late onset Pompe disease and meeting the ClinGen LSD VCEP’s specifications for PP4 who is compound heterozygous for the variant and c.-32-13T>G has been reported (PMID 22676651). In addition, twins meeting PP4 are compound heterozygous for the variant and c.1942G>A (p.Gly648Ser) (PMID 26575883). However, the in trans data from this family will be used in the assessment of p.Gly648Ser and is not included here in order to avoid circular logic. Other cases have been reported but were not included because the residual GAA activity was reported and therefore PP4 cannot be assessed (PMID 29523196), cDNA nomenclature was not provided (PMID 20033296), or pseudodeficiency alleles were present (PMID 21644219). This data meets PM3_Supporting.","An individual with late onset Pompe disease and meeting the ClinGen LSD VCEP’s specifications for PP4 who is compound heterozygous for the variant and c.-32-13T>G has been reported (PMID 22676651). In addition, twins meeting PP4 are compound heterozygous for the variant and c.1942G>A (p.Gly648Ser) (PMID 26575883). However, the in trans data from this family will be used in the assessment of p.Gly648Ser and is not included here in order to avoid circular logic. Other cases have been reported but were not included because the residual GAA activity was reported and therefore PP4 cannot be assessed (PMID 29523196), cDNA nomenclature was not provided (PMID 20033296), or pseudodeficiency alleles were present (PMID 21644219). This data meets PM3_Supporting. ",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1318,NM_000152.4(GAA):c.1051delG (p.Val351Cysfs),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-05-26,PP4,met,PubMed:22676651,Patient 4 has GAA activity in the affected range when compared to the laboratory’s control range.  GAA activity measured  in isolated lymphocytes with 4-methylumbelliferyl-α-D-glucopyranoside as substrate without acarbose was 0.01 nmole/mg/hr (normal range of 0.19-0.45 nmole/mg/hr),"Three individuals have been reported with this variant and GAA activity <10% normal in lymphocytes, leukocytes or muscle samples, or <30% normal in cultured fibroblasts, or in the affected range in a clinically validated dried blood spot assay (PMIDs 20033296, 20817528, 22676651). This meets the specifications for PP4.","Three individuals have been reported with this variant and GAA activity <10% normal in lymphocytes, leukocytes or muscle samples, or <30% normal in cultured fibroblasts, or in the affected range in a clinically validated dried blood spot assay (PMIDs 20033296, 20817528, 22676651). This meets the specifications for PP4. Patient 4 has GAA activity in the affected range when compared to the laboratory’s control range.  GAA activity measured  in isolated lymphocytes with 4-methylumbelliferyl-α-D-glucopyranoside as substrate without acarbose was 0.01 nmole/mg/hr (normal range of 0.19-0.45 nmole/mg/hr)",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1344,NM_000152.3(GAA):c.118C>T (p.Arg40Ter),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-05-28,PP4,met,PubMed:24107549,"Report of a family with 10 out of 13 siblings affected by late-onset Pompe disease. Three variants segregated in the family. One sibling, with a progressive undefined myopathy, was deceased. Seven siblings were compound heterozygous for c.118C > T [p.R40X] and c.2647-7G>A [p.N882fs] in GAA. Six siblings with this genotype had muscle GAA activity ranging from 2.3-3.1 pmol/min/mg protein (normal range 34 – 138) (<10% the lower limit of normal) and one (II-4) had GAA activity of 4.2 pmol/min/mg protein). In dried blood spots, the value was 0.09-0.31 (normal 1.86-219 nmol/h/l) in 6 siblings and 4.2 in II-4.","Multiple individuals have been reported with this variant and GAA activity <10% normal in lymphocytes, leukocytes or muscle samples, or <30% normal in cultured fibroblasts, or in the affected range in a clinically validated dried blood spot assay (PMIDs 24107549, 22958975, 22676651). This data meets the ClinGen LSD VCEP's specifications for PP4.","Multiple individuals have been reported with this variant and GAA activity <10% normal in lymphocytes, leukocytes or muscle samples, or <30% normal in cultured fibroblasts, or in the affected range in a clinically validated dried blood spot assay (PMIDs 24107549, 22958975, 22676651). This data meets the ClinGen LSD VCEP's specifications for PP4. Report of a family with 10 out of 13 siblings affected by late-onset Pompe disease. Three variants segregated in the family. One sibling, with a progressive undefined myopathy, was deceased. Seven siblings were compound heterozygous for c.118C > T [p.R40X] and c.2647-7G>A [p.N882fs] in GAA. Six siblings with this genotype had muscle GAA activity ranging from 2.3-3.1 pmol/min/mg protein (normal range 34 – 138) (<10% the lower limit of normal) and one (II-4) had GAA activity of 4.2 pmol/min/mg protein). In dried blood spots, the value was 0.09-0.31 (normal 1.86-219 nmol/h/l) in 6 siblings and 4.2 in II-4.",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1344,NM_000152.3(GAA):c.118C>T (p.Arg40Ter),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-05-28,PP4,met,PubMed:22676651,Patient 12 is compound heterozygous for c.118C>T (p.Arg40Ter) and c.-32-13T>G. The phase of the variants is unknown. GAA activity in lymphocytes is 0.5 (normal range of 9-42 nmole/mg/hr). (0.5 points),"Multiple individuals have been reported with this variant and GAA activity <10% normal in lymphocytes, leukocytes or muscle samples, or <30% normal in cultured fibroblasts, or in the affected range in a clinically validated dried blood spot assay (PMIDs 24107549, 22958975, 22676651). This data meets the ClinGen LSD VCEP's specifications for PP4.","Multiple individuals have been reported with this variant and GAA activity <10% normal in lymphocytes, leukocytes or muscle samples, or <30% normal in cultured fibroblasts, or in the affected range in a clinically validated dried blood spot assay (PMIDs 24107549, 22958975, 22676651). This data meets the ClinGen LSD VCEP's specifications for PP4. Patient 12 is compound heterozygous for c.118C>T (p.Arg40Ter) and c.-32-13T>G. The phase of the variants is unknown. GAA activity in lymphocytes is 0.5 (normal range of 9-42 nmole/mg/hr). (0.5 points)",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,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
1410,NM_000152.5(GAA):c.352C>T (p.Gln118Ter),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-06-03,PP4,met,PubMed:31342611,,"This variant has been reported in a patient with <30% normal GAA activity in skin fibroblasts (PMID 22252923, personal communication), meeting PP4.","This variant has been reported in a patient with <30% normal GAA activity in skin fibroblasts (PMID 22252923, personal communication), meeting 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
1320,NM_000152.5(GAA):c.655G>A (p.Gly219Arg),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-05-26,PM3-Strong,not_met,PubMed:23787031,,"At least eight individuals with Pompe disease and residual GAA activity meeting the ClinGen LSD VCEP’s specifications for PP4 have been reported. Of these individuals, four are compound heterozygous for the variant and another pathogenic variant in GAA, phase unknown, including c.-32-13T>G (PMID 21550241, 24844452; 0.5 points), c.169C>T (p.Gln57Ter) (PMID 29124014; 0.5 points), or c.2560C>T (p.Arg854Ter)(PMID 23266370; 0.5 points), and one is homozygous for the variant (PMID 25139343; 0.5 points). A total of 2 points were given, meeting PM3_Strong. A further three individuals are compound heterozygous for the variant and either c.1735G>A (p.Glu579Lys) (PMIDs 23601496, 31193175), c.546G>A (PMID 25037089), or c.784G>A (p.Glu262Lys) (PMID 11738358). However, the in trans data for these patients will be used in the assessment of those respective variants and was not included here in order to avoid a circular argument. Additional patients have been reported but were not included because the residual GAA activity was not reported and therefore PP4 cannot be assessed, patients with the same genotype had already been included, or no cDNA sequence change was provided for the variant (PMIDs 14695532, 18429042, 20033296, 21550241, 23787031, 25139343, 27711114, 30023291, 30155607).","At least eight individuals with Pompe disease and residual GAA activity meeting the ClinGen LSD VCEP’s specifications for PP4 have been reported. Of these individuals, four are compound heterozygous for the variant and another pathogenic variant in GAA, phase unknown, including c.-32-13T>G (PMID 21550241, 24844452; 0.5 points), c.169C>T (p.Gln57Ter) (PMID 29124014; 0.5 points), or c.2560C>T (p.Arg854Ter)(PMID 23266370; 0.5 points), and one is homozygous for the variant (PMID 25139343; 0.5 points). A total of 2 points were given, meeting PM3_Strong. A further three individuals are compound heterozygous for the variant and either c.1735G>A (p.Glu579Lys) (PMIDs 23601496, 31193175), c.546G>A (PMID 25037089), or c.784G>A (p.Glu262Lys) (PMID 11738358). However, the in trans data for these patients will be used in the assessment of those respective variants and was not included here in order to avoid a circular argument. Additional patients have been reported but were not included because the residual GAA activity was not reported and therefore PP4 cannot be assessed, patients with the same genotype had already been included, or no cDNA sequence change was provided for the variant (PMIDs 14695532, 18429042, 20033296, 21550241, 23787031, 25139343, 27711114, 30023291, 30155607). ",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1320,NM_000152.5(GAA):c.655G>A (p.Gly219Arg),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-05-26,PM3-Strong,not_met,PubMed:31193175,,"At least eight individuals with Pompe disease and residual GAA activity meeting the ClinGen LSD VCEP’s specifications for PP4 have been reported. Of these individuals, four are compound heterozygous for the variant and another pathogenic variant in GAA, phase unknown, including c.-32-13T>G (PMID 21550241, 24844452; 0.5 points), c.169C>T (p.Gln57Ter) (PMID 29124014; 0.5 points), or c.2560C>T (p.Arg854Ter)(PMID 23266370; 0.5 points), and one is homozygous for the variant (PMID 25139343; 0.5 points). A total of 2 points were given, meeting PM3_Strong. A further three individuals are compound heterozygous for the variant and either c.1735G>A (p.Glu579Lys) (PMIDs 23601496, 31193175), c.546G>A (PMID 25037089), or c.784G>A (p.Glu262Lys) (PMID 11738358). However, the in trans data for these patients will be used in the assessment of those respective variants and was not included here in order to avoid a circular argument. Additional patients have been reported but were not included because the residual GAA activity was not reported and therefore PP4 cannot be assessed, patients with the same genotype had already been included, or no cDNA sequence change was provided for the variant (PMIDs 14695532, 18429042, 20033296, 21550241, 23787031, 25139343, 27711114, 30023291, 30155607).","At least eight individuals with Pompe disease and residual GAA activity meeting the ClinGen LSD VCEP’s specifications for PP4 have been reported. Of these individuals, four are compound heterozygous for the variant and another pathogenic variant in GAA, phase unknown, including c.-32-13T>G (PMID 21550241, 24844452; 0.5 points), c.169C>T (p.Gln57Ter) (PMID 29124014; 0.5 points), or c.2560C>T (p.Arg854Ter)(PMID 23266370; 0.5 points), and one is homozygous for the variant (PMID 25139343; 0.5 points). A total of 2 points were given, meeting PM3_Strong. A further three individuals are compound heterozygous for the variant and either c.1735G>A (p.Glu579Lys) (PMIDs 23601496, 31193175), c.546G>A (PMID 25037089), or c.784G>A (p.Glu262Lys) (PMID 11738358). However, the in trans data for these patients will be used in the assessment of those respective variants and was not included here in order to avoid a circular argument. Additional patients have been reported but were not included because the residual GAA activity was not reported and therefore PP4 cannot be assessed, patients with the same genotype had already been included, or no cDNA sequence change was provided for the variant (PMIDs 14695532, 18429042, 20033296, 21550241, 23787031, 25139343, 27711114, 30023291, 30155607). ",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1320,NM_000152.5(GAA):c.655G>A (p.Gly219Arg),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-05-26,PM3-Strong,not_met,PubMed:27711114,,"At least eight individuals with Pompe disease and residual GAA activity meeting the ClinGen LSD VCEP’s specifications for PP4 have been reported. Of these individuals, four are compound heterozygous for the variant and another pathogenic variant in GAA, phase unknown, including c.-32-13T>G (PMID 21550241, 24844452; 0.5 points), c.169C>T (p.Gln57Ter) (PMID 29124014; 0.5 points), or c.2560C>T (p.Arg854Ter)(PMID 23266370; 0.5 points), and one is homozygous for the variant (PMID 25139343; 0.5 points). A total of 2 points were given, meeting PM3_Strong. A further three individuals are compound heterozygous for the variant and either c.1735G>A (p.Glu579Lys) (PMIDs 23601496, 31193175), c.546G>A (PMID 25037089), or c.784G>A (p.Glu262Lys) (PMID 11738358). However, the in trans data for these patients will be used in the assessment of those respective variants and was not included here in order to avoid a circular argument. Additional patients have been reported but were not included because the residual GAA activity was not reported and therefore PP4 cannot be assessed, patients with the same genotype had already been included, or no cDNA sequence change was provided for the variant (PMIDs 14695532, 18429042, 20033296, 21550241, 23787031, 25139343, 27711114, 30023291, 30155607).","At least eight individuals with Pompe disease and residual GAA activity meeting the ClinGen LSD VCEP’s specifications for PP4 have been reported. Of these individuals, four are compound heterozygous for the variant and another pathogenic variant in GAA, phase unknown, including c.-32-13T>G (PMID 21550241, 24844452; 0.5 points), c.169C>T (p.Gln57Ter) (PMID 29124014; 0.5 points), or c.2560C>T (p.Arg854Ter)(PMID 23266370; 0.5 points), and one is homozygous for the variant (PMID 25139343; 0.5 points). A total of 2 points were given, meeting PM3_Strong. A further three individuals are compound heterozygous for the variant and either c.1735G>A (p.Glu579Lys) (PMIDs 23601496, 31193175), c.546G>A (PMID 25037089), or c.784G>A (p.Glu262Lys) (PMID 11738358). However, the in trans data for these patients will be used in the assessment of those respective variants and was not included here in order to avoid a circular argument. Additional patients have been reported but were not included because the residual GAA activity was not reported and therefore PP4 cannot be assessed, patients with the same genotype had already been included, or no cDNA sequence change was provided for the variant (PMIDs 14695532, 18429042, 20033296, 21550241, 23787031, 25139343, 27711114, 30023291, 30155607). ",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1320,NM_000152.5(GAA):c.655G>A (p.Gly219Arg),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-05-26,PM3-Strong,not_met,PubMed:30023291,,"At least eight individuals with Pompe disease and residual GAA activity meeting the ClinGen LSD VCEP’s specifications for PP4 have been reported. Of these individuals, four are compound heterozygous for the variant and another pathogenic variant in GAA, phase unknown, including c.-32-13T>G (PMID 21550241, 24844452; 0.5 points), c.169C>T (p.Gln57Ter) (PMID 29124014; 0.5 points), or c.2560C>T (p.Arg854Ter)(PMID 23266370; 0.5 points), and one is homozygous for the variant (PMID 25139343; 0.5 points). A total of 2 points were given, meeting PM3_Strong. A further three individuals are compound heterozygous for the variant and either c.1735G>A (p.Glu579Lys) (PMIDs 23601496, 31193175), c.546G>A (PMID 25037089), or c.784G>A (p.Glu262Lys) (PMID 11738358). However, the in trans data for these patients will be used in the assessment of those respective variants and was not included here in order to avoid a circular argument. Additional patients have been reported but were not included because the residual GAA activity was not reported and therefore PP4 cannot be assessed, patients with the same genotype had already been included, or no cDNA sequence change was provided for the variant (PMIDs 14695532, 18429042, 20033296, 21550241, 23787031, 25139343, 27711114, 30023291, 30155607).","At least eight individuals with Pompe disease and residual GAA activity meeting the ClinGen LSD VCEP’s specifications for PP4 have been reported. Of these individuals, four are compound heterozygous for the variant and another pathogenic variant in GAA, phase unknown, including c.-32-13T>G (PMID 21550241, 24844452; 0.5 points), c.169C>T (p.Gln57Ter) (PMID 29124014; 0.5 points), or c.2560C>T (p.Arg854Ter)(PMID 23266370; 0.5 points), and one is homozygous for the variant (PMID 25139343; 0.5 points). A total of 2 points were given, meeting PM3_Strong. A further three individuals are compound heterozygous for the variant and either c.1735G>A (p.Glu579Lys) (PMIDs 23601496, 31193175), c.546G>A (PMID 25037089), or c.784G>A (p.Glu262Lys) (PMID 11738358). However, the in trans data for these patients will be used in the assessment of those respective variants and was not included here in order to avoid a circular argument. Additional patients have been reported but were not included because the residual GAA activity was not reported and therefore PP4 cannot be assessed, patients with the same genotype had already been included, or no cDNA sequence change was provided for the variant (PMIDs 14695532, 18429042, 20033296, 21550241, 23787031, 25139343, 27711114, 30023291, 30155607). ",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1320,NM_000152.5(GAA):c.655G>A (p.Gly219Arg),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-05-26,PM3-Strong,not_met,PubMed:29124014,,"At least eight individuals with Pompe disease and residual GAA activity meeting the ClinGen LSD VCEP’s specifications for PP4 have been reported. Of these individuals, four are compound heterozygous for the variant and another pathogenic variant in GAA, phase unknown, including c.-32-13T>G (PMID 21550241, 24844452; 0.5 points), c.169C>T (p.Gln57Ter) (PMID 29124014; 0.5 points), or c.2560C>T (p.Arg854Ter)(PMID 23266370; 0.5 points), and one is homozygous for the variant (PMID 25139343; 0.5 points). A total of 2 points were given, meeting PM3_Strong. A further three individuals are compound heterozygous for the variant and either c.1735G>A (p.Glu579Lys) (PMIDs 23601496, 31193175), c.546G>A (PMID 25037089), or c.784G>A (p.Glu262Lys) (PMID 11738358). However, the in trans data for these patients will be used in the assessment of those respective variants and was not included here in order to avoid a circular argument. Additional patients have been reported but were not included because the residual GAA activity was not reported and therefore PP4 cannot be assessed, patients with the same genotype had already been included, or no cDNA sequence change was provided for the variant (PMIDs 14695532, 18429042, 20033296, 21550241, 23787031, 25139343, 27711114, 30023291, 30155607).","At least eight individuals with Pompe disease and residual GAA activity meeting the ClinGen LSD VCEP’s specifications for PP4 have been reported. Of these individuals, four are compound heterozygous for the variant and another pathogenic variant in GAA, phase unknown, including c.-32-13T>G (PMID 21550241, 24844452; 0.5 points), c.169C>T (p.Gln57Ter) (PMID 29124014; 0.5 points), or c.2560C>T (p.Arg854Ter)(PMID 23266370; 0.5 points), and one is homozygous for the variant (PMID 25139343; 0.5 points). A total of 2 points were given, meeting PM3_Strong. A further three individuals are compound heterozygous for the variant and either c.1735G>A (p.Glu579Lys) (PMIDs 23601496, 31193175), c.546G>A (PMID 25037089), or c.784G>A (p.Glu262Lys) (PMID 11738358). However, the in trans data for these patients will be used in the assessment of those respective variants and was not included here in order to avoid a circular argument. Additional patients have been reported but were not included because the residual GAA activity was not reported and therefore PP4 cannot be assessed, patients with the same genotype had already been included, or no cDNA sequence change was provided for the variant (PMIDs 14695532, 18429042, 20033296, 21550241, 23787031, 25139343, 27711114, 30023291, 30155607). ",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1731,NM_000152.5(GAA):c.525del (p.Glu176fs),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-11-12,PM3-Very Strong,not_met,PubMed:29149851,,"c.525delT is one of the most common GAA variants and has been reported in more than 70 patients with Pompe disease (http://www.pompevariantdatabase.nl/). Thirty patients meeting the ClinGen LSD VCEP's specifications for PP4 are listed here (PMIDs 8558570, 24590251, 25243733, 26497565, 27142047, 29422078) and include patients who are homozygous for the variant, or compound heterozygous for the variant and either c.-32-13T>G, exon 18 deletion, c.1802C>A (p.Ser601Ter), c.2608C>T (p.Arg870Ter), c.1548G>A (p.Trp516Ter), c.2237G>A (p.Trp746Ter), and c.670C>T (p.Arg224Trp). The maximum strength for PM3 was applied (PM3_VeryStrong).","c.525delT is one of the most common GAA variants and has been reported in more than 70 patients with Pompe disease (http://www.pompevariantdatabase.nl/). Thirty patients meeting the ClinGen LSD VCEP's specifications for PP4 are listed here (PMIDs 8558570, 24590251, 25243733, 26497565, 27142047, 29422078) and include patients who are homozygous for the variant, or compound heterozygous for the variant and either c.-32-13T>G, exon 18 deletion, c.1802C>A (p.Ser601Ter), c.2608C>T (p.Arg870Ter), c.1548G>A (p.Trp516Ter), c.2237G>A (p.Trp746Ter), and c.670C>T (p.Arg224Trp). The maximum strength for PM3 was applied (PM3_VeryStrong). ",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1731,NM_000152.5(GAA):c.525del (p.Glu176fs),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-11-12,PM3-Very Strong,not_met,PubMed:29422078,,"c.525delT is one of the most common GAA variants and has been reported in more than 70 patients with Pompe disease (http://www.pompevariantdatabase.nl/). Thirty patients meeting the ClinGen LSD VCEP's specifications for PP4 are listed here (PMIDs 8558570, 24590251, 25243733, 26497565, 27142047, 29422078) and include patients who are homozygous for the variant, or compound heterozygous for the variant and either c.-32-13T>G, exon 18 deletion, c.1802C>A (p.Ser601Ter), c.2608C>T (p.Arg870Ter), c.1548G>A (p.Trp516Ter), c.2237G>A (p.Trp746Ter), and c.670C>T (p.Arg224Trp). The maximum strength for PM3 was applied (PM3_VeryStrong).","c.525delT is one of the most common GAA variants and has been reported in more than 70 patients with Pompe disease (http://www.pompevariantdatabase.nl/). Thirty patients meeting the ClinGen LSD VCEP's specifications for PP4 are listed here (PMIDs 8558570, 24590251, 25243733, 26497565, 27142047, 29422078) and include patients who are homozygous for the variant, or compound heterozygous for the variant and either c.-32-13T>G, exon 18 deletion, c.1802C>A (p.Ser601Ter), c.2608C>T (p.Arg870Ter), c.1548G>A (p.Trp516Ter), c.2237G>A (p.Trp746Ter), and c.670C>T (p.Arg224Trp). The maximum strength for PM3 was applied (PM3_VeryStrong). ",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
8834,NM_000203.5(IDUA):c.544G>A (p.Glu182Lys),IDUA,mucopolysaccharidosis type 1,MONDO:0001586,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2024-12-16,PS3-Supporting,not_met,PubMed:33198351,"After viral delivery of IDUA cDNA containing the variant into IDUA-deficient HAP1 cells and isolation of single cell expression clones, enzyme activity was measured for two clones (p.Glu182Lys-C5, p.Glu182Lys-D1) and was extremely low (0.0076 and 0.0003% of WT for activity/total protein; and 0.031% and 0.001% WT activity/enzyme abundance respectively). The authors describe the variant as “catalytically dead” and use is as a control for an variant that obliterates the activity.
","When expressed in CHO cells and HAP1 cells , the variant resulted in no IDUA activity across multiple studies (PMID: 11555618, 12559846, 33198351) (PS3_Supporting).","When expressed in CHO cells and HAP1 cells , the variant resulted in no IDUA activity across multiple studies (PMID: 11555618, 12559846, 33198351) (PS3_Supporting). After viral delivery of IDUA cDNA containing the variant into IDUA-deficient HAP1 cells and isolation of single cell expression clones, enzyme activity was measured for two clones (p.Glu182Lys-C5, p.Glu182Lys-D1) and was extremely low (0.0076 and 0.0003% of WT for activity/total protein; and 0.031% and 0.001% WT activity/enzyme abundance respectively). The authors describe the variant as “catalytically dead” and use is as a control for an variant that obliterates the activity.
",ClinGenLysosomalDiseasesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforIDUAVersion1.0.0_version=1.0.0.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
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
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
182,NM_000257.3(MYH7):c.2722C>G (p.Leu908Val),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PS4,met,PubMed:27532257,Variant identified in 5 probands with HCM,>20 probands with HCM including ClinVar SCV000059471.5; ClinVar SCV000692499.1; SHaRe data,>20 probands with HCM including ClinVar SCV000059471.5; ClinVar SCV000692499.1; SHaRe data Variant identified in 5 probands with HCM,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
183,NM_000257.3(MYH7):c.2717A>G (p.Asp906Gly),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PS4,met,PubMed:27532257,Variant identified in 7 probands with HCM,Variant identified in >20 probands with HCM including ClinVar SCV000059468.5,Variant identified in >20 probands with HCM including ClinVar SCV000059468.5 Variant identified in 7 probands with HCM,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
186,NM_000257.3(MYH7):c.2609G>A (p.Arg870His),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PS4,met,PubMed:27532257,Variant identified in 13 probands with HCM,>20 probands with HCM including ClinVar SCV000059458.5 and SHaRe data,>20 probands with HCM including ClinVar SCV000059458.5 and SHaRe data Variant identified in 13 probands with HCM,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
194,NM_000257.3(MYH7):c.2167C>T (p.Arg723Cys),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PS4,met,PubMed:27532257,Variant identified in 4 probands with HCM,Variant identified in >20 probands with HCM (including ClinVar SCV000059423.5 and ClinVar SCV000212630.1),Variant identified in >20 probands with HCM (including ClinVar SCV000059423.5 and ClinVar SCV000212630.1) Variant identified in 4 probands with HCM,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,PS4,met,PubMed:27532257,Variant identified in 1 proband with HCM,12 proband with HCM including ClinVar SCV000059422.5 and SHaRe data,12 proband with HCM including ClinVar SCV000059422.5 and SHaRe data Variant identified in 1 proband with HCM,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,PS4,met,PubMed:18411228,Variant identified in 1 proband with HCM,">30 probands with HCM including SHaRe data, ClinVar SCV000059421.5 and ClinVar SCV000212634.1",">30 probands with HCM including SHaRe data, ClinVar SCV000059421.5 and ClinVar SCV000212634.1 Variant identified in 1 proband with HCM",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,PS4,met,PubMed:27532257,Variant identified in 4 probands with HCM,>20 probands with HCM (icluding SHaRe data and ClinVar SCV000059419.5),>20 probands with HCM (icluding SHaRe data and ClinVar SCV000059419.5) Variant identified in 4 probands with HCM,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,PS4,met,PubMed:22429680,Variant identified in 1 proband with HCM,>20 probands with HCM (icluding SHaRe data and ClinVar SCV000059419.5),>20 probands with HCM (icluding SHaRe data and ClinVar SCV000059419.5) Variant identified in 1 proband with HCM,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,PS4,met,PubMed:27532257,Variant identified in cases with HCM,>30 probands with HCM (including ClinVar SCV000212629.1; ClinVar SCV000219103.7; ClinVar SCV000059409.5; SHaRe data),>30 probands with HCM (including ClinVar SCV000212629.1; ClinVar SCV000219103.7; ClinVar SCV000059409.5; SHaRe data) Variant identified in cases with HCM,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,PS4,met,PubMed:27532257,Variant identified in 4 probands with HCM,>25 probands with HCM (including data from: ClinVar SCV000692503.1; ClinVar SCV000253815.4; ClinVar SCV000059359.5; SHaRe data),>25 probands with HCM (including data from: ClinVar SCV000692503.1; ClinVar SCV000253815.4; ClinVar SCV000059359.5; SHaRe data) Variant identified in 4 probands with HCM,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,PS4,met,PubMed:22429680,Variant identified in proband with HCM. Proband also carried Q882E variant in MYH7,">12 probands with HCM including ClinVar SCV000059369.5, ClinVar SCV000253816.4, SHaRe data",">12 probands with HCM including ClinVar SCV000059369.5, ClinVar SCV000253816.4, SHaRe data Variant identified in proband with HCM. Proband also carried Q882E variant in MYH7",ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
2308,NM_000257.3(MYH7):c.3981C>A (p.Asn1327Lys),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Likely Benign,Autosomal dominant inheritance,Cardiomyopathy,2021-06-16,PS4,not_met,PubMed:27532257,Variant identified in 2 probands with HCM,">15 probands with HCM identified (including ClinVar SCV000059529.5, ClinVar SCV000254446.5, and SHaRe data) however PS4 not applied as PM2 criterion was not met",">15 probands with HCM identified (including ClinVar SCV000059529.5, ClinVar SCV000254446.5, and SHaRe data) however PS4 not applied as PM2 criterion was not met Variant identified in 2 probands with HCM",ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
174,NM_000257.4(MYH7):c.5740G>A (p.Glu1914Lys),MYH7,dilated cardiomyopathy,MONDO:0005021,Likely Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2021-08-25,PS4-Moderate,not_met,PubMed:27532257,Variant identified in 1 proband with DCM,"SUMMARY: The c.5740G>A (p.Glu1914Lys) variant in MYH7 has been reported in 7 individuals with complex cardiomyopathy presentations, including predominantly dilated cardiomyopathy, features of LVNC, and restrictive physiology with early-onset in multiple instances (Lakdawala 2012 PMID22464770; Pugh 2014 PMID24503780; Lamont 2015 PMID:20301606; Walsh 2017 PMID:27532257; Wang 2017 PMID:28855170; Miura 2019 PMID:30996762).


