VCI/split_evidence_sufficiency/train.csv

entry_index,variant,hgnc_gene,disease,mondo_id,assertion,mode_inheritance,expert_panel,pub_date,evidence_code,met_status,pmid,comments,summary,summary_comments,path
5922,NM_000277.1:c.971T>A,PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2023-12-30,PP4-Moderate,not_met,PubMed:24705691,BH4 defect excluded via sequencing of all genes associated with primary BH4 defects.  Single patient,"It has been previously reported in at least 12 patients with PKU and BH4 deficiency formally excluded, including in confirmed trans with Pathogenic or Likely Pathogenic variants (PM3_VeryStrong (7.5 points total); PP4_Moderate). It was reported in presumed trans with p.R241C (Pathogenic per ClinGen PAH VCEP) in a Chinese proband with mild PKU (plasma Phe 760 μmol/L) and BH4 deficiency was said to be excluded (PMID: 28982351); in presumed trans with p.R111* (Pathogenic by ClinGen PAH VCEP) in a Chinese proband with classic PKU and in presumed trans with c.509+1G>A (Pathogenic by ClinGen PAH VCEP) in a Chinese proband with classic PKU (plasma Phe levels not specified; BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes). It has also been reported in confirmed trans with c.1066-11G>A (Pathogenic by ClinGen PAH VCEP) in a Chinese proband with PKU and BH4 deficiency excluded by sequencing of genes in the BH4 cofactor metabolism pathway) (PMID: 24705691); in a Chinese proband with PKU in confirmed trans with the c.442–1G>A variant (Pathogenic by ClinGen PAH VCEP) and in another Chinese proband with PKU in confirmed trans with the p.G247R variant (Likely Pathogenic by ClinGen PAH VCEP) (PMID: 29353259). It has been noted in a patient with PKU in presumed trans with p.T418P variant (Pathogenic by ClinGen PAH VCEP) (plasma Phe levels not noted; BH4 deficiency excluded by sequencing of genes in the BH4 cofactor metabolism pathway) (PMID: 29731766); in a Chinese patient with mild PKU (plasma Phe 780 umol/L) in presumed trans with the p.R243Q variant (Pathogenic by ClinGen PAH VCEP) and BH4 deficiency excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PMID: 28754886). Finally, it has been noted among multiple Chinese PKU patients with BH4 deficiency excluded by urinary pterin analysis, including in the homozygous state in a Chinese patient with classic PKU (plasma Phe not noted), in another patient with PKU (phenotype not further specified) in presumed trans with the c.611A>G (p.Ex6-96A>G) variant (Pathogenic by ClinGen PAH VCEP), in presumed trans with the p.V399V variant (Pathogenic by ClinGen PAH VCEP) in another Chinese patient with mild PKU, and in presumed trans with the p.Y356* variant (Pathogenic by ClinGen PAH VCEP) (PMID: 30050108).","It has been previously reported in at least 12 patients with PKU and BH4 deficiency formally excluded, including in confirmed trans with Pathogenic or Likely Pathogenic variants (PM3_VeryStrong (7.5 points total); PP4_Moderate). It was reported in presumed trans with p.R241C (Pathogenic per ClinGen PAH VCEP) in a Chinese proband with mild PKU (plasma Phe 760 μmol/L) and BH4 deficiency was said to be excluded (PMID: 28982351); in presumed trans with p.R111* (Pathogenic by ClinGen PAH VCEP) in a Chinese proband with classic PKU and in presumed trans with c.509+1G>A (Pathogenic by ClinGen PAH VCEP) in a Chinese proband with classic PKU (plasma Phe levels not specified; BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes). It has also been reported in confirmed trans with c.1066-11G>A (Pathogenic by ClinGen PAH VCEP) in a Chinese proband with PKU and BH4 deficiency excluded by sequencing of genes in the BH4 cofactor metabolism pathway) (PMID: 24705691); in a Chinese proband with PKU in confirmed trans with the c.442–1G>A variant (Pathogenic by ClinGen PAH VCEP) and in another Chinese proband with PKU in confirmed trans with the p.G247R variant (Likely Pathogenic by ClinGen PAH VCEP) (PMID: 29353259). It has been noted in a patient with PKU in presumed trans with p.T418P variant (Pathogenic by ClinGen PAH VCEP) (plasma Phe levels not noted; BH4 deficiency excluded by sequencing of genes in the BH4 cofactor metabolism pathway) (PMID: 29731766); in a Chinese patient with mild PKU (plasma Phe 780 umol/L) in presumed trans with the p.R243Q variant (Pathogenic by ClinGen PAH VCEP) and BH4 deficiency excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PMID: 28754886). Finally, it has been noted among multiple Chinese PKU patients with BH4 deficiency excluded by urinary pterin analysis, including in the homozygous state in a Chinese patient with classic PKU (plasma Phe not noted), in another patient with PKU (phenotype not further specified) in presumed trans with the c.611A>G (p.Ex6-96A>G) variant (Pathogenic by ClinGen PAH VCEP), in presumed trans with the p.V399V variant (Pathogenic by ClinGen PAH VCEP) in another Chinese patient with mild PKU, and in presumed trans with the p.Y356* variant (Pathogenic by ClinGen PAH VCEP) (PMID: 30050108). BH4 defect excluded via sequencing of all genes associated with primary BH4 defects.  