LMM - Seen in 1 proband with DCM (same as Lakdawala 2012, Pugh 2014, and Walsh 2017)
Pugh 2014 PMID24503780 - Seen in 1 proband with DCM at LMM (same as Lakdawala)
Lakdawala 2012 PMID22464770 - Seen in 1 proband with DCM at LMM

GeneDx - Seen in 1 proband with NICM and LVNC s/p heart transplant at 19 yo

Walsh 2017 PMID:27532257 - Seen in 1 proband with DCM from OMGL (Paper lists at HCM, but per Kate Thomson the referral was for HCM, but they had a clinical diagnosis of DCM) & 1 proband with DCM from LMM (same as Lakdawala 2012 & Pugh 2014)

Lamont 2014 PMID:24664454 - Seen as de novo (parentage confirmed by haplotyping - mentioned in discussion section) in 2 infants with features of DCM and myopathy

Lamont 2015 PMID:20301606 - GeneReviews summary, mentions variant and references back to 2014 article

Wang 2017 PMID:28855170 - Seen in 1 Japanese proband with LVNC with reduced EF (limited details on participants provided in Supp Table S7)

Miura 2019 PMID:30996762 - Seen in 3 siblings with biventricular LVNC and restrictive physiology (need clinician input to confirm phenotype details)

PMID: 29624713 - unclear if included, unable to access
Martinez 2020 In press (no PMID)","SUMMARY: The c.5740G>A (p.Glu1914Lys) variant in MYH7 has been reported in 7 individuals with complex cardiomyopathy presentations, including predominantly dilated cardiomyopathy, features of LVNC, and restrictive physiology with early-onset in multiple instances (Lakdawala 2012 PMID22464770; Pugh 2014 PMID24503780; Lamont 2015 PMID:20301606; Walsh 2017 PMID:27532257; Wang 2017 PMID:28855170; Miura 2019 PMID:30996762).


LMM - Seen in 1 proband with DCM (same as Lakdawala 2012, Pugh 2014, and Walsh 2017)
Pugh 2014 PMID24503780 - Seen in 1 proband with DCM at LMM (same as Lakdawala)
Lakdawala 2012 PMID22464770 - Seen in 1 proband with DCM at LMM

GeneDx - Seen in 1 proband with NICM and LVNC s/p heart transplant at 19 yo

Walsh 2017 PMID:27532257 - Seen in 1 proband with DCM from OMGL (Paper lists at HCM, but per Kate Thomson the referral was for HCM, but they had a clinical diagnosis of DCM) & 1 proband with DCM from LMM (same as Lakdawala 2012 & Pugh 2014)

Lamont 2014 PMID:24664454 - Seen as de novo (parentage confirmed by haplotyping - mentioned in discussion section) in 2 infants with features of DCM and myopathy

Lamont 2015 PMID:20301606 - GeneReviews summary, mentions variant and references back to 2014 article

Wang 2017 PMID:28855170 - Seen in 1 Japanese proband with LVNC with reduced EF (limited details on participants provided in Supp Table S7)

Miura 2019 PMID:30996762 - Seen in 3 siblings with biventricular LVNC and restrictive physiology (need clinician input to confirm phenotype details)

PMID: 29624713 - unclear if included, unable to access
Martinez 2020 In press (no PMID) Variant identified in 1 proband with DCM",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
254,NM_000257.3(MYH7):c.1207C>T (p.Arg403Trp),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PP1-Strong,not_met,PubMed:17612745,Variant segregated with disease in 11 family members,>20 segregations,>20 segregations Variant segregated with disease in 11 family members,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
4003,NM_000257.4(MYH7):c.709C>T (p.Arg237Trp),MYH7,dilated cardiomyopathy,MONDO:0005021,Likely Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2022-07-30,PS3,not_met,PubMed:29867217,"Measure the detachment rate of single molecules of human β-cardiac myosin and its load dependence. We find that both can be modulated by both small-molecule compounds and cardiomyopathy-causing mutations. Furthermore, effects of mutations can be reversed by introducing appropriate compounds.","Please review both papers below to determine if studies are eligible for consideration towards this rule. 
PMID: 29666183 and PMID: 29867217 - I do not understand the implications of the results 

In vitro and in silico functional studies provide some evidence that this variant impacts protein function; however, this data is currently insufficient to establish functional impact and apply PS3 (Ujfalusi 2018 PMID:29666183; Liu 2018 PMID:29867217).","Please review both papers below to determine if studies are eligible for consideration towards this rule. 
PMID: 29666183 and PMID: 29867217 - I do not understand the implications of the results 

In vitro and in silico functional studies provide some evidence that this variant impacts protein function; however, this data is currently insufficient to establish functional impact and apply PS3 (Ujfalusi 2018 PMID:29666183; Liu 2018 PMID:29867217). Measure the detachment rate of single molecules of human β-cardiac myosin and its load dependence. We find that both can be modulated by both small-molecule compounds and cardiomyopathy-causing mutations. Furthermore, effects of mutations can be reversed by introducing appropriate compounds.",ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
4003,NM_000257.4(MYH7):c.709C>T (p.Arg237Trp),MYH7,dilated cardiomyopathy,MONDO:0005021,Likely Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2022-07-30,BS3,not_met,PubMed:29867217,"Measure the detachment rate of single molecules of human β-cardiac myosin and its load dependence. We find that both can be modulated by both small-molecule compounds and cardiomyopathy-causing mutations. Furthermore, effects of mutations can be reversed by introducing appropriate compounds.",," Measure the detachment rate of single molecules of human β-cardiac myosin and its load dependence. We find that both can be modulated by both small-molecule compounds and cardiomyopathy-causing mutations. Furthermore, effects of mutations can be reversed by introducing appropriate compounds.",ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.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
353,NM_004333.4(BRAF):c.1785T>G (p.Phe595Leu),BRAF,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 BRAF (PM1; PMID 29493581, 16439621).","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 BRAF (PM1; PMID 29493581, 16439621).","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 BRAF (PM1; PMID 29493581, 16439621). 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 BRAF (PM1; PMID 29493581, 16439621).",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.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
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
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
400,NM_004333.4(BRAF):c.770A>G (p.Gln257Arg),BRAF,cardiofaciocutaneous syndrome,MONDO:0015280,Pathogenic,Autosomal dominant inheritance,RASopathy,2018-12-10,PS3,met,PubMed:19376813,Phosphorylation of myelin basic protein in a coupled MEK/ERK2 kinase assay,, Phosphorylation of myelin basic protein in a coupled MEK/ERK2 kinase assay,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,PS3,met,PubMed:24935154,Mutant exhibited reduced catalytic activity,"In vitro functional studies provide some evidence that the p.Thr468Met variant may impact protein function (PS3; PMID: 24935154, 18372317, 16638574, 18849586).","In vitro functional studies provide some evidence that the p.Thr468Met variant may impact protein function (PS3; PMID: 24935154, 18372317, 16638574, 18849586). Mutant exhibited reduced catalytic activity",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
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
1237,NM_002834.4(PTPN11):c.782T>A (p.Leu261His),PTPN11,RASopathy,MONDO:0021060,Likely Pathogenic,Autosomal dominant inheritance,RASopathy,2020-03-24,PS4,met,PubMed:22253195,,"This variant was observed in 7 probands with Noonan syndrome (PMID: 28074573, 22253195, 23756559).","This variant was observed in 7 probands with Noonan syndrome (PMID: 28074573, 22253195, 23756559). ",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
1237,NM_002834.4(PTPN11):c.782T>A (p.Leu261His),PTPN11,RASopathy,MONDO:0021060,Likely Pathogenic,Autosomal dominant inheritance,RASopathy,2020-03-24,PS4,met,PubMed:23756559,,"This variant was observed in 7 probands with Noonan syndrome (PMID: 28074573, 22253195, 23756559).","This variant was observed in 7 probands with Noonan syndrome (PMID: 28074573, 22253195, 23756559). ",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,PS4,met,PubMed:21387466,"Four cohorts were included in this study...143 clinically well-characterized patients with NS of European/Italian ancestry, patients from the Sarkozy 2009 study, (N= 358) anonymous samples from individuals with phenotypes suggestive of NS from commercial DNA diagnostic testing, finally a cohort of 59 subjects with nonsyndromic CHD's. This was a large study of patients with clinical features of a RASopathy that has been described elsewhere. This study describes c.1656G>C (p.Arg552Ser) in 2 sporadic, 7 fam unknown cases","This variant was reported in at least 7 patients with clinical features of NS (PMID: 26297936, 25862627, 17143282, 21387466, 19020799, 23885229, 22190897, 19352411)","This variant was reported in at least 7 patients with clinical features of NS (PMID: 26297936, 25862627, 17143282, 21387466, 19020799, 23885229, 22190897, 19352411) Four cohorts were included in this study...143 clinically well-characterized patients with NS of European/Italian ancestry, patients from the Sarkozy 2009 study, (N= 358) anonymous samples from individuals with phenotypes suggestive of NS from commercial DNA diagnostic testing, finally a cohort of 59 subjects with nonsyndromic CHD's. This was a large study of patients with clinical features of a RASopathy that has been described elsewhere. This study describes c.1656G>C (p.Arg552Ser) in 2 sporadic, 7 fam unknown cases",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
1583,NM_005633.3(SOS1):c.1655G>A (p.Arg552Lys),SOS1,Noonan syndrome,MONDO:0018997,Pathogenic,Autosomal dominant inheritance,RASopathy,2019-06-28,PS4,met,PubMed:21387466,"Four cohorts were included in this study...143 clinically well-characterized patients with NS of European/Italian ancestry, patients from the Sarkozy 2009 study, 
 (N= 358) anonymous samples from individuals with phenotypes suggestive of NS from commercial DNA diagnostic testing, finally a cohort of 59 subjects with nonsyndromic CHD's. The variant was identified in 2 sporadic cases with NS and 2 ""fam.unknown"" cases in this study.","Kilinc et al. 2014: Variant was detected 12 year old boy with tooth anomalies, low set ears, bilateral proptosis, sparse eyebrows, epicanthal folds, hypertelorism, downslanting palpebral fissures, depressed nasal bridge, webbed neck, low posterior hairline, pectus excavatum, cubitus valgus, non palpable left testicle, myopia, scoliosis, diagnossi considered NS.

Partners LMM: The variant has been identified in 6 affected patients with NS at this lab. Inheritance is unknown for these individuals.

GeneDx:","Kilinc et al. 2014: Variant was detected 12 year old boy with tooth anomalies, low set ears, bilateral proptosis, sparse eyebrows, epicanthal folds, hypertelorism, downslanting palpebral fissures, depressed nasal bridge, webbed neck, low posterior hairline, pectus excavatum, cubitus valgus, non palpable left testicle, myopia, scoliosis, diagnossi considered NS.

Partners LMM: The variant has been identified in 6 affected patients with NS at this lab. Inheritance is unknown for these individuals.

GeneDx: Four cohorts were included in this study...143 clinically well-characterized patients with NS of European/Italian ancestry, patients from the Sarkozy 2009 study, 
 (N= 358) anonymous samples from individuals with phenotypes suggestive of NS from commercial DNA diagnostic testing, finally a cohort of 59 subjects with nonsyndromic CHD's. The variant was identified in 2 sporadic cases with NS and 2 ""fam.unknown"" cases in this study.",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
1583,NM_005633.3(SOS1):c.1655G>A (p.Arg552Lys),SOS1,Noonan syndrome,MONDO:0018997,Pathogenic,Autosomal dominant inheritance,RASopathy,2019-06-28,PS4,met,PubMed:30266093,Patient 133-PRE is a prenatal patient with an AD/de novo heterozygous variant. The phenotypic information for this fetus was not recorded and therefore the clinical suspicion for NS cannot be used for PS4 or PM6/PS2,"Kilinc et al. 2014: Variant was detected 12 year old boy with tooth anomalies, low set ears, bilateral proptosis, sparse eyebrows, epicanthal folds, hypertelorism, downslanting palpebral fissures, depressed nasal bridge, webbed neck, low posterior hairline, pectus excavatum, cubitus valgus, non palpable left testicle, myopia, scoliosis, diagnossi considered NS.

Partners LMM: The variant has been identified in 6 affected patients with NS at this lab. Inheritance is unknown for these individuals.

GeneDx:","Kilinc et al. 2014: Variant was detected 12 year old boy with tooth anomalies, low set ears, bilateral proptosis, sparse eyebrows, epicanthal folds, hypertelorism, downslanting palpebral fissures, depressed nasal bridge, webbed neck, low posterior hairline, pectus excavatum, cubitus valgus, non palpable left testicle, myopia, scoliosis, diagnossi considered NS.

Partners LMM: The variant has been identified in 6 affected patients with NS at this lab. Inheritance is unknown for these individuals.

GeneDx: Patient 133-PRE is a prenatal patient with an AD/de novo heterozygous variant. The phenotypic information for this fetus was not recorded and therefore the clinical suspicion for NS cannot be used for PS4 or PM6/PS2",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
1583,NM_005633.3(SOS1):c.1655G>A (p.Arg552Lys),SOS1,Noonan syndrome,MONDO:0018997,Pathogenic,Autosomal dominant inheritance,RASopathy,2019-06-28,PM6,not_met,PubMed:30266093,Patient 133-PRE is a prenatal patient with an AD/de novo heterozygous variant. The phenotypic information for this fetus was not recorded and therefore the clinical suspicion for NS cannot be used for PS4 or PM6/PS2,Would be met but PS2_VS is applied so cannot be applied.,Would be met but PS2_VS is applied so cannot be applied. Patient 133-PRE is a prenatal patient with an AD/de novo heterozygous variant. The phenotypic information for this fetus was not recorded and therefore the clinical suspicion for NS cannot be used for PS4 or PM6/PS2,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
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
1579,NM_005633.3(SOS1):c.1655G>T (p.Arg552Met),SOS1,RASopathy,MONDO:0021060,Likely Pathogenic,Autosomal dominant inheritance,RASopathy,2019-06-28,PS4-Moderate,not_met,PubMed:21387466,"Patient NS25: 11y 7m old Male with neonatal/infantile growth failure, short stature, delayed bone age, craniofacial anomalies, high forehead bitemporal narrowing, downslanting palpebral fissures and epicanthal folds has p.Arg552Met variant in sporadic case with inheritance unknown.

This paper states that there are 2 patients with this variant and clinical features of NS but clinical information for the second patient is not available.","GeneDx- Variant seen in a proband, sibling, and parent all with Noonan syndrome

Invitae- observed p.Arg552Met once in patient with clinical features of RASopathy Didn’t do additional family testing

Lepri 2011: Patient NS25 is one patient with the p.Arg552Met variant","GeneDx- Variant seen in a proband, sibling, and parent all with Noonan syndrome

Invitae- observed p.Arg552Met once in patient with clinical features of RASopathy Didn’t do additional family testing

Lepri 2011: Patient NS25 is one patient with the p.Arg552Met variant Patient NS25: 11y 7m old Male with neonatal/infantile growth failure, short stature, delayed bone age, craniofacial anomalies, high forehead bitemporal narrowing, downslanting palpebral fissures and epicanthal folds has p.Arg552Met variant in sporadic case with inheritance unknown.

This paper states that there are 2 patients with this variant and clinical features of NS but clinical information for the second patient is not available.",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
1582,NM_005633.3(SOS1):c.1655G>C (p.Arg552Thr),SOS1,Noonan syndrome,MONDO:0018997,Pathogenic,Autosomal dominant inheritance,RASopathy,2024-08-23,PS4-Moderate,not_met,PubMed:21387466,"Four cohorts were included in this study...143 clinically well-characterized patients with NS of European/Italian ancestry, patients from the Sarkozy 2009 study, (N= 358) anonymous samples from individuals with phenotypes suggestive of NS from commercial DNA diagnostic testing, finally a cohort of 59 subjects with nonsyndromic CHD's. The variant was identified in 1 patient with an unknown family history. This was a large study of patients with clinical features of a RASopathy that has been described elsewhere.","The c.1655G>C (p.Arg552Thr) variant in SOS1 has been identified in at least 4 independent occurrences in patients with clinical features of a RASopathy, one of which was de novo (PS4_Moderate; GeneDx, St. George's Hospital, London internal data; GTR Lab ID: 26957 SCV000209121.12; PMID: 21387466, 19352411).","The c.1655G>C (p.Arg552Thr) variant in SOS1 has been identified in at least 4 independent occurrences in patients with clinical features of a RASopathy, one of which was de novo (PS4_Moderate; GeneDx, St. George's Hospital, London internal data; GTR Lab ID: 26957 SCV000209121.12; PMID: 21387466, 19352411). Four cohorts were included in this study...143 clinically well-characterized patients with NS of European/Italian ancestry, patients from the Sarkozy 2009 study, (N= 358) anonymous samples from individuals with phenotypes suggestive of NS from commercial DNA diagnostic testing, finally a cohort of 59 subjects with nonsyndromic CHD's. The variant was identified in 1 patient with an unknown family history. This was a large study of patients with clinical features of a RASopathy that has been described elsewhere.",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,PS2-Very Strong,not_met,PubMed:19684605,de novo case,"The c.4A>G (p.Ser2Gly) variant in SHOC2 has been reported as a confirmed de novo occurrence in a patient with clinical features of a RASopathy (PS2_VeryStrong; Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data; GTR ID's: 21766, 506381, 28338; ClinVar SCV000062456.5, SCV000209051.10, SCV000263045.1 PMID 19684605, 21548061, 23918763, 22528146).","The c.4A>G (p.Ser2Gly) variant in SHOC2 has been reported as a confirmed de novo occurrence in a patient with clinical features of a RASopathy (PS2_VeryStrong; Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data; GTR ID's: 21766, 506381, 28338; ClinVar SCV000062456.5, SCV000209051.10, SCV000263045.1 PMID 19684605, 21548061, 23918763, 22528146). de novo case",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSHOC2Version2.3.0_version=2.3.0.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,PP1-Strong,not_met,PubMed:24767283,1 segregation (Father and son affected with the variant.),"The c.1403C>T (p.Thr468Met) variant in PTPN11 has been reported in the literature to segregate with clinical features of a RASopathy in at least 7 family members (PP1_Strong; 24767283, 17935252, 15520399, 20883402).","The c.1403C>T (p.Thr468Met) variant in PTPN11 has been reported in the literature to segregate with clinical features of a RASopathy in at least 7 family members (PP1_Strong; 24767283, 17935252, 15520399, 20883402). 1 segregation (Father and son affected with the variant.)",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,PM6-Strong,not_met,PubMed:25884655,Patient with NSML and de novo p.Thr468Met variant,"The c.1403C>T (p.Thr468Met) variant in PTPN11 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 25884655, 19864201 ).","The c.1403C>T (p.Thr468Met) variant in PTPN11 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 25884655, 19864201 ). Patient with NSML and de novo p.Thr468Met variant",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
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
510,NM_004360.4(CDH1):c.1137G>A (p.Thr379=),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Pathogenic,Autosomal dominant inheritance,CDH1,2023-08-29,PS4,met,PubMed:27995193,c.1137G>A variant identified in a patient with SRC cancer meeting IGCLC criteria for HDGC.,Proband is an obligate carrier with a strong family history of DGC.  Seven HDGC families with the c.1137G>A variant have been reported in the literature. Total of 8 families.,Proband is an obligate carrier with a strong family history of DGC.  Seven HDGC families with the c.1137G>A variant have been reported in the literature. Total of 8 families. c.1137G>A variant identified in a patient with SRC cancer meeting IGCLC criteria for HDGC.,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,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
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
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
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
1432,NM_004360.5(CDH1):c.1137+2T>C,CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Likely Pathogenic,Autosomal dominant inheritance,CDH1,2023-11-10,BS3,not_met,PubMed:31642931,Abnormal splicing has been observed associated with the CDH1 c.1137+1delG allele.,"To our knowledge, this variant has not been assessed for splicing defects in vitro.","To our knowledge, this variant has not been assessed for splicing defects in vitro. Abnormal splicing has been observed associated with the CDH1 c.1137+1delG allele.",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
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
1432,NM_004360.5(CDH1):c.1137+2T>C,CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Likely Pathogenic,Autosomal dominant inheritance,CDH1,2023-11-10,PS3,not_met,PubMed:31642931,Abnormal splicing has been observed associated with the CDH1 c.1137+1delG allele.,"To our knowledge, this variant has not been assessed for splicing defects in vitro.","To our knowledge, this variant has not been assessed for splicing defects in vitro. Abnormal splicing has been observed associated with the CDH1 c.1137+1delG allele.",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
905,NM_004360.4(CDH1):c.1023T>G (p.Tyr341Ter),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Pathogenic,Autosomal dominant inheritance,CDH1,2023-08-29,PS4-Supporting,not_met,PubMed:27192129,One Northern Brazilian family that fulfils the clinical criteria for HDGC of the International Gastric Cancer Linkage Consortium. Case1 and case 3 are siblings and both carriers (1 meiosis).,One Northern Brazilian family that fulfils the clinical criteria for HDGC (PMID: 27192129),One Northern Brazilian family that fulfils the clinical criteria for HDGC (PMID: 27192129) One Northern Brazilian family that fulfils the clinical criteria for HDGC of the International Gastric Cancer Linkage Consortium. Case1 and case 3 are siblings and both carriers (1 meiosis).,ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
905,NM_004360.4(CDH1):c.1023T>G (p.Tyr341Ter),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Pathogenic,Autosomal dominant inheritance,CDH1,2023-08-29,PS4-Supporting,not_met,PubMed:22225527,References the proband from Guilford et al 2010,One Northern Brazilian family that fulfils the clinical criteria for HDGC (PMID: 27192129),One Northern Brazilian family that fulfils the clinical criteria for HDGC (PMID: 27192129) References the proband from Guilford et al 2010,ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
1092,NM_004360.4(CDH1):c.1612delG (p.Asp538Thrfs),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Pathogenic,Autosomal dominant inheritance,CDH1,2023-08-25,PS4-Supporting,not_met,PubMed:29295527,Same patient as in PMID: 29131691,PMID: 29131691 - 41-year-old with metastatic GC characterized by the presence of signet ring cells.,PMID: 29131691 - 41-year-old with metastatic GC characterized by the presence of signet ring cells. Same patient as in PMID: 29131691,ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
1092,NM_004360.4(CDH1):c.1612delG (p.Asp538Thrfs),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Pathogenic,Autosomal dominant inheritance,CDH1,2023-08-25,PS4-Supporting,not_met,PubMed:29131691,41-year-old with metastatic GC characterized by the presence of signet ring cells,PMID: 29131691 - 41-year-old with metastatic GC characterized by the presence of signet ring cells.,PMID: 29131691 - 41-year-old with metastatic GC characterized by the presence of signet ring cells. 41-year-old with metastatic GC characterized by the presence of signet ring cells,ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
511,NM_004360.5(CDH1):c.48+1G>A,CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Pathogenic,Autosomal dominant inheritance,CDH1,2023-08-29,PS4-Moderate,not_met,PubMed:24366306,"Identified in an individual with bilateral LCIS and ILC, age of dx of 51 and family history of breast cancer.","Proband with DGC and age of dx of 74, and two first-degree relatives with GC (one diffuse and one unknown type). Reported in a patient with signet cell carcinoma of the cecum and a family history of diffuse gastric cancer. (PMID: 20719348). Additionally reported in an individual with bilateral LCIS and ILC, age of dx of 51 and family history of breast cancer (no family history of gastric cancer) (PMID: 24366306).","Proband with DGC and age of dx of 74, and two first-degree relatives with GC (one diffuse and one unknown type). Reported in a patient with signet cell carcinoma of the cecum and a family history of diffuse gastric cancer. (PMID: 20719348). Additionally reported in an individual with bilateral LCIS and ILC, age of dx of 51 and family history of breast cancer (no family history of gastric cancer) (PMID: 24366306). Identified in an individual with bilateral LCIS and ILC, age of dx of 51 and family history of breast cancer.",ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
901,NM_004360.4(CDH1):c.60G>A (p.Trp20Ter),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Pathogenic,Autosomal dominant inheritance,CDH1,2023-08-29,PS4-Moderate,not_met,PubMed:28688938,"The Trp20X variant is found in one family meeting HDGC criteria, according to authors.",Variant reported in 2 families meeting HDGC criteria,"Variant reported in 2 families meeting HDGC criteria The Trp20X variant is found in one family meeting HDGC criteria, according to authors.",ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
1554,NM_004360.5(CDH1):c.833-2A>G,CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Pathogenic,Autosomal dominant inheritance,CDH1,2023-08-28,PS4-Moderate,not_met,PubMed:22225527,References the report of the variant in Rogers et al 2008,"At least two families fulfilling HDGC clinical criteria (PMID: 22118538, 18391748, 21424370, 20624523). Another family from internal laboratory meets HDGC clinical criteria.","At least two families fulfilling HDGC clinical criteria (PMID: 22118538, 18391748, 21424370, 20624523). Another family from internal laboratory meets HDGC clinical criteria. References the report of the variant in Rogers et al 2008",ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
510,NM_004360.4(CDH1):c.1137G>A (p.Thr379=),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Pathogenic,Autosomal dominant inheritance,CDH1,2023-08-29,PP4,not_met,PubMed:27995193,c.1137G>A variant identified in a patient with SRC cancer meeting IGCLC criteria for HDGC.,Proband is an obligate carrier with a strong family history of DGC. Several HDGC families with the c.1137G>A variant have been reported in the literature.,Proband is an obligate carrier with a strong family history of DGC. Several HDGC families with the c.1137G>A variant have been reported in the literature. c.1137G>A variant identified in a patient with SRC cancer meeting IGCLC criteria for HDGC.,ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
511,NM_004360.5(CDH1):c.48+1G>A,CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Pathogenic,Autosomal dominant inheritance,CDH1,2023-08-29,PP4,not_met,PubMed:24366306,"Identified in an individual with bilateral LCIS and ILC, age of dx of 51 and family history of breast cancer.","Proband with DGC and age of dx of 74, and two first-degree relatives with GC (one diffuse and one unknown type). Reported in a patient with signet cell carcinoma of the cecum and a family history of diffuse gastric cancer.
Additionally reported in an individual with bilateral LCIS and ILC, age of dx of 51 and family history of breast cancer (no family history of gastric cancer).","Proband with DGC and age of dx of 74, and two first-degree relatives with GC (one diffuse and one unknown type). Reported in a patient with signet cell carcinoma of the cecum and a family history of diffuse gastric cancer.
Additionally reported in an individual with bilateral LCIS and ILC, age of dx of 51 and family history of breast cancer (no family history of gastric cancer). Identified in an individual with bilateral LCIS and ILC, age of dx of 51 and family history of breast cancer.",ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
499,NM_004360.4(CDH1):c.1298A>G (p.Asp433Gly),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Benign,Autosomal dominant inheritance,CDH1,2023-08-10,PS1,not_met,PubMed:20921021,Potentially pathogenic CDH1 c.1297G>A (D433N) variant identified in a patient with LBC and no FHx of GC.,, Potentially pathogenic CDH1 c.1297G>A (D433N) variant identified in a patient with LBC and no FHx of GC.,ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
499,NM_004360.4(CDH1):c.1298A>G (p.Asp433Gly),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Benign,Autosomal dominant inheritance,CDH1,2023-08-10,PM5,not_met,PubMed:20921021,Potentially pathogenic CDH1 c.1297G>A (D433N) variant identified in a patient with LBC and no FHx of GC.,, Potentially pathogenic CDH1 c.1297G>A (D433N) variant identified in a patient with LBC and no FHx of GC.,ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
507,NM_004360.4(CDH1):c.2413G>A (p.Asp805Asn),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Benign,Autosomal dominant inheritance,CDH1,2023-08-08,BS2,not_met,PubMed:24728327,Variant reported in at least one healthy individual undergoing exome sequencing.,Variant reported in at least one healthy individual undergoing exome sequencing and at least one person undergoing testing for Lynch syndrome.,Variant reported in at least one healthy individual undergoing exome sequencing and at least one person undergoing testing for Lynch syndrome. Variant reported in at least one healthy individual undergoing exome sequencing.,ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
1100,NM_004360.4(CDH1):c.1565+2dupT,CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Pathogenic,Autosomal dominant inheritance,CDH1,2023-08-30,PP1-Moderate,not_met,PubMed:25315765,"One meiosis across a family that meets HDGC clinical criteria, which includes two sisters with DGC.","Five meioses reported in 3 families that meets HDGC criteria (PMID: 25315765, 22020549, SCV000665426.2)","Five meioses reported in 3 families that meets HDGC criteria (PMID: 25315765, 22020549, SCV000665426.2) One meiosis across a family that meets HDGC clinical criteria, which includes two sisters with DGC.",ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
1100,NM_004360.4(CDH1):c.1565+2dupT,CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Pathogenic,Autosomal dominant inheritance,CDH1,2023-08-30,BS4,not_met,PubMed:25315765,"One meiosis across a family that meets HDGC clinical criteria, which includes two sisters with DGC.",," One meiosis across a family that meets HDGC clinical criteria, which includes two sisters with DGC.",ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.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,PS4,met,PubMed:22729224,"13 w/ MPPH: hydrocephalus, ventriculomegaly and PMG","16 COSMIC, 27 cBioPortal
This variant met criteria to meet PS4_VS >16 ","16 COSMIC, 27 cBioPortal
This variant met criteria to meet PS4_VS >16  13 w/ MPPH: hydrocephalus, ventriculomegaly and PMG",ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2752,NM_004958.4(MTOR):c.4448G>A (p.Cys1483Tyr),MTOR,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,PS4,met,PubMed:26619011,1 tumor sample,2 COSMIC tumor samples,2 COSMIC tumor samples 1 tumor sample,ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2755,NM_004958.3(MTOR):c.4447T>C (p.Cys1483Arg),MTOR,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:28864461,FCD Iib w/ neuopath,3 tumor samples in COSMIC,3 tumor samples in COSMIC FCD Iib w/ neuopath,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,PS4,met,PubMed:22729224,"LR09-006 MCAP, LR11-070 had megalencephaly,vascular malformation,connective tissue dysplasia, ventriculomegaly and cerebellar tonsillar ectopia, LR06-341 had overgrowth, vasulcar malformation, connective tissued dyspalsia, and polymicrogyria",also present in 2 tumor samples in COSMIC Upgraded to very strong,"also present in 2 tumor samples in COSMIC Upgraded to very strong LR09-006 MCAP, LR11-070 had megalencephaly,vascular malformation,connective tissue dysplasia, ventriculomegaly and cerebellar tonsillar ectopia, LR06-341 had overgrowth, vasulcar malformation, connective tissued dyspalsia, and polymicrogyria",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,PS4,met,PubMed:22729224,"001P, 333, 261 all have MCAP","15MCAP, 104 tumors in cosmic","15MCAP, 104 tumors in cosmic 001P, 333, 261 all have MCAP",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,PS4,met,PubMed:27631024,10 individuals with MCAP,"15MCAP, 104 tumors in cosmic","15MCAP, 104 tumors in cosmic 10 individuals with MCAP",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
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,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
2775,NM_004958.3(MTOR):c.6644C>T (p.Ser2215Phe),MTOR,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:27830187,"2 IIb, 1 IIa with somatic mutations (no functional assay)",," 2 IIb, 1 IIa with somatic mutations (no functional assay)",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,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
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
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
2775,NM_004958.3(MTOR):c.6644C>T (p.Ser2215Phe),MTOR,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:27830187,"2 IIb, 1 IIa with somatic mutations (no functional assay)",," 2 IIb, 1 IIa with somatic mutations (no functional assay)",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
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,PS3-Moderate,not_met,PubMed:22370636,"In this study, we report the development of a knock-in mouse model for breast cancer where the endogenous Pik3ca allele was modified to allow tissue-specific conditional expression of a frequently found Pik3ca(H1047R) (Pik3ca(e20H1047R)) mutant allele. We found that activation of the latent Pik3ca(H1047R) allele resulted in breast tumors with multiple histological types.",Animal model with increased tumor burden,"Animal model with increased tumor burden In this study, we report the development of a knock-in mouse model for breast cancer where the endogenous Pik3ca allele was modified to allow tissue-specific conditional expression of a frequently found Pik3ca(H1047R) (Pik3ca(e20H1047R)) mutant allele. We found that activation of the latent Pik3ca(H1047R) allele resulted in breast tumors with multiple histological types.",ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
794,NM_001754.5(RUNX1):c.467C>A (p.Ala156Glu),RUNX1,hereditary thrombocytopenia and hematologic cancer predisposition syndrome,MONDO:0011071,Likely Pathogenic,Autosomal dominant inheritance,Myeloid Malignancy,2024-06-24,BS4,not_met,PubMed:27112265,The same family (Pedigree B) reported in PMID: 19357396.,Segregation was not found to be absent in two or more informative meiosis.,Segregation was not found to be absent in two or more informative meiosis. The same family (Pedigree B) reported in PMID: 19357396.,ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
797,NM_001754.4(RUNX1):c.602G>A (p.Arg201Gln),RUNX1,hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome,MONDO:0011071,Pathogenic,Autosomal dominant inheritance,Myeloid Malignancy,2019-08-02,BS4,not_met,PubMed:27112265,"Pedigree C, family also reported in PMID: 22898599 and PMID: 23692290 (Family A) - 4 affected individuals meeting phenotype criteria, but unclear whether all were genotyped. Counting only the two individuals explicitly stated to have been genotyped.",," Pedigree C, family also reported in PMID: 22898599 and PMID: 23692290 (Family A) - 4 affected individuals meeting phenotype criteria, but unclear whether all were genotyped. Counting only the two individuals explicitly stated to have been genotyped.",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
1067,NM_001754.5(RUNX1):c.611G>A (p.Arg204Gln),RUNX1,hereditary thrombocytopenia and hematologic cancer predisposition syndrome,MONDO:0011071,Pathogenic,Autosomal dominant inheritance,Myeloid Malignancy,2024-03-26,BS4,not_met,PubMed:27112265,"3 affected individuals in Pedigree D with FPD/AML, 2 meioses in segregation.",Segregation was not found to be absent in two or more informative meiosis.,"Segregation was not found to be absent in two or more informative meiosis. 3 affected individuals in Pedigree D with FPD/AML, 2 meioses in segregation.",ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
797,NM_001754.4(RUNX1):c.602G>A (p.Arg201Gln),RUNX1,hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome,MONDO:0011071,Pathogenic,Autosomal dominant inheritance,Myeloid Malignancy,2019-08-02,PS4,met,PubMed:28748566,1 proband (Patient 64) with lifelong history of severe thrombocytopenia and bleeding tendency. She developed myelodysplasia when aged 65 years and 1 proband with chronic thrombocytopenia.,4 probands counted across publications.,4 probands counted across publications. 1 proband (Patient 64) with lifelong history of severe thrombocytopenia and bleeding tendency. She developed myelodysplasia when aged 65 years and 1 proband with chronic thrombocytopenia.,ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
823,NM_001754.4(RUNX1):c.1098_1103dupCGGCAT (p.Gly367_Met368insIleGly),RUNX1,hereditary thrombocytopenia and hematologic cancer predisposition syndrome,MONDO:0011071,Likely Benign,Autosomal dominant inheritance,Myeloid Malignancy,2023-11-13,PS4,not_met,PubMed:28659335,The variant was reported in a 14-year-old female with familial platelet disorder with hematological malignancy.,"The variant has to be either absent from gnomAD or only present once to apply PS4 codes. Although this variant was reported twice in probands meeting RUNX1 phenotypic criteria (PMID: 27210295, PMID: 28659335), it presents 17 times in gnomAD v2.1.1 and 16 times in gnomAD v.3.1.","The variant has to be either absent from gnomAD or only present once to apply PS4 codes. Although this variant was reported twice in probands meeting RUNX1 phenotypic criteria (PMID: 27210295, PMID: 28659335), it presents 17 times in gnomAD v2.1.1 and 16 times in gnomAD v.3.1. The variant was reported in a 14-year-old female with familial platelet disorder with hematological malignancy.",ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1761,NM_001754.4(RUNX1):c.952T>G (p.Ser318Ala),RUNX1,hereditary thrombocytopenia and hematologic cancer predisposition syndrome,MONDO:0011071,Benign,Autosomal dominant inheritance,Myeloid Malignancy,2021-01-11,PS4,not_met,PubMed:28933735,"NM_001754.4(RUNX1):c.952T>G p.S318A (VAF=14.9%) detected in a patient with newly diagnosed AML.  However, the patient also had NM_001754.4(RUNX1):c.954dupC p.S319fs (VAF=14.4%) and NM_001754.4(RUNX1):c.950T>G p.L317R (VAF=15.0%).",PS4 cannot be applied because the variant presents more than 1 time in gnomAD.,"PS4 cannot be applied because the variant presents more than 1 time in gnomAD. NM_001754.4(RUNX1):c.952T>G p.S318A (VAF=14.9%) detected in a patient with newly diagnosed AML.  However, the patient also had NM_001754.4(RUNX1):c.954dupC p.S319fs (VAF=14.4%) and NM_001754.4(RUNX1):c.950T>G p.L317R (VAF=15.0%).",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,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
7186,NM_001754.5(RUNX1):c.613+14C>G,RUNX1,hereditary thrombocytopenia and hematologic cancer predisposition syndrome,MONDO:0011071,Likely Benign,Autosomal dominant inheritance,Myeloid Malignancy,2024-06-24,PS3,not_met,PubMed:33692461,not evaluated,"To our knowledge, this synonymous variant was not evaluated in transactivation assays.","To our knowledge, this synonymous variant was not evaluated in transactivation assays. not evaluated",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,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
797,NM_001754.4(RUNX1):c.602G>A (p.Arg201Gln),RUNX1,hereditary thrombocytopenia with normal platelets-hematological cancer predisposition syndrome,MONDO:0011071,Pathogenic,Autosomal dominant inheritance,Myeloid Malignancy,2019-08-02,PP1,met,PubMed:27112265,"Pedigree C, family also reported in PMID: 22898599 and PMID: 23692290 (Family A) - 4 affected individuals meeting phenotype criteria, but unclear whether all were genotyped. Counting only the two individuals explicitly stated to have been genotyped.",4 segregations counted additively across publications,"4 segregations counted additively across publications Pedigree C, family also reported in PMID: 22898599 and PMID: 23692290 (Family A) - 4 affected individuals meeting phenotype criteria, but unclear whether all were genotyped. Counting only the two individuals explicitly stated to have been genotyped.",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
7186,NM_001754.5(RUNX1):c.613+14C>G,RUNX1,hereditary thrombocytopenia and hematologic cancer predisposition syndrome,MONDO:0011071,Likely Benign,Autosomal dominant inheritance,Myeloid Malignancy,2024-06-24,BS3,not_met,PubMed:33692461,not evaluated,"To our knowledge, this synonymous variant was not evaluated in transactivation assays.","To our knowledge, this synonymous variant was not evaluated in transactivation assays. not evaluated",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
794,NM_001754.5(RUNX1):c.467C>A (p.Ala156Glu),RUNX1,hereditary thrombocytopenia and hematologic cancer predisposition syndrome,MONDO:0011071,Likely Pathogenic,Autosomal dominant inheritance,Myeloid Malignancy,2024-06-24,PP1-Strong,not_met,PubMed:27112265,The same family (Pedigree B) reported in PMID: 19357396.,8 affected individuals in one pedigree with 7 meioses.,8 affected individuals in one pedigree with 7 meioses. The same family (Pedigree B) reported in PMID: 19357396.,ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
794,NM_001754.5(RUNX1):c.467C>A (p.Ala156Glu),RUNX1,hereditary thrombocytopenia and hematologic cancer predisposition syndrome,MONDO:0011071,Likely Pathogenic,Autosomal dominant inheritance,Myeloid Malignancy,2024-06-24,PS4-Supporting,not_met,PubMed:27112265,The same family (Pedigree B) reported in PMID: 19357396.,"1 affected proband in a family with FPD/AML (PMID: 19357396, PMID: 27112265).","1 affected proband in a family with FPD/AML (PMID: 19357396, PMID: 27112265). The same family (Pedigree B) reported in PMID: 19357396.",ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1771,NM_001754.5(RUNX1):c.484A>G (p.Arg162Gly),RUNX1,hereditary thrombocytopenia and hematologic cancer predisposition syndrome,MONDO:0011071,Pathogenic,Autosomal dominant inheritance,Myeloid Malignancy,2024-03-26,PM1,met,PubMed:28231333,"“In Runx1, Arg135 and Arg139 interact with G105–A107 and G4–C6, respectively (green), while Arg80 interacts with A106–T107, and Lys83 interacts with T107, T109, and A7 (yellow).”","This variant affects at least one of the following hotspot residues within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204 (PM1).","This variant affects at least one of the following hotspot residues within the RHD: R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R201, R204 (PM1). “In Runx1, Arg135 and Arg139 interact with G105–A107 and G4–C6, respectively (green), while Arg80 interacts with A106–T107, and Lys83 interacts with T107, T109, and A7 (yellow).”",ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
9445,NM_001754.5(RUNX1):c.433A>G (p.Arg145Gly),RUNX1,hereditary thrombocytopenia and hematologic cancer predisposition syndrome,MONDO:0011071,Uncertain Significance,Autosomal dominant inheritance,Myeloid Malignancy,2025-01-15,PS3-Moderate,not_met,PubMed:33692461,"Variant displays varying levels of transactivation, and multiple secondary assays were abnormal compared to WT controls. This paper labeled this variant as ""likely non-functional.""","Data from two or more secondary assays (FRET assay and SEUSS) demonstrates altered function: decreased phosphorylation of RUNX1 and decreased gene expression (PS3_Moderate; PMID: 33692461, 32943879).","Data from two or more secondary assays (FRET assay and SEUSS) demonstrates altered function: decreased phosphorylation of RUNX1 and decreased gene expression (PS3_Moderate; PMID: 33692461, 32943879). Variant displays varying levels of transactivation, and multiple secondary assays were abnormal compared to WT controls. This paper labeled this variant as ""likely non-functional.""",ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1067,NM_001754.5(RUNX1):c.611G>A (p.Arg204Gln),RUNX1,hereditary thrombocytopenia and hematologic cancer predisposition syndrome,MONDO:0011071,Pathogenic,Autosomal dominant inheritance,Myeloid Malignancy,2024-03-26,PS4-Moderate,not_met,PubMed:27112265,Pedigree D with FPD/AML,This variant has been reported in three probands meeting at least one of the RUNX1-phenotypic criteria.,This variant has been reported in three probands meeting at least one of the RUNX1-phenotypic criteria. Pedigree D with FPD/AML,ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1594,NM_000546.5(TP53):c.221C>T (p.Ala74Val),TP53,Li-Fraumeni syndrome,MONDO:0018875,Likely Benign,Autosomal dominant inheritance,TP53,2025-01-16,BS3,met,PubMed:30224644,"Giacomelli A549_p53NULL_Etoposide_Z-score (LOF <=-0.21) = 0.700463717