Single patient",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,PP4-Moderate,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.","p.[A156P] reported 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 by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes.  PMID: 26322415","p.[A156P] reported 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 by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes.  PMID: 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.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
23,NM_000277.2(PAH):c.158G>A (p.Arg53His),PAH,phenylketonuria,MONDO:0009861,Uncertain Significance,Autosomal recessive inheritance,Phenylketonuria,2019-04-08,PP4-Moderate,not_met,PubMed:26322415,"c.158G>A p.R53H identified on 8 alleles. 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.","Detected in multiple patients with mild hyperphenylalaninemia (MHP, Phe levels<10 mg/dl), BH4 deficiency excluded.","Detected in multiple patients with mild hyperphenylalaninemia (MHP, Phe levels<10 mg/dl), BH4 deficiency excluded. c.158G>A p.R53H identified on 8 alleles. 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
2071,NM_000277.3(PAH):c.529G>C (p.Val177Leu),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2021-04-09,PP4-Moderate,not_met,PubMed:23842451,183 patients from six Dutch university medical centres. Detected in the cohort.,Detected in multiple patients with PAH deficiency. BH4 deficiency excluded in one report.  PMID: 22526846,Detected in multiple patients with PAH deficiency. BH4 deficiency excluded in one report.  PMID: 22526846 183 patients from six Dutch university medical centres. Detected in the cohort.,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:28982351,Patients with BH4 cofactor deficiency were excluded. Patient 328 has mPKU (Phe level 720) and genotype EX6-96A>G/p.Gln429Lys,"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 Patients with BH4 cofactor deficiency were excluded. Patient 328 has mPKU (Phe level 720) and genotype EX6-96A>G/p.Gln429Lys",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1563,NM_000277.2(PAH):c.932T>C (p.Leu311Pro),PAH,phenylketonuria,MONDO:0009861,Pathogenic,,Phenylketonuria,2020-02-22,PP4-Moderate,not_met,PubMed:23842451,"BH4 responsiveness predicted with 48hr loading test
Subjects – 183 patients in 6 dutch university medical centers Nov 2009 – Dec 2010
Single patient, I65T/L311P. with classic PKU.  I65T is pathogenic in clinvar.  Patient had no BH4 responsiveness.","BH4 defect excluded in all patients (PMID: 9634518,  PMID: 23842451)","BH4 defect excluded in all patients (PMID: 9634518,  PMID: 23842451) BH4 responsiveness predicted with 48hr loading test
Subjects – 183 patients in 6 dutch university medical centers Nov 2009 – Dec 2010
Single patient, I65T/L311P. with classic PKU.  I65T is pathogenic in clinvar.  Patient had no BH4 responsiveness.",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,PP4-Moderate,not_met,PubMed:26413448,One homozygous proband with c.168+5G>A had classical PKU with (PHE > 1200 umol/L). No reported testing to rule out BH4 deficiency.,"Four probands have been described with this variant ranging from mild HPA to classic PKU, in two of these probands BH4 deficiency was ruled out.","Four probands have been described with this variant ranging from mild HPA to classic PKU, in two of these probands BH4 deficiency was ruled out. One homozygous proband with c.168+5G>A had classical PKU with (PHE > 1200 umol/L). No reported testing to rule out BH4 deficiency.",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,PP4-Moderate,not_met,PubMed:26322415,"L48S was detected on 1 allele. 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.","Detected in multiple patients with PKU (mild and classic). Bh4 deficiency excluded.  PMID: 26322415, PMID: 16879198,  PMID: 1679030","Detected in multiple patients with PKU (mild and classic). Bh4 deficiency excluded.  PMID: 26322415, PMID: 16879198,  PMID: 1679030 L48S was detected on 1 allele. 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