Giacomelli A549_p53WT_Nutlin-3_Z-score (DN=>0.61) = -0.214822468","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). Giacomelli A549_p53NULL_Etoposide_Z-score (LOF <=-0.21) = 0.700463717

Giacomelli A549_p53WT_Nutlin-3_Z-score (DN=>0.61) = -0.214822468",ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
1605,NM_000546.5(TP53):c.144C>A (p.Asp48Glu),TP53,Li-Fraumeni syndrome,MONDO:0018875,Likely Benign,Autosomal dominant inheritance,TP53,2025-01-16,BS3,met,PubMed:30224644,Non-functional,"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). Non-functional",ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
2332,NM_001126112.2(TP53):c.998G>A (p.Arg333His),TP53,Li-Fraumeni syndrome 1,MONDO:0007903,Likely Benign,Autosomal dominant inheritance,TP53,2021-06-16,BS3,met,PubMed:30224644,No evidence of DNE or LOF,Kato functional; no evidence of DNE or LOF by Giacomelli; Kotler N/A; Kawaguchi shows normal tetramer formation.,Kato functional; no evidence of DNE or LOF by Giacomelli; Kotler N/A; Kawaguchi shows normal tetramer formation. No evidence of DNE or LOF,ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.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
2659,NM_000546.5(TP53):c.11C>T (p.Pro4Leu),TP53,Li-Fraumeni syndrome,MONDO:0018875,Likely Benign,Autosomal dominant inheritance,TP53,2025-01-16,BS3,met,PubMed:30224644,"No dominant negative effect (p53WTNutlin3 Z-score -0.367(< 0.61)), and no loss of function (Etoposide Z-score 0.356(> -0.21 )). ","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).
 No dominant negative effect (p53WTNutlin3 Z-score -0.367(< 0.61)), and no loss of function (Etoposide Z-score 0.356(> -0.21 )). ",ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
2662,NM_000546.5(TP53):c.1151T>C (p.Met384Thr),TP53,Li-Fraumeni syndrome,MONDO:0018875,Benign,Autosomal dominant inheritance,TP53,2025-01-16,BS3,met,PubMed:30224644,noDNE+noLOF,"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).
 noDNE+noLOF",ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
2663,NM_000546.5(TP53):c.875A>G (p.Lys292Arg),TP53,Li-Fraumeni syndrome,MONDO:0018875,Likely Benign,Autosomal dominant inheritance,TP53,2025-01-16,BS3,met,PubMed:30224644,noDNE+noLOF,"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). noDNE+noLOF",ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
2664,NM_000546.6(TP53):c.556G>A (p.Asp186Asn),TP53,Li-Fraumeni syndrome,MONDO:0018875,Likely Benign,Autosomal dominant inheritance,TP53,2025-01-16,BS3,met,PubMed:30224644,"A549_p53WT_Nutlin-3_Z-score (DN=>0.61)
 = 0.095621624; A549_p53NULL_Etoposide_Z-score (LOF <=-0.21) = 0.307883038","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). A549_p53WT_Nutlin-3_Z-score (DN=>0.61)
 = 0.095621624; A549_p53NULL_Etoposide_Z-score (LOF <=-0.21) = 0.307883038",ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
2665,NM_000546.5(TP53):c.37C>T (p.Pro13Ser),TP53,Li-Fraumeni syndrome 1,MONDO:0007903,Uncertain Significance,Autosomal dominant inheritance,TP53,2022-06-27,BS3,met,PubMed:30224644,A549_p53WT_Nutlin-3_Z-score (DN=>0.61) = -0.45635397; A549_p53NULL_Etoposide_Z-score (LOF <=-0.21) = 0.124669083,"Transactivation assays in yeast demonstrate a functional allele (99.75% activity, based on data from Kato et al) and there is no evidence of a dominant negative effect (DNE) and no evidence of LOF from Giacomelli et al","Transactivation assays in yeast demonstrate a functional allele (99.75% activity, based on data from Kato et al) and there is no evidence of a dominant negative effect (DNE) and no evidence of LOF from Giacomelli et al A549_p53WT_Nutlin-3_Z-score (DN=>0.61) = -0.45635397; A549_p53NULL_Etoposide_Z-score (LOF <=-0.21) = 0.124669083",ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
2667,NM_000546.5(TP53):c.353C>T (p.Thr118Ile),TP53,Li-Fraumeni syndrome 1,MONDO:0007903,Uncertain Significance,Autosomal dominant inheritance,TP53,2021-09-24,BS3,met,PubMed:30224644,noLOF/noDNE,"Kato functional, Giacomelli noLOF/noDNE, Kotler noLOF","Kato functional, Giacomelli noLOF/noDNE, Kotler noLOF noLOF/noDNE",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
2719,NM_001126112.2(TP53):c.188C>T (p.Ala63Val),TP53,Li-Fraumeni syndrome,MONDO:0018875,Benign,Autosomal dominant inheritance,TP53,2025-01-16,BS3,met,PubMed:30224644,No LOF,"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). No LOF",ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
9457,NM_000546.6(TP53):c.143A>G (p.Asp48Gly),TP53,Li-Fraumeni syndrome,MONDO:0018875,Likely Benign,Autosomal dominant inheritance,TP53,2025-01-16,BS3,met,PubMed:30224644,noLOF,"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). noLOF",ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
1588,NM_000546.5(TP53):c.800G>A (p.Arg267Gln),TP53,Li-Fraumeni syndrome,MONDO:0018875,Uncertain Significance,Autosomal dominant inheritance,TP53,2020-08-14,BS3-Supporting,not_met,PubMed:30224644,DN score of 0.4 (not dominant negative) and Etoposide score of  -0.01 (no loss of growth suppression).,"This technically meets the BS_3 supporting criteria, with partially functional transactivation and no evidence of DNE or loss of growth suppression.  However, some of the transactivation values from Kato are lower than 20% (the median is 21%).","This technically meets the BS_3 supporting criteria, with partially functional transactivation and no evidence of DNE or loss of growth suppression.  However, some of the transactivation values from Kato are lower than 20% (the median is 21%). DN score of 0.4 (not dominant negative) and Etoposide score of  -0.01 (no loss of growth suppression).",ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
1592,NM_000546.5(TP53):c.541C>A (p.Arg181Ser),TP53,Li-Fraumeni syndrome,MONDO:0018875,Uncertain Significance,,TP53,2020-08-14,BS3-Supporting,not_met,PubMed:30224644,Score of 0.19,"Arg181Ser is partially functional in Kato data from IARC. Giacomelli et al is 0.19 ( less than 0.61 cut off), and Kotler data is -2.3 RFS score.  (PMID: 12826609, 30224644 ).","Arg181Ser is partially functional in Kato data from IARC. Giacomelli et al is 0.19 ( less than 0.61 cut off), and Kotler data is -2.3 RFS score.  (PMID: 12826609, 30224644 ). Score of 0.19",ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
1606,NM_001126112.2(TP53):c.784G>A (p.Gly262Ser),TP53,Li-Fraumeni syndrome,MONDO:0018875,Uncertain Significance,Autosomal dominant inheritance,TP53,2020-09-04,PS3,not_met,PubMed:30224644,,"Present in Kato (11,9 = Non-functional)/DNE+LOF:  Z-score < 0.61; Etoposide Z-score > -0.2","Present in Kato (11,9 = Non-functional)/DNE+LOF:  Z-score < 0.61; Etoposide Z-score > -0.2 ",ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
2349,NM_001126112.2(TP53):c.1136G>T (p.Arg379Leu),TP53,Li-Fraumeni syndrome,MONDO:0018875,Likely Benign,Autosomal dominant inheritance,TP53,2025-01-16,PS3,not_met,PubMed:30224644,noDNE+noLOF,"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; however a third assay corroborating these findings was not available (BS3 not met; PMIDs: 12826609, 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; however a third assay corroborating these findings was not available (BS3 not met; PMIDs: 12826609, 30224644). noDNE+noLOF",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,PS4,not_met,PubMed:23894400,"Detected in a male with history of Hodgkin's lymphoma, melanoma, and sarcoma diagnosed at ages 34, 47, and 60 years, respectively.  Sarcoma showed LOH for TP53 variant. (Does not meet classic or Chompret criteria based on this information alone.)
This individual also appears to be documented in IARC as having an an additional skin cancer at age 63 and a mother presumed to have the same mutation with CML diagnosed at age 91.  IARC classifies this family as meeting Chompret criteria.","This variant received a total of 0.5 points across 1 unrelated proband from an individual laboratory, and therefore PS4 cannot be applied. (PS4 not met; SCV000149650.14).","This variant received a total of 0.5 points across 1 unrelated proband from an individual laboratory, and therefore PS4 cannot be applied. (PS4 not met; SCV000149650.14). Detected in a male with history of Hodgkin's lymphoma, melanoma, and sarcoma diagnosed at ages 34, 47, and 60 years, respectively.  Sarcoma showed LOH for TP53 variant. (Does not meet classic or Chompret criteria based on this information alone.)
This individual also appears to be documented in IARC as having an an additional skin cancer at age 63 and a mother presumed to have the same mutation with CML diagnosed at age 91.  IARC classifies this family as meeting Chompret criteria.",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
2332,NM_001126112.2(TP53):c.998G>A (p.Arg333His),TP53,Li-Fraumeni syndrome 1,MONDO:0007903,Likely Benign,Autosomal dominant inheritance,TP53,2021-06-16,PM1,not_met,PubMed:26619011,Basis of cancerhotspots.com,Not in cancerhotspots.com,Not in cancerhotspots.com Basis of cancerhotspots.com,ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.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
4808,m.14674T>C,MT-TE,mitochondrial disease,MONDO:0044970,Likely Pathogenic,Mitochondrial inheritance,Mitochondrial Diseases,2023-03-14,PS3-Supporting,not_met,PubMed:19720722,"Northern blotting of skeletal muscle of Patients 7, 11 and 14 and primary cell cultures of Patients 7 and 14 showed that that the steady-state level of mt-tRNAGlu was significantly decreased compared to controls, with the most severe decrease (16-30% of controls) seen in muscle taken between 1-3 months old. Muscle taken after recovery had less severely decreased steady-state levels (30-60% controls). Immunoblotting with monoclonal antibodies against mitochondrial-encoded COX and complex I subunits showed markedly decreased levels in early biopsies, when the children showed severe symptoms and this normalized in biopsies after recovery (and was normal in biopsies from healthy mothers).
","Several studies in skeletal muscle and primary cell cultures of affected individuals (PMID: 19720722), cybrids (PMID: 21194154), and transcriptome and proteomic analyses (PMID: 33128823) support the functional impact of this variant (PS3_supporting). ","Several studies in skeletal muscle and primary cell cultures of affected individuals (PMID: 19720722), cybrids (PMID: 21194154), and transcriptome and proteomic analyses (PMID: 33128823) support the functional impact of this variant (PS3_supporting).  Northern blotting of skeletal muscle of Patients 7, 11 and 14 and primary cell cultures of Patients 7 and 14 showed that that the steady-state level of mt-tRNAGlu was significantly decreased compared to controls, with the most severe decrease (16-30% of controls) seen in muscle taken between 1-3 months old. Muscle taken after recovery had less severely decreased steady-state levels (30-60% controls). Immunoblotting with monoclonal antibodies against mitochondrial-encoded COX and complex I subunits showed markedly decreased levels in early biopsies, when the children showed severe symptoms and this normalized in biopsies after recovery (and was normal in biopsies from healthy mothers).
",ClinGenMitochondrialDiseaseNuclearandMitochondrialExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_mtDNA_version=1.0.0.csv
4808,m.14674T>C,MT-TE,mitochondrial disease,MONDO:0044970,Likely Pathogenic,Mitochondrial inheritance,Mitochondrial Diseases,2023-03-14,PS3-Supporting,not_met,PubMed:33128823,"Several additional cases were reported in this publication, and modifiers for reduced penetrance discussed that were identified by transcriptome and proteomic analysis. Integrated stress response associated with increased FGF21 and GDF15 (authors found these were profoundly increased in muscle in acute phase and normalized after recovery) expression enhances the metabolism modulated by serine biosynthesis, one carbon metabolism, TCA lipid oxidation, and amino acid availability. mTOR activation then leads to increased mitochondrial biogenesis. They also compared expression of patients with digenic EARS2 variants vs those without these and found significantly lower expression of mtDNA-encoded proteins.

","Several studies in skeletal muscle and primary cell cultures of affected individuals (PMID: 19720722), cybrids (PMID: 21194154), and transcriptome and proteomic analyses (PMID: 33128823) support the functional impact of this variant (PS3_supporting). ","Several studies in skeletal muscle and primary cell cultures of affected individuals (PMID: 19720722), cybrids (PMID: 21194154), and transcriptome and proteomic analyses (PMID: 33128823) support the functional impact of this variant (PS3_supporting).  Several additional cases were reported in this publication, and modifiers for reduced penetrance discussed that were identified by transcriptome and proteomic analysis. Integrated stress response associated with increased FGF21 and GDF15 (authors found these were profoundly increased in muscle in acute phase and normalized after recovery) expression enhances the metabolism modulated by serine biosynthesis, one carbon metabolism, TCA lipid oxidation, and amino acid availability. mTOR activation then leads to increased mitochondrial biogenesis. They also compared expression of patients with digenic EARS2 variants vs those without these and found significantly lower expression of mtDNA-encoded proteins.

",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
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
8789,m.3249G>A,,mitochondrial disease,MONDO:0044970,Uncertain Significance,Mitochondrial inheritance,Mitochondrial Diseases,2024-11-20,PS3-Supporting,not_met,PubMed:33380464,"The m.3249G>A mutation leads to >50% decrease in nuclease activity catalyzed by RNAse P. The mutation was found to impact not only RNAse P binding, but also 5' end cleavage and m1A9 methylation.
","There are no cybrids or single fiber studies reported on this variant, however two processing studies have shown termination blockage (PMID: 20550934) and RNAseP binding interference (PMID: 33380464), and this variant was also found to negatively impact 5' end cleavage and m1A9 methylation (PMID: 33380464; PS3_supporting). ","There are no cybrids or single fiber studies reported on this variant, however two processing studies have shown termination blockage (PMID: 20550934) and RNAseP binding interference (PMID: 33380464), and this variant was also found to negatively impact 5' end cleavage and m1A9 methylation (PMID: 33380464; PS3_supporting).  The m.3249G>A mutation leads to >50% decrease in nuclease activity catalyzed by RNAse P. The mutation was found to impact not only RNAse P binding, but also 5' end cleavage and m1A9 methylation.
",ClinGenMitochondrialDiseaseNuclearandMitochondrialExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_mtDNA_version=1.0.0.csv
3115,NC_012920.1:m.9055G>A,MT-ATP6,mitochondrial disease,MONDO:0044970,Benign,Mitochondrial inheritance,Mitochondrial Diseases,2022-01-05,BA1,met,PubMed:32461654,gnomAD v3.1 has a homoplasmic AF of 5.393% in 56368 mt sequences,"The highest population minor allele frequency in GenBank (51,863 GenBank sequences) is 4.24%; in gnomad v3.1.2 is 5.393% (homoplasmic occurrences); and in Helix (196,554 sequences, 91% lineage N bias) is 8.05%. These are all higher than the ClinGen Mitochondrial  Disease Nuclear and Mitochondrial Variant Curation Expert Panel - mtDNA specifications - threshold (>0.01 or 1%). Furthermore, m.9055G>A is a haplogroup-defining variant for K at 99.7%. It is also found in Z3b (100%), U8b (100%).  Therefore, this meets this criterion (BA1).

As a note, the K haplogroup is common in the Ashkenazi Jewish population. m.9055 G>A is a haplogroup-defining variant for K at 99.7%. Subgroup frequencies are K1 (99.3%), K2 (99.7%). However, if an individual with this variant is a member of a different haplogroup than those where the variant is a marker, consider further evaluation.
","The highest population minor allele frequency in GenBank (51,863 GenBank sequences) is 4.24%; in gnomad v3.1.2 is 5.393% (homoplasmic occurrences); and in Helix (196,554 sequences, 91% lineage N bias) is 8.05%. These are all higher than the ClinGen Mitochondrial  Disease Nuclear and Mitochondrial Variant Curation Expert Panel - mtDNA specifications - threshold (>0.01 or 1%). Furthermore, m.9055G>A is a haplogroup-defining variant for K at 99.7%. It is also found in Z3b (100%), U8b (100%).  Therefore, this meets this criterion (BA1).

As a note, the K haplogroup is common in the Ashkenazi Jewish population. m.9055 G>A is a haplogroup-defining variant for K at 99.7%. Subgroup frequencies are K1 (99.3%), K2 (99.7%). However, if an individual with this variant is a member of a different haplogroup than those where the variant is a marker, consider further evaluation.
 gnomAD v3.1 has a homoplasmic AF of 5.393% in 56368 mt sequences",ClinGenMitochondrialDiseaseNuclearandMitochondrialExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_mtDNA_version=1.0.0.csv
5405,NC_012920.1(MT-CO1):m.6951G>A,MT-CO1,mitochondrial disease,MONDO:0044970,Likely Benign,Mitochondrial inheritance,Mitochondrial Diseases,2023-08-03,BA1,not_met,PubMed:34072215,m.6951G>A is a subclade marker in Phylotree: in small hg H4a1a4b2 in Phylotree.org (Phylotree 17) and in hg C4a1a* Phylotree 17 - Forensic Update 1.2 (this publication),"This variant is present at low frequency in population databases. The frequency in gnomAD v3.1.2 is 26/56,416 (0.046%) with 26 homoplasmic  occurrences and one heteroplasmic occurrence spread over eight top level haplogroups (single letter) with European, Asian, and African ancestry. The frequency in MITOMAP GenBank sequences is 20/59,389 (0.034%) spread over eight top level haplogroups with European, and Asian ancestry. The frequency in the Helix dataset is 75/195,983 (0.038%, all homoplasmic) plus an additional 13 heteroplasmic occurrences, all spread over 17 top level haplogroups with European, Asian, and African ancestry.  Therefore, the frequency of this variant meets neither criteria for pathogenicity (<0.002%) nor benign status (>0.5%). ","This variant is present at low frequency in population databases. The frequency in gnomAD v3.1.2 is 26/56,416 (0.046%) with 26 homoplasmic  occurrences and one heteroplasmic occurrence spread over eight top level haplogroups (single letter) with European, Asian, and African ancestry. The frequency in MITOMAP GenBank sequences is 20/59,389 (0.034%) spread over eight top level haplogroups with European, and Asian ancestry. The frequency in the Helix dataset is 75/195,983 (0.038%, all homoplasmic) plus an additional 13 heteroplasmic occurrences, all spread over 17 top level haplogroups with European, Asian, and African ancestry.  Therefore, the frequency of this variant meets neither criteria for pathogenicity (<0.002%) nor benign status (>0.5%).  m.6951G>A is a subclade marker in Phylotree: in small hg H4a1a4b2 in Phylotree.org (Phylotree 17) and in hg C4a1a* Phylotree 17 - Forensic Update 1.2 (this publication)",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
5112,NC_012920.1:m.3460G>A,MT-ND1,mitochondrial disease,MONDO:0044970,Pathogenic,Mitochondrial inheritance,Mitochondrial Diseases,2023-05-19,PS3-Moderate,not_met,PubMed:35383288,"Authors injected mouse eye with variant, mice then had progressive loss of RGC function and number, as well as optic nerve degeneration. Injection of a second MTS-AAV vector carrying wild-type human ND1 restores mitochondrial respiratory complex I activity, the rate of ATP synthesis and protects RGCs and their axons from dysfunction and degeneration.",," Authors injected mouse eye with variant, mice then had progressive loss of RGC function and number, as well as optic nerve degeneration. Injection of a second MTS-AAV vector carrying wild-type human ND1 restores mitochondrial respiratory complex I activity, the rate of ATP synthesis and protects RGCs and their axons from dysfunction and degeneration.",ClinGenMitochondrialDiseaseNuclearandMitochondrialExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_mtDNA_version=1.0.0.csv
5405,NC_012920.1(MT-CO1):m.6951G>A,MT-CO1,mitochondrial disease,MONDO:0044970,Likely Benign,Mitochondrial inheritance,Mitochondrial Diseases,2023-08-03,PM2,not_met,PubMed:34072215,m.6951G>A is a subclade marker in Phylotree: in small hg H4a1a4b2 in Phylotree.org (Phylotree 17) and in hg C4a1a* Phylotree 17 - Forensic Update 1.2 (this publication),"This variant is present at low frequency in population databases. The frequency in gnomAD v3.1.2 is 26/56,416 (0.046%) with 26 homoplasmic  occurrences and one heteroplasmic occurrence spread over eight top level haplogroups (single letter) with European, Asian, and African ancestry. The frequency in MITOMAP GenBank sequences is 20/59,389 (0.034%) spread over eight top level haplogroups with European, and Asian ancestry. The frequency in the Helix dataset is 75/195,983 (0.038%, all homoplasmic) plus an additional 13 heteroplasmic occurrences, all spread over 17 top level haplogroups with European, Asian, and African ancestry.  Therefore, the frequency of this variant meets neither criteria for pathogenicity (<0.002%) nor benign status (>0.5%). ","This variant is present at low frequency in population databases. The frequency in gnomAD v3.1.2 is 26/56,416 (0.046%) with 26 homoplasmic  occurrences and one heteroplasmic occurrence spread over eight top level haplogroups (single letter) with European, Asian, and African ancestry. The frequency in MITOMAP GenBank sequences is 20/59,389 (0.034%) spread over eight top level haplogroups with European, and Asian ancestry. The frequency in the Helix dataset is 75/195,983 (0.038%, all homoplasmic) plus an additional 13 heteroplasmic occurrences, all spread over 17 top level haplogroups with European, Asian, and African ancestry.  Therefore, the frequency of this variant meets neither criteria for pathogenicity (<0.002%) nor benign status (>0.5%).  m.6951G>A is a subclade marker in Phylotree: in small hg H4a1a4b2 in Phylotree.org (Phylotree 17) and in hg C4a1a* Phylotree 17 - Forensic Update 1.2 (this publication)",ClinGenMitochondrialDiseaseNuclearandMitochondrialExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_mtDNA_version=1.0.0.csv
5405,NC_012920.1(MT-CO1):m.6951G>A,MT-CO1,mitochondrial disease,MONDO:0044970,Likely Benign,Mitochondrial inheritance,Mitochondrial Diseases,2023-08-03,BS1,not_met,PubMed:34072215,m.6951G>A is a subclade marker in Phylotree: in small hg H4a1a4b2 in Phylotree.org (Phylotree 17) and in hg C4a1a* Phylotree 17 - Forensic Update 1.2 (this publication),"Population frequencies for this variant do not reach the criteria to meet BS1 (>0.5%) in either Mitomap, gnomAD, or Helix.
Mitomap has 20/59,389 sequences (0.034%) spread over 7 haplogroups with European and Asian ancestry; gnomAD has 26/56,416 (0.046%) spread over 8 haplogroups with European, Asian, and African ancestry; Helix has 75/195,983 seq (0.038%), spread over 17 haplogroups with European, Asian, and African ancestry. The variant is seen in the updated Phylotree 17.1.2 as a marker for two very minor sub-clades, H4a1a4b2 and C4a1a* .
","Population frequencies for this variant do not reach the criteria to meet BS1 (>0.5%) in either Mitomap, gnomAD, or Helix.
Mitomap has 20/59,389 sequences (0.034%) spread over 7 haplogroups with European and Asian ancestry; gnomAD has 26/56,416 (0.046%) spread over 8 haplogroups with European, Asian, and African ancestry; Helix has 75/195,983 seq (0.038%), spread over 17 haplogroups with European, Asian, and African ancestry. The variant is seen in the updated Phylotree 17.1.2 as a marker for two very minor sub-clades, H4a1a4b2 and C4a1a* .
 m.6951G>A is a subclade marker in Phylotree: in small hg H4a1a4b2 in Phylotree.org (Phylotree 17) and in hg C4a1a* Phylotree 17 - Forensic Update 1.2 (this publication)",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
4940,NM_024675.4(PALB2):c.2014G>C (p.Glu672Gln),PALB2,hereditary breast cancer,MONDO:0016419,Benign,Autosomal dominant inheritance,"Hereditary Breast, Ovarian and Pancreatic Cancer",2023-04-07,BS3,not_met,PubMed:31636395,"Assay: In vitro expression of HA-tagged full-length cDNA constructs in cell line, homology directed repair (HDR) fluorescent reporter assay to assess functional capacity of variants. Material: Mouse mammary tumor cell line B400 (Palb2-/-; Trp53-/-) with stably integrated DR-GFP reporter (GFP gene interrupted by I-SceI site, with adjacent native GFP gene). Readout: Quantitative; HDR (measured by GFP+ cells) fold change, normalized & rescaled relative to 1:5 ratio of p.Y551X pathogenic variant control and wild-type PALB2 control, displayed with SEM of independent replicates. Controls: wild type cDNA, 7 LP/P controls, 4 LB/B controls Threshold for normal readout: >2.4 Threshold for abnormal readout: ≤1.7 (34% activity); ≤2.4 (48% activity) for hypomorphic Assay result: 4.4 Assay result assertion: Normal Standard error mean: 0.39","Homology-directed repair (HDR) protein assays in mouse mammary tumor cell line B400 (Palb2-/-; Trp53-/-), mouse embryonic stem cell line 129/Ola E14 IB10 (Palb2-/-; Trp53-/), and HEK293T cells showed no significant change in HDR (4.4 fold change in HDR compared to 5.0 fold change in HDR for wild type PALB2 in B400 cells, 83.25% HDR efficiency compared to wild type PALB2 in 129/Ola E14 IB10 cells, 1.1 normalized HR/NHEJ ratio in HEK293T cells) and a PARP inhibition assay in 129/Ola E14 IB10 (Palb2-/-; Trp53-/) cells showed no significant change in cell survival (103.53% survival compared to wild type PALB2) indicating that this variant does not impact protein function (PMID: 31636395, PMID: 31757951, PMID: 33964450); however, due to a lack of positive missense controls with known clinical impact, these assays do not meet the requirements for use by the HBOP VCEP.","Homology-directed repair (HDR) protein assays in mouse mammary tumor cell line B400 (Palb2-/-; Trp53-/-), mouse embryonic stem cell line 129/Ola E14 IB10 (Palb2-/-; Trp53-/), and HEK293T cells showed no significant change in HDR (4.4 fold change in HDR compared to 5.0 fold change in HDR for wild type PALB2 in B400 cells, 83.25% HDR efficiency compared to wild type PALB2 in 129/Ola E14 IB10 cells, 1.1 normalized HR/NHEJ ratio in HEK293T cells) and a PARP inhibition assay in 129/Ola E14 IB10 (Palb2-/-; Trp53-/) cells showed no significant change in cell survival (103.53% survival compared to wild type PALB2) indicating that this variant does not impact protein function (PMID: 31636395, PMID: 31757951, PMID: 33964450); however, due to a lack of positive missense controls with known clinical impact, these assays do not meet the requirements for use by the HBOP VCEP. Assay: In vitro expression of HA-tagged full-length cDNA constructs in cell line, homology directed repair (HDR) fluorescent reporter assay to assess functional capacity of variants. Material: Mouse mammary tumor cell line B400 (Palb2-/-; Trp53-/-) with stably integrated DR-GFP reporter (GFP gene interrupted by I-SceI site, with adjacent native GFP gene). Readout: Quantitative; HDR (measured by GFP+ cells) fold change, normalized & rescaled relative to 1:5 ratio of p.Y551X pathogenic variant control and wild-type PALB2 control, displayed with SEM of independent replicates. Controls: wild type cDNA, 7 LP/P controls, 4 LB/B controls Threshold for normal readout: >2.4 Threshold for abnormal readout: ≤1.7 (34% activity); ≤2.4 (48% activity) for hypomorphic Assay result: 4.4 Assay result assertion: Normal Standard error mean: 0.39","ClinGenHereditaryBreast,OvarianandPancreaticCancerExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPALB2Version1.1.0_version=1.1.0.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"
4964,NM_024675.3(PALB2):c.3089C>T (p.Thr1030Ile),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,"PARP inhibitor sensitivity function in HeLa cells showed 58% survival relative to WT, which falls in the indeterminant range established by the HBOP VCEP. Mammalian two-hybrid in HEK293 cells showed <10% BRCA2 binding, which falls in the abnormal function rage established by the HBOP VCEP. RAD51C foci formation in HeLa cells showed 56% decreased in foci number and 59% decrease in intensity per focus, which falls in the indeterminant function range established by the HBOP VCEP. Homology-directed repair function in U2OS cells showed 23.6% activity of WT, which falls in the indeterminant function range 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

","Multiple studies showed a normal protein function (33964450, 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 HBOP VCEP   

","Multiple studies showed a normal protein function (33964450, 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 HBOP VCEP   

 PARP inhibitor sensitivity function in HeLa cells showed 58% survival relative to WT, which falls in the indeterminant range established by the HBOP VCEP. Mammalian two-hybrid in HEK293 cells showed <10% BRCA2 binding, which falls in the abnormal function rage established by the HBOP VCEP. RAD51C foci formation in HeLa cells showed 56% decreased in foci number and 59% decrease in intensity per focus, which falls in the indeterminant function range established by the HBOP VCEP. Homology-directed repair function in U2OS cells showed 23.6% activity of WT, which falls in the indeterminant function range 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"
4964,NM_024675.3(PALB2):c.3089C>T (p.Thr1030Ile),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,"Homology-directed repair function in  B400 mouse mammary tumor
cells showed 3.0 normalized fold change, which falls in the normal function range 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
","Multiple studies showed a normal protein function (33964450, 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 HBOP VCEP   

","Multiple studies showed a normal protein function (33964450, 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 HBOP VCEP   

 Homology-directed repair function in  B400 mouse mammary tumor
cells showed 3.0 normalized fold change, which falls in the normal function range 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"
4964,NM_024675.3(PALB2):c.3089C>T (p.Thr1030Ile),PALB2,hereditary breast cancer,MONDO:0016419,Uncertain Significance,Autosomal dominant inheritance,"Hereditary Breast, Ovarian and Pancreatic Cancer",2023-04-07,BS3,not_met,PubMed:31757951,"Homology-directed repair function in mES cells showed 14.68% 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 14.8% 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","Multiple studies showed a normal protein function (33964450, 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 HBOP VCEP   

","Multiple studies showed a normal protein function (33964450, 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 HBOP VCEP   

 Homology-directed repair function in mES cells showed 14.68% 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 14.8% 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"
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"
4962,NM_024675.3(PALB2):c.2831T>A (p.Ile944Asn),PALB2,hereditary breast cancer,MONDO:0016419,Uncertain Significance,Autosomal dominant inheritance,"Hereditary Breast, Ovarian and Pancreatic Cancer",2023-04-07,PS3,not_met,PubMed:31636395,This variant had ≤1.7 fold change in a homology directed DNA repair assay which is below the threshold for a non-functional variant (PMID 31636395; PS3_Supporting),"This variant is non-functional in multiple different protein assays (PMIDs: 31757951, 31636395); however due to a lack of known positive controls, do not apply functional criteria at this time.  ","This variant is non-functional in multiple different protein assays (PMIDs: 31757951, 31636395); however due to a lack of known positive controls, do not apply functional criteria at this time.   This variant had ≤1.7 fold change in a homology directed DNA repair assay which is below the threshold for a non-functional variant (PMID 31636395; PS3_Supporting)","ClinGenHereditaryBreast,OvarianandPancreaticCancerExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPALB2Version1.1.0_version=1.1.0.csv"
4964,NM_024675.3(PALB2):c.3089C>T (p.Thr1030Ile),PALB2,hereditary breast cancer,MONDO:0016419,Uncertain Significance,Autosomal dominant inheritance,"Hereditary Breast, Ovarian and Pancreatic Cancer",2023-04-07,PS3,not_met,PubMed:31586400,"PARP inhibitor sensitivity function in HeLa cells showed 58% survival relative to WT, which falls in the indeterminant range established by the HBOP VCEP. Mammalian two-hybrid in HEK293 cells showed <10% BRCA2 binding, which falls in the abnormal function rage established by the HBOP VCEP. RAD51C foci formation in HeLa cells showed 56% decreased in foci number and 59% decrease in intensity per focus, which falls in the indeterminant function range established by the HBOP VCEP. Homology-directed repair function in U2OS cells showed 23.6% activity of WT, which falls in the indeterminant function range 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

","Multiple studies showed an abnormal protein function (31757951, 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 ","Multiple studies showed an abnormal protein function (31757951, 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  PARP inhibitor sensitivity function in HeLa cells showed 58% survival relative to WT, which falls in the indeterminant range established by the HBOP VCEP. Mammalian two-hybrid in HEK293 cells showed <10% BRCA2 binding, which falls in the abnormal function rage established by the HBOP VCEP. RAD51C foci formation in HeLa cells showed 56% decreased in foci number and 59% decrease in intensity per focus, which falls in the indeterminant function range established by the HBOP VCEP. Homology-directed repair function in U2OS cells showed 23.6% activity of WT, which falls in the indeterminant function range 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"
4964,NM_024675.3(PALB2):c.3089C>T (p.Thr1030Ile),PALB2,hereditary breast cancer,MONDO:0016419,Uncertain Significance,Autosomal dominant inheritance,"Hereditary Breast, Ovarian and Pancreatic Cancer",2023-04-07,PS3,not_met,PubMed:24141787,"In vitro binding assay:  T10301 shows ""statistically significant"" reduction in RAD51C, RAD51 interaction, but not BRCA2 or XRCC3. Translation inhibition with CHX shows reduced stability of T10301I that is restored by treatment with proteosome inhibitor (MG132); suggesting the T1030I is degraded in a proteasome dependent manner.  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   ","Multiple studies showed an abnormal protein function (31757951, 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 ","Multiple studies showed an abnormal protein function (31757951, 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  In vitro binding assay:  T10301 shows ""statistically significant"" reduction in RAD51C, RAD51 interaction, but not BRCA2 or XRCC3. Translation inhibition with CHX shows reduced stability of T10301I that is restored by treatment with proteosome inhibitor (MG132); suggesting the T1030I is degraded in a proteasome dependent manner.  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"
4964,NM_024675.3(PALB2):c.3089C>T (p.Thr1030Ile),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 14.68% 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 14.8% 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","Multiple studies showed an abnormal protein function (31757951, 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 ","Multiple studies showed an abnormal protein function (31757951, 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  Homology-directed repair function in mES cells showed 14.68% 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 14.8% 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"
3161,NM_000261.2:c.624C>G,MYOC,primary open angle glaucoma,MONDO:0007665,Likely Benign,Autosomal dominant inheritance,Glaucoma,2022-07-11,PS3,not_met,PubMed:27092720,"The D208E protein is secreted.
This study does not meet the OddsPath threshold for  BS3_Supporting.","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 D208E protein is secreted.
This study does not meet the OddsPath threshold for  BS3_Supporting.",ClinGenGlaucomaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYOCVersion2.0.0_version=2.0.0.csv
3163,NM_000261.2(MYOC):c.734G>A (p.Cys245Tyr),MYOC,juvenile open angle glaucoma,MONDO:0020367,Uncertain Significance,Autosomal dominant inheritance,Glaucoma,2022-07-11,PS3,not_met,PubMed:27092720,"The C245Y protein is not secreted.
This study does not meet the OddsPath threshold for PS3_Supporting (> 2.1).  ","The studies reporting functional evidence (PMIDs: 19234343, 27092720) demonstrated that the Cys245Tyr protein had reduced secretion and solubility levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (> 2.1) for PS3_Supporting to be applied.","The studies reporting functional evidence (PMIDs: 19234343, 27092720) demonstrated that the Cys245Tyr protein had reduced secretion and solubility levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (> 2.1) for PS3_Supporting to be applied. The C245Y 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
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
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
5162,NM_000261.2:c.1348A>T,MYOC,juvenile open angle glaucoma,MONDO:0020367,Likely Pathogenic,Autosomal dominant inheritance,Glaucoma,2023-06-01,PS3,met,PubMed:35615698,"A transgenic mouse model carrying human MYOC N450Y and displaying non secretion of N450Y protein in vivo exhibited a glaucoma phenotype (IOP elevation, retina ganglion cell loss) ","A transgenic mouse model carrying human MYOC Asn450Tyr (PMID: 35615698), and displaying non secretion of the Asn450Tyr protein in vivo, exhibited a glaucoma phenotype (IOP elevation, retina ganglion cell loss) in a similar fashion to a transgenic mouse carrying another variant classified pathogenic by the ClinGen Glaucoma VCEP (c.1309T>C, p.Tyr437His, PMID: 18436825).","A transgenic mouse model carrying human MYOC Asn450Tyr (PMID: 35615698), and displaying non secretion of the Asn450Tyr protein in vivo, exhibited a glaucoma phenotype (IOP elevation, retina ganglion cell loss) in a similar fashion to a transgenic mouse carrying another variant classified pathogenic by the ClinGen Glaucoma VCEP (c.1309T>C, p.Tyr437His, PMID: 18436825). A transgenic mouse model carrying human MYOC N450Y and displaying non secretion of N450Y protein in vivo exhibited a glaucoma phenotype (IOP elevation, retina ganglion cell loss) ",ClinGenGlaucomaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYOCVersion2.0.0_version=2.0.0.csv
5162,NM_000261.2:c.1348A>T,MYOC,juvenile open angle glaucoma,MONDO:0020367,Likely Pathogenic,Autosomal dominant inheritance,Glaucoma,2023-06-01,PS3,met,PubMed:32818018,"The N450Y protein is not secreted.
This study does not meet the OddsPath threshold for PS3_Supporting (> 2.1). ","A transgenic mouse model carrying human MYOC Asn450Tyr (PMID: 35615698), and displaying non secretion of the Asn450Tyr protein in vivo, exhibited a glaucoma phenotype (IOP elevation, retina ganglion cell loss) in a similar fashion to a transgenic mouse carrying another variant classified pathogenic by the ClinGen Glaucoma VCEP (c.1309T>C, p.Tyr437His, PMID: 18436825).","A transgenic mouse model carrying human MYOC Asn450Tyr (PMID: 35615698), and displaying non secretion of the Asn450Tyr protein in vivo, exhibited a glaucoma phenotype (IOP elevation, retina ganglion cell loss) in a similar fashion to a transgenic mouse carrying another variant classified pathogenic by the ClinGen Glaucoma VCEP (c.1309T>C, p.Tyr437His, PMID: 18436825). The N450Y 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
3163,NM_000261.2(MYOC):c.734G>A (p.Cys245Tyr),MYOC,juvenile open angle glaucoma,MONDO:0020367,Uncertain Significance,Autosomal dominant inheritance,Glaucoma,2022-07-11,BS3,not_met,PubMed:27092720,"The C245Y 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 C245Y 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
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
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
3604,NM_000261.2(MYOC):c.1430T>A (p.Ile477Asn),MYOC,juvenile open angle glaucoma,MONDO:0020367,Likely Pathogenic,Autosomal dominant inheritance,Glaucoma,2022-05-25,PS3-Moderate,not_met,PubMed:27092720,"The I477N protein is not secreted.
This study does not meet the OddsPath threshold for PS3_Supporting (> 2.1).  ","A previous study (PMID: 16466712) demonstrated that the Ile477Asn protein had reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function.","A previous study (PMID: 16466712) demonstrated that the Ile477Asn protein had reduced secretion levels compared to wild type myocilin protein and met the OddsPath threshold for PS3_Moderate (> 4.3), indicating that this variant did impact protein function. The I477N 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
1832,NM_000212.2(ITGB3):c.433G>T (p.Asp145Tyr),ITGB3,Glanzmann's thrombasthenia,MONDO:0010119,Pathogenic,Autosomal recessive inheritance,Platelet Disorders,2021-01-28,PP4-Moderate,not_met,PubMed:30828542,"5wo male infant with sudden episode of limpness, cyanosis, and apnea, petechiae over his face and chest, nose and mouth bleeding, easy bruising. Osteopetrosis and pulmonary hemorrhage were diagnosed. Exome sequencing revealed homozygous Asp145Tyr variant. GT was not initially diagnosed in the patient. Platelet aggregation or expression studies were not done. Proband does not meet criteria for PP4.","Proband of PMID: 15583747 had a history of mucocutaneous bleeding episodes and unprovoked bruising, prolonged bleeding time, normal platelet count and size, absent aggregation in response to ADP, adrenaline, and arachidonic acid, normal ristocetin-induced platelet agglutination. Surface expression, measured by flow cytometry and western blotting, was only reduced ~60% however binding of Fibrinogen and PAC-1 was significantly reduced. Meets the criteria for PP4_moderate; including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression/dysfunction of αIIbβ3.","Proband of PMID: 15583747 had a history of mucocutaneous bleeding episodes and unprovoked bruising, prolonged bleeding time, normal platelet count and size, absent aggregation in response to ADP, adrenaline, and arachidonic acid, normal ristocetin-induced platelet agglutination. Surface expression, measured by flow cytometry and western blotting, was only reduced ~60% however binding of Fibrinogen and PAC-1 was significantly reduced. Meets the criteria for PP4_moderate; including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression/dysfunction of αIIbβ3. 5wo male infant with sudden episode of limpness, cyanosis, and apnea, petechiae over his face and chest, nose and mouth bleeding, easy bruising. Osteopetrosis and pulmonary hemorrhage were diagnosed. Exome sequencing revealed homozygous Asp145Tyr variant. GT was not initially diagnosed in the patient. Platelet aggregation or expression studies were not done. Proband does not meet criteria for PP4.",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,PP4-Moderate,not_met,PubMed:25539746,All GT patients from this study had a history of bleeding with normal platelet number and size. There was impaired aggregation to ADP and arachidonic acid but normal or only mildly reduced agglutination with ristocetin. On flow cytometry GT-6 was classified as type II GT (αIIbβ3 expression between 5% and 20%) and exhibited no binding of PAC-1 activation-specific anti- αIIbβ3 antibody upon stimulation with ADP or TRAP.,"All three compound heterozygous probands reported in the literature meet the criteria for PP4_moderate; including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of αIIbβ3.","All three compound heterozygous probands reported in the literature meet the criteria for PP4_moderate; including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of αIIbβ3. All GT patients from this study had a history of bleeding with normal platelet number and size. There was impaired aggregation to ADP and arachidonic acid but normal or only mildly reduced agglutination with ristocetin. On flow cytometry GT-6 was classified as type II GT (αIIbβ3 expression between 5% and 20%) and exhibited no binding of PAC-1 activation-specific anti- αIIbβ3 antibody upon stimulation with ADP or TRAP.",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,PP4-Moderate,not_met,PubMed:28983057,"Case 37 had a ISTH-BAT score of 5 with a normal platelet count of 238x10^9/L. There was severely impaired platelet aggregation with TRAP, ADP, epinephrine, arachidonic acid, and collagen. Platelet aggregation with ristocetin was low-normal. There was undetectable GPIIb/IIIa platelet expression by flow cytometry and <20% agonist induced fibrinogen binding.","All three compound heterozygous probands reported in the literature meet the criteria for PP4_moderate; including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of αIIbβ3.","All three compound heterozygous probands reported in the literature meet the criteria for PP4_moderate; including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of αIIbβ3. Case 37 had a ISTH-BAT score of 5 with a normal platelet count of 238x10^9/L. There was severely impaired platelet aggregation with TRAP, ADP, epinephrine, arachidonic acid, and collagen. Platelet aggregation with ristocetin was low-normal. There was undetectable GPIIb/IIIa platelet expression by flow cytometry and <20% agonist induced fibrinogen binding.",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,PM3,met,PubMed:28983057,"Case 37 is a compound heterozygote for this Val982Met variant and a c.2965del frameshift variant. No confirmation was reported that the variants are in trans phase. However, to avoid circularity the proband was counted only towards the classification of c.2965del not Val982Met.","This variant has been observed in compound heterozygotes; once with the splice variant c.1946+1G>A (classified as Pathogenic by the ClinGen Platelet Disorders VCEP), as well as with Glu538Ter (classified as Pathogenic by the ClinGen Platelet Disorders VCEP).","This variant has been observed in compound heterozygotes; once with the splice variant c.1946+1G>A (classified as Pathogenic by the ClinGen Platelet Disorders VCEP), as well as with Glu538Ter (classified as Pathogenic by the ClinGen Platelet Disorders VCEP). Case 37 is a compound heterozygote for this Val982Met variant and a c.2965del frameshift variant. No confirmation was reported that the variants are in trans phase. However, to avoid circularity the proband was counted only towards the classification of c.2965del not Val982Met.",ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2.1_version=2.1.0.csv
2488,NM_000212.2:c.31T>C,ITGB3,Glanzmann thrombasthenia,MONDO:0010119,Pathogenic,Autosomal recessive inheritance,Platelet Disorders,2023-12-13,PM3,met,PubMed:28748566,Patient 1 is homozygous for the Trp11Arg variant.,"This Trp11Arg variant has been observed twice in homozygous cases in the literature (PMIDs: 25728920, 28748566). 1pt  And confirmed in trans with Likely Pathogenic variant Cys486Trp (PMID: 25373348), not considered here to avoid circularity.","This Trp11Arg variant has been observed twice in homozygous cases in the literature (PMIDs: 25728920, 28748566). 1pt  And confirmed in trans with Likely Pathogenic variant Cys486Trp (PMID: 25373348), not considered here to avoid circularity. Patient 1 is homozygous for the Trp11Arg variant.",ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2.1_version=2.1.0.csv
1843,NM_000212.2:c.565C>T,ITGB3,Glanzmann's thrombasthenia,MONDO:0010119,Pathogenic,Autosomal recessive inheritance,Platelet Disorders,2021-01-28,PP4-Strong,not_met,PubMed:24236036,,"At least three probands have been reported with this variant that meet the criteria for PP4; including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of  αIIbβ3. At least one (PMID: 25728920) meets criteria for PP4_strong as ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries.","At least three probands have been reported with this variant that meet the criteria for PP4; including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of  αIIbβ3. At least one (PMID: 25728920) meets criteria for PP4_strong as ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries. ",ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2.1_version=2.1.0.csv
1799,NM_000419.4(ITGA2B):c.2965G>A (p.Ala989Thr),ITGA2B,Glanzmann's thrombasthenia,MONDO:0010119,Likely Benign,Autosomal recessive inheritance,Platelet Disorders,2021-01-28,BP2,met,PubMed:25539746,"GT-6 was described to have triple heterozygosity with a paternally inherited nonsense, Glu538Ter, variant and both Val982Met and Ala958Thr occurring as de novo variants. No confirmation was reported that the variants are in trans phase.","This variant has been observed in cis with the VCEP-curated pathogenic variant Val982Met (PMID 15099289 and 20020534). In an additional proband (PMID 25539746), this variant has also been reported in combination with Val982Met and Glu538Ter, however, the phase of the variants was not confirmed.","This variant has been observed in cis with the VCEP-curated pathogenic variant Val982Met (PMID 15099289 and 20020534). In an additional proband (PMID 25539746), this variant has also been reported in combination with Val982Met and Glu538Ter, however, the phase of the variants was not confirmed. GT-6 was described to have triple heterozygosity with a paternally inherited nonsense, Glu538Ter, variant and both Val982Met and Ala958Thr occurring as de novo variants. No confirmation was reported that the variants are in trans phase.",ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2.1_version=2.1.0.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
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
7210,NM_000551.4(VHL):c.562C>G (p.Leu188Val),VHL,von Hippel-Lindau disease,MONDO:0008667,Uncertain Significance,Autosomal dominant inheritance,VHL,2024-06-25,PS3-Supporting,not_met,PubMed:19030229,1) interaction with Elongin C / VBC complex similar to WT,"In most studies reviewed, results for this variant were consistent with aberrant extra cellular matrix formation / fibronectin assembly (PMIDs: 19602254, 16452184, 17700531, 15574766, 16585181, 11331612, 18567581). However, for HIF1/2 alpha interaction/regulation and VCB complex formation/stability, most studies showed intact function with some slight effects on complex stability.  (PMIDs: 30890701 ,15574766, 12944410, 10878807, 16585181, 19030229, 11331612, 11331613, 19228690, 16452184, 23772956, 19602254.) (PS3_Supporting). ","In most studies reviewed, results for this variant were consistent with aberrant extra cellular matrix formation / fibronectin assembly (PMIDs: 19602254, 16452184, 17700531, 15574766, 16585181, 11331612, 18567581). However, for HIF1/2 alpha interaction/regulation and VCB complex formation/stability, most studies showed intact function with some slight effects on complex stability.  (PMIDs: 30890701 ,15574766, 12944410, 10878807, 16585181, 19030229, 11331612, 11331613, 19228690, 16452184, 23772956, 19602254.) (PS3_Supporting).  1) interaction with Elongin C / VBC complex similar to WT",ClinGenVHLExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforVHLVersion1.1.0_version=1.1.0.csv
7210,NM_000551.4(VHL):c.562C>G (p.Leu188Val),VHL,von Hippel-Lindau disease,MONDO:0008667,Uncertain Significance,Autosomal dominant inheritance,VHL,2024-06-25,PS3-Supporting,not_met,PubMed:31980715,Variant used as a known mutant in evaluation of effect of Thrombospondin-1 (TSP-1) on tumor cell invasiveness.,"In most studies reviewed, results for this variant were consistent with aberrant extra cellular matrix formation / fibronectin assembly (PMIDs: 19602254, 16452184, 17700531, 15574766, 16585181, 11331612, 18567581). However, for HIF1/2 alpha interaction/regulation and VCB complex formation/stability, most studies showed intact function with some slight effects on complex stability.  (PMIDs: 30890701 ,15574766, 12944410, 10878807, 16585181, 19030229, 11331612, 11331613, 19228690, 16452184, 23772956, 19602254.) (PS3_Supporting). ","In most studies reviewed, results for this variant were consistent with aberrant extra cellular matrix formation / fibronectin assembly (PMIDs: 19602254, 16452184, 17700531, 15574766, 16585181, 11331612, 18567581). However, for HIF1/2 alpha interaction/regulation and VCB complex formation/stability, most studies showed intact function with some slight effects on complex stability.  (PMIDs: 30890701 ,15574766, 12944410, 10878807, 16585181, 19030229, 11331612, 11331613, 19228690, 16452184, 23772956, 19602254.) (PS3_Supporting).  Variant used as a known mutant in evaluation of effect of Thrombospondin-1 (TSP-1) on tumor cell invasiveness.",ClinGenVHLExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforVHLVersion1.1.0_version=1.1.0.csv
7210,NM_000551.4(VHL):c.562C>G (p.Leu188Val),VHL,von Hippel-Lindau disease,MONDO:0008667,Uncertain Significance,Autosomal dominant inheritance,VHL,2024-06-25,PS3-Supporting,not_met,PubMed:19602254,"1) Regulates HIF2alpha and GLUT1 similar to WT
2) Organized epithelial morphology, similar to WT
3) Low levels of integrins, ECM adhesion proteins that are associated with cell morphological changes, similar to WT
4) Stable VHL protein, similar to WT","In most studies reviewed, results for this variant were consistent with aberrant extra cellular matrix formation / fibronectin assembly (PMIDs: 19602254, 16452184, 17700531, 15574766, 16585181, 11331612, 18567581). However, for HIF1/2 alpha interaction/regulation and VCB complex formation/stability, most studies showed intact function with some slight effects on complex stability.  (PMIDs: 30890701 ,15574766, 12944410, 10878807, 16585181, 19030229, 11331612, 11331613, 19228690, 16452184, 23772956, 19602254.) (PS3_Supporting). ","In most studies reviewed, results for this variant were consistent with aberrant extra cellular matrix formation / fibronectin assembly (PMIDs: 19602254, 16452184, 17700531, 15574766, 16585181, 11331612, 18567581). However, for HIF1/2 alpha interaction/regulation and VCB complex formation/stability, most studies showed intact function with some slight effects on complex stability.  (PMIDs: 30890701 ,15574766, 12944410, 10878807, 16585181, 19030229, 11331612, 11331613, 19228690, 16452184, 23772956, 19602254.) (PS3_Supporting).  1) Regulates HIF2alpha and GLUT1 similar to WT
2) Organized epithelial morphology, similar to WT
3) Low levels of integrins, ECM adhesion proteins that are associated with cell morphological changes, similar to WT
4) Stable VHL protein, similar to WT",ClinGenVHLExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforVHLVersion1.1.0_version=1.1.0.csv
7210,NM_000551.4(VHL):c.562C>G (p.Leu188Val),VHL,von Hippel-Lindau disease,MONDO:0008667,Uncertain Significance,Autosomal dominant inheritance,VHL,2024-06-25,PS3-Supporting,not_met,PubMed:27517496,"a cell line with L188V was used as a example of a mutant to test the effect of ubiquitin-specific protease 9X (USP9X), which is a deubiquitinase that binds and promotes degradation of both wild-type and mutants of pVHL that retain E3 ligase function, thus activating the HIF pathway. Not really an eval of L188V.","In most studies reviewed, results for this variant were consistent with aberrant extra cellular matrix formation / fibronectin assembly (PMIDs: 19602254, 16452184, 17700531, 15574766, 16585181, 11331612, 18567581). However, for HIF1/2 alpha interaction/regulation and VCB complex formation/stability, most studies showed intact function with some slight effects on complex stability.  (PMIDs: 30890701 ,15574766, 12944410, 10878807, 16585181, 19030229, 11331612, 11331613, 19228690, 16452184, 23772956, 19602254.) (PS3_Supporting). ","In most studies reviewed, results for this variant were consistent with aberrant extra cellular matrix formation / fibronectin assembly (PMIDs: 19602254, 16452184, 17700531, 15574766, 16585181, 11331612, 18567581). However, for HIF1/2 alpha interaction/regulation and VCB complex formation/stability, most studies showed intact function with some slight effects on complex stability.  (PMIDs: 30890701 ,15574766, 12944410, 10878807, 16585181, 19030229, 11331612, 11331613, 19228690, 16452184, 23772956, 19602254.) (PS3_Supporting).  a cell line with L188V was used as a example of a mutant to test the effect of ubiquitin-specific protease 9X (USP9X), which is a deubiquitinase that binds and promotes degradation of both wild-type and mutants of pVHL that retain E3 ligase function, thus activating the HIF pathway. Not really an eval of L188V.",ClinGenVHLExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforVHLVersion1.1.0_version=1.1.0.csv
7210,NM_000551.4(VHL):c.562C>G (p.Leu188Val),VHL,von Hippel-Lindau disease,MONDO:0008667,Uncertain Significance,Autosomal dominant inheritance,VHL,2024-06-25,PS3-Supporting,not_met,PubMed:18567581,"1) defective RhoA activation, associated with defective fibronectin matrix assembly","In most studies reviewed, results for this variant were consistent with aberrant extra cellular matrix formation / fibronectin assembly (PMIDs: 19602254, 16452184, 17700531, 15574766, 16585181, 11331612, 18567581). However, for HIF1/2 alpha interaction/regulation and VCB complex formation/stability, most studies showed intact function with some slight effects on complex stability.  (PMIDs: 30890701 ,15574766, 12944410, 10878807, 16585181, 19030229, 11331612, 11331613, 19228690, 16452184, 23772956, 19602254.) (PS3_Supporting). ","In most studies reviewed, results for this variant were consistent with aberrant extra cellular matrix formation / fibronectin assembly (PMIDs: 19602254, 16452184, 17700531, 15574766, 16585181, 11331612, 18567581). However, for HIF1/2 alpha interaction/regulation and VCB complex formation/stability, most studies showed intact function with some slight effects on complex stability.  (PMIDs: 30890701 ,15574766, 12944410, 10878807, 16585181, 19030229, 11331612, 11331613, 19228690, 16452184, 23772956, 19602254.) (PS3_Supporting).  1) defective RhoA activation, associated with defective fibronectin matrix assembly",ClinGenVHLExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforVHLVersion1.1.0_version=1.1.0.csv
7210,NM_000551.4(VHL):c.562C>G (p.Leu188Val),VHL,von Hippel-Lindau disease,MONDO:0008667,Uncertain Significance,Autosomal dominant inheritance,VHL,2024-06-25,PS3-Supporting,not_met,PubMed:28235946,"1) decreased VCAM-1 expression, which is inversely correlated with tumor malignancy, similar to Pos control","In most studies reviewed, results for this variant were consistent with aberrant extra cellular matrix formation / fibronectin assembly (PMIDs: 19602254, 16452184, 17700531, 15574766, 16585181, 11331612, 18567581). However, for HIF1/2 alpha interaction/regulation and VCB complex formation/stability, most studies showed intact function with some slight effects on complex stability.  (PMIDs: 30890701 ,15574766, 12944410, 10878807, 16585181, 19030229, 11331612, 11331613, 19228690, 16452184, 23772956, 19602254.) (PS3_Supporting). ","In most studies reviewed, results for this variant were consistent with aberrant extra cellular matrix formation / fibronectin assembly (PMIDs: 19602254, 16452184, 17700531, 15574766, 16585181, 11331612, 18567581). However, for HIF1/2 alpha interaction/regulation and VCB complex formation/stability, most studies showed intact function with some slight effects on complex stability.  (PMIDs: 30890701 ,15574766, 12944410, 10878807, 16585181, 19030229, 11331612, 11331613, 19228690, 16452184, 23772956, 19602254.) (PS3_Supporting).  1) decreased VCAM-1 expression, which is inversely correlated with tumor malignancy, similar to Pos control",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
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
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
2042,NM_000540.3(RYR1):c.103T>C (p.Cys35Arg),RYR1,"malignant hyperthermia, susceptibility to, 1",MONDO:0007783,Pathogenic,Autosomal dominant inheritance,Malignant Hyperthermia Susceptibility,2021-03-31,PS3,not_met,PubMed:26115329,Variant did not show significant lowered EC50 as compared to WT construct.,Conflicting data.,Conflicting data. Variant did not show significant lowered EC50 as compared to WT construct.,ClinGenMalignantHyperthermiaSusceptibilityExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRYR1Version2_version=2.0.0.csv
2042,NM_000540.3(RYR1):c.103T>C (p.Cys35Arg),RYR1,"malignant hyperthermia, susceptibility to, 1",MONDO:0007783,Pathogenic,Autosomal dominant inheritance,Malignant Hyperthermia Susceptibility,2021-03-31,BS3,not_met,PubMed:26115329,Variant did not show significant lowered EC50 as compared to WT construct.,Conflicting data.,Conflicting data. Variant did not show significant lowered EC50 as compared to WT construct.,ClinGenMalignantHyperthermiaSusceptibilityExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRYR1Version2_version=2.0.0.csv
2052,NM_000540.2(RYR1):c.488G>T (p.Arg163Leu),RYR1,"malignant hyperthermia, susceptibility to, 1",MONDO:0007783,Pathogenic,Autosomal dominant inheritance,Malignant Hyperthermia Susceptibility,2023-05-22,PS3-Moderate,not_met,PubMed:26115329,HEK293 assay,"Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:16163667, PMID:26115329). ","Functional studies in HEK293 cells show an increased sensitivity to RYR1 agonists, PS3_Moderate (PMID:16163667, PMID:26115329).  HEK293 assay",ClinGenMalignantHyperthermiaSusceptibilityExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRYR1Version2_version=2.0.0.csv
2168,NM_003159.2(CDKL5):c.533G>A (p.Arg178Gln),CDKL5,CDKL5 disorder,MONDO:0100039,Pathogenic,X-linked inheritance (dominant (HP:0001423)),Rett and Angelman-like Disorders,2021-05-10,PS4,met,PubMed:24564546,The p.Arg178Gln variant was observed in a male individual with CDKL5 disease.,"The p.Arg178Gln variant has been observed in at least 7 other individuals with CDKL5 disease (PMIDs 26482601, 21770923,  29852413, 29190809, 24564546, ClinVar Variation ID 94113).","The p.Arg178Gln variant has been observed in at least 7 other individuals with CDKL5 disease (PMIDs 26482601, 21770923,  29852413, 29190809, 24564546, ClinVar Variation ID 94113). The p.Arg178Gln variant was observed in a male individual with CDKL5 disease.",ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
2168,NM_003159.2(CDKL5):c.533G>A (p.Arg178Gln),CDKL5,CDKL5 disorder,MONDO:0100039,Pathogenic,X-linked inheritance (dominant (HP:0001423)),Rett and Angelman-like Disorders,2021-05-10,PS4,met,PubMed:29190809,The p.Arg178Gln variant was observed in a female individual with epileptic encephalopathy.,"The p.Arg178Gln variant has been observed in at least 7 other individuals with CDKL5 disease (PMIDs 26482601, 21770923,  29852413, 29190809, 24564546, ClinVar Variation ID 94113).","The p.Arg178Gln variant has been observed in at least 7 other individuals with CDKL5 disease (PMIDs 26482601, 21770923,  29852413, 29190809, 24564546, ClinVar Variation ID 94113). The p.Arg178Gln variant was observed in a female individual with epileptic encephalopathy.",ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
2168,NM_003159.2(CDKL5):c.533G>A (p.Arg178Gln),CDKL5,CDKL5 disorder,MONDO:0100039,Pathogenic,X-linked inheritance (dominant (HP:0001423)),Rett and Angelman-like Disorders,2021-05-10,PS2-Very Strong,not_met,PubMed:24564546,The p.Arg178Gln variant in CDKL5 occurs in the unconfirmed de novo state in a male patient with CDKL5 disorder.,"The p.Arg178Gln variant in CDKL5 has been reported in the mosaic state in a male patient with epileptic encephalopathy (PMID 26482601).  The presence of the variant in the mosaic state confirms its de novo nature (PS2). The p.Arg178Gln variant in CDKL5 has been reported as an unconfirmed de novo occurrence in at least 4 individuals with CDKL5 disorder (PMIDs 21770923,  29852413, 29190809, 24564546) (PM6_very strong). Note that PM6_very strong is not available in the drop-down so PS2_VS is applied instead. ","The p.Arg178Gln variant in CDKL5 has been reported in the mosaic state in a male patient with epileptic encephalopathy (PMID 26482601).  The presence of the variant in the mosaic state confirms its de novo nature (PS2). The p.Arg178Gln variant in CDKL5 has been reported as an unconfirmed de novo occurrence in at least 4 individuals with CDKL5 disorder (PMIDs 21770923,  29852413, 29190809, 24564546) (PM6_very strong). Note that PM6_very strong is not available in the drop-down so PS2_VS is applied instead.  The p.Arg178Gln variant in CDKL5 occurs in the unconfirmed de novo state in a male patient with CDKL5 disorder.",ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
2168,NM_003159.2(CDKL5):c.533G>A (p.Arg178Gln),CDKL5,CDKL5 disorder,MONDO:0100039,Pathogenic,X-linked inheritance (dominant (HP:0001423)),Rett and Angelman-like Disorders,2021-05-10,PS2-Very Strong,not_met,PubMed:29190809,The p.Arg178Gln variant in CDKL5 occurs in the unconfirmed de novo state in a female patient with epileptic encephalopathy.,"The p.Arg178Gln variant in CDKL5 has been reported in the mosaic state in a male patient with epileptic encephalopathy (PMID 26482601).  The presence of the variant in the mosaic state confirms its de novo nature (PS2). The p.Arg178Gln variant in CDKL5 has been reported as an unconfirmed de novo occurrence in at least 4 individuals with CDKL5 disorder (PMIDs 21770923,  29852413, 29190809, 24564546) (PM6_very strong). Note that PM6_very strong is not available in the drop-down so PS2_VS is applied instead. ","The p.Arg178Gln variant in CDKL5 has been reported in the mosaic state in a male patient with epileptic encephalopathy (PMID 26482601).  The presence of the variant in the mosaic state confirms its de novo nature (PS2). The p.Arg178Gln variant in CDKL5 has been reported as an unconfirmed de novo occurrence in at least 4 individuals with CDKL5 disorder (PMIDs 21770923,  29852413, 29190809, 24564546) (PM6_very strong). Note that PM6_very strong is not available in the drop-down so PS2_VS is applied instead.  The p.Arg178Gln variant in CDKL5 occurs in the unconfirmed de novo state in a female patient with epileptic encephalopathy.",ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
2218,NM_003159.2(CDKL5):c.215T>C (p.Ile72Thr),CDKL5,CDKL5 disorder,MONDO:0100039,Pathogenic,X-linked inheritance (dominant (HP:0001423)),Rett and Angelman-like Disorders,2021-05-17,PS4-Moderate,not_met,PubMed:25657822,The p.Ile72Thr variant was observed in an individual with CDKL5 disorder.,"The p.Ile72Thr variant has been observed in at least 3 other individuals with CDKL5 disorder (PMID 19396824, 19241098, 25657822, ClinVar).","The p.Ile72Thr variant has been observed in at least 3 other individuals with CDKL5 disorder (PMID 19396824, 19241098, 25657822, ClinVar). The p.Ile72Thr variant was observed in an individual with CDKL5 disorder.",ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_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,PM6-Strong,not_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 at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with Pitt–Hopkins syndrome (PMID 29322350; 26993267, described as p.Ser355Arg)","The p.Ser253Arg variant in TCF4 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with Pitt–Hopkins syndrome (PMID 29322350; 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
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
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,PS4-Moderate,not_met,PubMed:26993267,Observed in 2 individuals with Pitt Hopkins syndrome,"The p.Ser253Arg variant has been observed in 3 other individuals with Pitt-Hopkins syndrome (PMID 29322350; 26993267, described as p.Ser355Arg)","The p.Ser253Arg variant has been observed in 3 other individuals with Pitt-Hopkins syndrome (PMID 29322350; 26993267, described as p.Ser355Arg) Observed in 2 individuals with Pitt Hopkins syndrome",ClinGenRettandAngelman-likeDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTCF4Version4.0.0_version=4.0.0.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
3066,NM_000545.6(HNF1A):c.1340C>T (p.Pro447Leu),HNF1A,monogenic diabetes,MONDO:0015967,Pathogenic,Autosomal dominant inheritance,Monogenic Diabetes,2022-07-11,PS3-Moderate,not_met,PubMed:27899486,Reported that the variant retained 20% of WT transcriptional activity,"Functional in vitro studies demonstrated that cells with this variant retained 20% of WT transcriptional activity, <10%-50% of WT transactivation activity, and low DNA binding","Functional in vitro studies demonstrated that cells with this variant retained 20% of WT transcriptional activity, <10%-50% of WT transactivation activity, and low DNA binding Reported that the variant retained 20% of WT transcriptional activity",ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF1AVersion2.1.0_version=2.1.0.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
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
4017,NM_001306179.2:c.613A>C,HNF1A,monogenic diabetes,MONDO:0015967,Uncertain Significance,Autosomal dominant inheritance,Monogenic Diabetes,2022-08-04,PM1,met,PubMed:28410371,Lys205 is an amino acid that directly binds DNA.,"This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1).","This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). Lys205 is an amino acid that directly binds DNA.",ClinGenMonogenicDiabetesExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforHNF1AVersion2.1.0_version=2.1.0.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
4102,NM_000540.2(RYR1):c.742G>C (p.Gly248Arg),RYR1,"malignant hyperthermia, susceptibility to, 1",MONDO:0007783,Pathogenic,Autosomal dominant inheritance,Malignant Hyperthermia Susceptibility,2022-09-08,PS3-Moderate,not_met,PubMed:26115329,HEK293 assay,HEK 293 assays show increased sensitivity,HEK 293 assays show increased sensitivity HEK293 assay,ClinGenMalignantHyperthermiaSusceptibilityExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRYR1Version2_version=2.0.0.csv
4102,NM_000540.2(RYR1):c.742G>C (p.Gly248Arg),RYR1,"malignant hyperthermia, susceptibility to, 1",MONDO:0007783,Pathogenic,Autosomal dominant inheritance,Malignant Hyperthermia Susceptibility,2022-09-08,PS3-Moderate,not_met,PubMed:27857962,HEK293 assay,HEK 293 assays show increased sensitivity,HEK 293 assays show increased sensitivity HEK293 assay,ClinGenMalignantHyperthermiaSusceptibilityExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforRYR1Version2_version=2.0.0.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
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
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
5613,NM_007294.4(BRCA1):c.5090G>A (p.Cys1697Tyr),BRCA1,BRCA1-related cancer predisposition,MONDO:0011450,Likely Pathogenic,Autosomal dominant inheritance,ENIGMA BRCA1 and BRCA2,2024-06-12,PS3,met,PubMed:30209399,Variant labelled as LOF,"Reported by two calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs: 30209399, PMID: 30765603) (PS3 met). 

","Reported by two calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs: 30209399, PMID: 30765603) (PS3 met). 

 Variant labelled as LOF",ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA1Version1.2.0_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
5629,NM_007294.4(BRCA1):c.5089T>C (p.Cys1697Arg),BRCA1,BRCA1-related cancer predisposition,MONDO:0011450,Pathogenic,Autosomal dominant inheritance,ENIGMA BRCA1 and BRCA2,2024-06-12,PS3,met,PubMed:30209399,Scores non-functional,"Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs: 30209399, 30257991, 30765603) (PS3 met).","Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs: 30209399, 30257991, 30765603) (PS3 met). Scores non-functional",ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA1Version1.2.0_version=1.2.0.csv
5643,NM_000059.4(BRCA2):c.8168A>C (p.Asp2723Ala),BRCA2,BRCA2-related cancer predisposition,MONDO:0012933,Pathogenic,Autosomal dominant inheritance,ENIGMA BRCA1 and BRCA2,2024-06-12,PS3,met,PubMed:33293522,Complete functional impact in assay measuring viability of knockout mouse embryonic stem cells,"Reported by two calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs: 33609447, 33293522) (PS3 met). ","Reported by two calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs: 33609447, 33293522) (PS3 met).  Complete functional impact in assay measuring viability of knockout mouse embryonic stem cells",ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA2Version1.2.0_version=1.2.0.csv
5643,NM_000059.4(BRCA2):c.8168A>C (p.Asp2723Ala),BRCA2,BRCA2-related cancer predisposition,MONDO:0012933,Pathogenic,Autosomal dominant inheritance,ENIGMA BRCA1 and BRCA2,2024-06-12,PS3,met,PubMed:33609447,Complete functional impact in homology directed repair assay,"Reported by two calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs: 33609447, 33293522) (PS3 met). ","Reported by two calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs: 33609447, 33293522) (PS3 met).  Complete functional impact in homology directed repair assay",ClinGenENIGMABRCA1andBRCA2ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBRCA2Version1.2.0_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
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
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
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
6921,NM_001204.7(BMPR2):c.1472G>A (p.Arg491Gln),BMPR2,pulmonary arterial hypertension,MONDO:0015924,Pathogenic,Autosomal dominant inheritance,Pulmonary Hypertension,2024-05-03,PM1-Strong,not_met,PubMed:31797984,Destabilization free energies were calculated using the Eris server. The R491Q mutation was studied using predictive tools. They show this mutation is highly destabilizing . ,Mutation R491Q is a critical residue located within the Kinase Domain of the protein. Arginine in position 491 of the BMPRII protein is indispensable for signaling.,Mutation R491Q is a critical residue located within the Kinase Domain of the protein. Arginine in position 491 of the BMPRII protein is indispensable for signaling. Destabilization free energies were calculated using the Eris server. The R491Q mutation was studied using predictive tools. They show this mutation is highly destabilizing . ,ClinGenPulmonaryHypertensionExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforBMPR2Version1.1.0_version=1.1.0.csv
6921,NM_001204.7(BMPR2):c.1472G>A (p.Arg491Gln),BMPR2,pulmonary arterial hypertension,MONDO:0015924,Pathogenic,Autosomal dominant inheritance,Pulmonary Hypertension,2024-05-03,PM1-Strong,not_met,PubMed:34400635,Mutations of the residues within the αH-αI linker in the BMPR2 kinase domain can disrupt ALK2/BMPR2 kinase dimerization and downstream signaling. ,Mutation R491Q is a critical residue located within the Kinase Domain of the protein. Arginine in position 491 of the BMPRII protein is indispensable for signaling.,Mutation R491Q is a critical residue located within the Kinase Domain of the protein. Arginine in position 491 of the BMPRII protein is indispensable for signaling. Mutations of the residues within the αH-αI linker in the BMPR2 kinase domain can disrupt ALK2/BMPR2 kinase dimerization and downstream signaling. ,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
6977,NM_006922.4(SCN3A):c.5407G>A (p.Asp1803Asn),SCN3A,developmental and epileptic encephalopathy,MONDO:0100062,Benign,Autosomal dominant inheritance,Epilepsy Sodium Channel,2024-05-09,PM1,met,PubMed:31871067,"Variant is located within a Pathogenic Enriched Regions (PERs) 
PER: Regions that are enriched for Pathogenic variants (ClinVar/HGMD) across gene families, lack population (gnomAD) variants",This variant resides within a region of SCN3A that is defined as a mutational hotspot by the ClinGen sodium channel VCEP.,"This variant resides within a region of SCN3A that is defined as a mutational hotspot by the ClinGen sodium channel VCEP. Variant is located within a Pathogenic Enriched Regions (PERs) 
PER: Regions that are enriched for Pathogenic variants (ClinVar/HGMD) across gene families, lack population (gnomAD) variants",ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN3AVersion2.0.0_version=2.0.0.csv
6977,NM_006922.4(SCN3A):c.5407G>A (p.Asp1803Asn),SCN3A,developmental and epileptic encephalopathy,MONDO:0100062,Benign,Autosomal dominant inheritance,Epilepsy Sodium Channel,2024-05-09,PM1,met,PubMed:32183904,"	
Variant is located within a Pathogenic Enriched Regions (PERs) 
PER: Regions that are enriched for Pathogenic variants (ClinVar/HGMD) across gene families, lack population (gnomAD) variants",This variant resides within a region of SCN3A that is defined as a mutational hotspot by the ClinGen sodium channel VCEP.,"This variant resides within a region of SCN3A that is defined as a mutational hotspot by the ClinGen sodium channel VCEP. 	
Variant is located within a Pathogenic Enriched Regions (PERs) 
PER: Regions that are enriched for Pathogenic variants (ClinVar/HGMD) across gene families, lack population (gnomAD) variants",ClinGenEpilepsySodiumChannelExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSCN3AVersion2.0.0_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
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
7553,NM_001369369.1(FOXN1):c.1370del (p.His457fs),FOXN1,"T-cell immunodeficiency, congenital alopecia, and nail dystrophy",MONDO:0011132,Pathogenic,Semidominant inheritance,Severe Combined Immunodeficiency Disease,2024-07-29,PS3,met,PubMed:34860543,"The transcriptional activity of wild-type and Δ550 FOXN1 were assayed in TEC4D6 cells cotransfected with a reporter plasmid containing a luciferase gene under the transcriptional control of the FOXN1-specific Psmb11 promoter, which normally controls β5t expression in TEC (2). Wild-type FOXN1 activated the luciferase gene in a gene dosage sensitive manner (Fig. 1E), whereas Δ550 FOXN1 failed to activate luciferase gene expression (Fig. 1F).","The heterozygous expression of Δ505 Foxn1 in mice, the ortholog of the human mutation, results in thymic hypoplasia, a limited population of peripheral T cells, and changes in the composition of the TEC scaffold.  FOXN1WT/Δ505 mice displayed a normal coat, whereas mice homozygous for the Δ505 mutation (designated FOXN1Δ505/Δ505) were hairless and lacked a thymus and peripheral T cells (fig. S2I). 

","The heterozygous expression of Δ505 Foxn1 in mice, the ortholog of the human mutation, results in thymic hypoplasia, a limited population of peripheral T cells, and changes in the composition of the TEC scaffold.  FOXN1WT/Δ505 mice displayed a normal coat, whereas mice homozygous for the Δ505 mutation (designated FOXN1Δ505/Δ505) were hairless and lacked a thymus and peripheral T cells (fig. S2I). 

 The transcriptional activity of wild-type and Δ550 FOXN1 were assayed in TEC4D6 cells cotransfected with a reporter plasmid containing a luciferase gene under the transcriptional control of the FOXN1-specific Psmb11 promoter, which normally controls β5t expression in TEC (2). Wild-type FOXN1 activated the luciferase gene in a gene dosage sensitive manner (Fig. 1E), whereas Δ550 FOXN1 failed to activate luciferase gene expression (Fig. 1F).",ClinGenSevereCombinedImmunodeficiencyDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforFOXN1Version1.0.0_version=1.0.0.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
7726,NM_000552.5(VWF):c.8317T>C (p.Cys2773Arg),VWF,von Willebrand disease type 2A,MONDO:0015628,Pathogenic,Autosomal dominant inheritance,von Willebrand Disease,2024-08-13,PS3,met,PubMed:34136746,"Fibronectin binding to recombinant VWF found p.2773R did not bind.

This is not an assay considered by the VWD VCEP for PS3.","Multimerization assay performed with the Cys2773Arg recombinant mutant and wt vWF expressed by COS7 cells showed abnormal multimers, including loss of HMWM and an extra central band, indicating that this variant has a damaging effect on protein function. Additionally, collagen binding was disrupted. (PMID: 11264172 Fig. 5; PS3) Similar results were also reported in PMID:24598842.
","Multimerization assay performed with the Cys2773Arg recombinant mutant and wt vWF expressed by COS7 cells showed abnormal multimers, including loss of HMWM and an extra central band, indicating that this variant has a damaging effect on protein function. Additionally, collagen binding was disrupted. (PMID: 11264172 Fig. 5; PS3) Similar results were also reported in PMID:24598842.
 Fibronectin binding to recombinant VWF found p.2773R did not bind.

This is not an assay considered by the VWD VCEP for PS3.",ClinGenvonWillebrandDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforVWFVersion1.0.0_version=1.0.0.csv
7726,NM_000552.5(VWF):c.8317T>C (p.Cys2773Arg),VWF,von Willebrand disease type 2A,MONDO:0015628,Pathogenic,Autosomal dominant inheritance,von Willebrand Disease,2024-08-13,PS3,met,PubMed:30645640,Found similar defects in dimerization using atomic force microscopy. ,"Multimerization assay performed with the Cys2773Arg recombinant mutant and wt vWF expressed by COS7 cells showed abnormal multimers, including loss of HMWM and an extra central band, indicating that this variant has a damaging effect on protein function. Additionally, collagen binding was disrupted. (PMID: 11264172 Fig. 5; PS3) Similar results were also reported in PMID:24598842.
","Multimerization assay performed with the Cys2773Arg recombinant mutant and wt vWF expressed by COS7 cells showed abnormal multimers, including loss of HMWM and an extra central band, indicating that this variant has a damaging effect on protein function. Additionally, collagen binding was disrupted. (PMID: 11264172 Fig. 5; PS3) Similar results were also reported in PMID:24598842.
 Found similar defects in dimerization using atomic force microscopy. ",ClinGenvonWillebrandDiseaseExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforVWFVersion1.0.0_version=1.0.0.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
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
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
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
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
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
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
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
9156,NM_001130987.2(DYSF):c.4076T>C (p.Leu1359Pro),DYSF,autosomal recessive limb-girdle muscular dystrophy,MONDO:0015152,Pathogenic,Autosomal recessive inheritance,Limb Girdle Muscular Dystrophy,2025-01-08,PS3,met,PubMed:23185377,"membrane resealing activity assay, which is not considered an acceptable assay for PS3 but is consistent with mouse model data","Knock-in mice homozygous for the murine equivalent of the human p.Leu1341Pro variant recapitulated key features of dysferlinopathy observed in human patients and tissue, including signs of progressive muscular dystrophy with onset in early adulthood, severely reduced expression of dysferlin at the plasma membrane in skeletal muscle, amyloid deposition, and delayed membrane repair (PMID: 30292141). In addition, immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Leu1341Pro protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538). (PS3)","Knock-in mice homozygous for the murine equivalent of the human p.Leu1341Pro variant recapitulated key features of dysferlinopathy observed in human patients and tissue, including signs of progressive muscular dystrophy with onset in early adulthood, severely reduced expression of dysferlin at the plasma membrane in skeletal muscle, amyloid deposition, and delayed membrane repair (PMID: 30292141). In addition, immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Leu1341Pro protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538). (PS3) membrane resealing activity assay, which is not considered an acceptable assay for PS3 but is consistent with mouse model data",ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDYSFVersion1.0.0_version=1.0.0.csv
9156,NM_001130987.2(DYSF):c.4076T>C (p.Leu1359Pro),DYSF,autosomal recessive limb-girdle muscular dystrophy,MONDO:0015152,Pathogenic,Autosomal recessive inheritance,Limb Girdle Muscular Dystrophy,2025-01-08,PS3,met,PubMed:30292141,"Generated a new mouse model (MMex38) carrying a missense mutation in exon 38 in analogy to a clinically relevant human DYSF variant (DYSF p.Leu1341Pro). The targeted mutation induces all characteristics of missense mutant dysferlinopathy, including a progressive dystrophic pattern, amyloid formation, and defects in membrane repair. Homozygous mutant newborn mice clinically and histopathologically do not display symptoms (data not shown). Signs of muscular dystrophy, such as necrotic and regenerating muscle fibers, fiber splitting, and fibrosis, first occurred in early adulthood (from week 12 onward) (Figure 1C; quantification and statistics are demonstrated in Figure S2), and they progressed significantly with age. At 60 months of age, more muscle fibers were replaced by fatty fibrosis (Figure 1C). On protein level Dysf p.Leu1360Pro led to a 90% reduction of dysferlin as assessed by western blot. Immunofluorescence stain for dysferlin on a frozen section revealed the absence of mutant dysferlin at the sarcolemma but occasional accumulations (Figure 1B). As described for the patients carrying DYSF missense mutations, MMex38 mouse muscle also displayed amyloid deposits at vessel walls (Figure 1D) and at the sarcolemma at older age. To assess dysferlin function in MMex38 mouse muscle, we performed the laser-wounding assay on isolated muscle fibers from MMex38 flexor digitorum brevis muscle ex vivo. Membrane repair was significantly delayed in MMex38 as compared to wild-type (WT) littermates (Figure 1E).
discussed with VCEP and agreed to score as PS3_Strong","Knock-in mice homozygous for the murine equivalent of the human p.Leu1341Pro variant recapitulated key features of dysferlinopathy observed in human patients and tissue, including signs of progressive muscular dystrophy with onset in early adulthood, severely reduced expression of dysferlin at the plasma membrane in skeletal muscle, amyloid deposition, and delayed membrane repair (PMID: 30292141). In addition, immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Leu1341Pro protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538). (PS3)","Knock-in mice homozygous for the murine equivalent of the human p.Leu1341Pro variant recapitulated key features of dysferlinopathy observed in human patients and tissue, including signs of progressive muscular dystrophy with onset in early adulthood, severely reduced expression of dysferlin at the plasma membrane in skeletal muscle, amyloid deposition, and delayed membrane repair (PMID: 30292141). In addition, immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Leu1341Pro protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538). (PS3) Generated a new mouse model (MMex38) carrying a missense mutation in exon 38 in analogy to a clinically relevant human DYSF variant (DYSF p.Leu1341Pro). The targeted mutation induces all characteristics of missense mutant dysferlinopathy, including a progressive dystrophic pattern, amyloid formation, and defects in membrane repair. Homozygous mutant newborn mice clinically and histopathologically do not display symptoms (data not shown). Signs of muscular dystrophy, such as necrotic and regenerating muscle fibers, fiber splitting, and fibrosis, first occurred in early adulthood (from week 12 onward) (Figure 1C; quantification and statistics are demonstrated in Figure S2), and they progressed significantly with age. At 60 months of age, more muscle fibers were replaced by fatty fibrosis (Figure 1C). On protein level Dysf p.Leu1360Pro led to a 90% reduction of dysferlin as assessed by western blot. Immunofluorescence stain for dysferlin on a frozen section revealed the absence of mutant dysferlin at the sarcolemma but occasional accumulations (Figure 1B). As described for the patients carrying DYSF missense mutations, MMex38 mouse muscle also displayed amyloid deposits at vessel walls (Figure 1D) and at the sarcolemma at older age. To assess dysferlin function in MMex38 mouse muscle, we performed the laser-wounding assay on isolated muscle fibers from MMex38 flexor digitorum brevis muscle ex vivo. Membrane repair was significantly delayed in MMex38 as compared to wild-type (WT) littermates (Figure 1E).
discussed with VCEP and agreed to score as PS3_Strong",ClinGenLimbGirdleMuscularDystrophyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforDYSFVersion1.0.0_version=1.0.0.csv
9156,NM_001130987.2(DYSF):c.4076T>C (p.Leu1359Pro),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 Leu1341Pro protein did not reach the cell membrane, indicating an impact on protein function","Knock-in mice homozygous for the murine equivalent of the human p.Leu1341Pro variant recapitulated key features of dysferlinopathy observed in human patients and tissue, including signs of progressive muscular dystrophy with onset in early adulthood, severely reduced expression of dysferlin at the plasma membrane in skeletal muscle, amyloid deposition, and delayed membrane repair (PMID: 30292141). In addition, immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Leu1341Pro protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538). (PS3)","Knock-in mice homozygous for the murine equivalent of the human p.Leu1341Pro variant recapitulated key features of dysferlinopathy observed in human patients and tissue, including signs of progressive muscular dystrophy with onset in early adulthood, severely reduced expression of dysferlin at the plasma membrane in skeletal muscle, amyloid deposition, and delayed membrane repair (PMID: 30292141). In addition, immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Leu1341Pro protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538). (PS3) Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Leu1341Pro protein did not reach the cell membrane, indicating an impact on protein function",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
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