1052,NM_000277.3(PAH):c.460T>C (p.Tyr154His),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-12-22,PP4-Moderate,not_met,PubMed:26503515,,"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. BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PMID: 26322415). This variant was also reported in a Chinese patient with classical PKU (Phe ≥1200 μmol/L) (PMID:16256386), and in two other Chinese patients with undetermined PKU/MHP phenotype (PMID: 26503515, and PMID: 19915519).","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. BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PMID: 26322415). This variant was also reported in a Chinese patient with classical PKU (Phe ≥1200 μmol/L) (PMID:16256386), and in two other Chinese patients with undetermined PKU/MHP phenotype (PMID: 26503515, and PMID: 19915519). ",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
5922,NM_000277.1:c.971T>A,PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2023-12-30,PP4-Moderate,not_met,PubMed:26322415,BH4 defect excluded with urine pterins and DHPR activity.  Single patient with this variant.,"It has been previously reported in at least 12 patients with PKU and BH4 deficiency formally excluded, including in confirmed trans with Pathogenic or Likely Pathogenic variants (PM3_VeryStrong (7.5 points total); PP4_Moderate). It was reported in presumed trans with p.R241C (Pathogenic per ClinGen PAH VCEP) in a Chinese proband with mild PKU (plasma Phe 760 μmol/L) and BH4 deficiency was said to be excluded (PMID: 28982351); in presumed trans with p.R111* (Pathogenic by ClinGen PAH VCEP) in a Chinese proband with classic PKU and in presumed trans with c.509+1G>A (Pathogenic by ClinGen PAH VCEP) in a Chinese proband with classic PKU (plasma Phe levels not specified; BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes). It has also been reported in confirmed trans with c.1066-11G>A (Pathogenic by ClinGen PAH VCEP) in a Chinese proband with PKU and BH4 deficiency excluded by sequencing of genes in the BH4 cofactor metabolism pathway) (PMID: 24705691); in a Chinese proband with PKU in confirmed trans with the c.442–1G>A variant (Pathogenic by ClinGen PAH VCEP) and in another Chinese proband with PKU in confirmed trans with the p.G247R variant (Likely Pathogenic by ClinGen PAH VCEP) (PMID: 29353259). It has been noted in a patient with PKU in presumed trans with p.T418P variant (Pathogenic by ClinGen PAH VCEP) (plasma Phe levels not noted; BH4 deficiency excluded by sequencing of genes in the BH4 cofactor metabolism pathway) (PMID: 29731766); in a Chinese patient with mild PKU (plasma Phe 780 umol/L) in presumed trans with the p.R243Q variant (Pathogenic by ClinGen PAH VCEP) and BH4 deficiency excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PMID: 28754886). Finally, it has been noted among multiple Chinese PKU patients with BH4 deficiency excluded by urinary pterin analysis, including in the homozygous state in a Chinese patient with classic PKU (plasma Phe not noted), in another patient with PKU (phenotype not further specified) in presumed trans with the c.611A>G (p.Ex6-96A>G) variant (Pathogenic by ClinGen PAH VCEP), in presumed trans with the p.V399V variant (Pathogenic by ClinGen PAH VCEP) in another Chinese patient with mild PKU, and in presumed trans with the p.Y356* variant (Pathogenic by ClinGen PAH VCEP) (PMID: 30050108).","It has been previously reported in at least 12 patients with PKU and BH4 deficiency formally excluded, including in confirmed trans with Pathogenic or Likely Pathogenic variants (PM3_VeryStrong (7.5 points total); PP4_Moderate). It was reported in presumed trans with p.R241C (Pathogenic per ClinGen PAH VCEP) in a Chinese proband with mild PKU (plasma Phe 760 μmol/L) and BH4 deficiency was said to be excluded (PMID: 28982351); in presumed trans with p.R111* (Pathogenic by ClinGen PAH VCEP) in a Chinese proband with classic PKU and in presumed trans with c.509+1G>A (Pathogenic by ClinGen PAH VCEP) in a Chinese proband with classic PKU (plasma Phe levels not specified; BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes). It has also been reported in confirmed trans with c.1066-11G>A (Pathogenic by ClinGen PAH VCEP) in a Chinese proband with PKU and BH4 deficiency excluded by sequencing of genes in the BH4 cofactor metabolism pathway) (PMID: 24705691); in a Chinese proband with PKU in confirmed trans with the c.442–1G>A variant (Pathogenic by ClinGen PAH VCEP) and in another Chinese proband with PKU in confirmed trans with the p.G247R variant (Likely Pathogenic by ClinGen PAH VCEP) (PMID: 29353259). It has been noted in a patient with PKU in presumed trans with p.T418P variant (Pathogenic by ClinGen PAH VCEP) (plasma Phe levels not noted; BH4 deficiency excluded by sequencing of genes in the BH4 cofactor metabolism pathway) (PMID: 29731766); in a Chinese patient with mild PKU (plasma Phe 780 umol/L) in presumed trans with the p.R243Q variant (Pathogenic by ClinGen PAH VCEP) and BH4 deficiency excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PMID: 28754886). Finally, it has been noted among multiple Chinese PKU patients with BH4 deficiency excluded by urinary pterin analysis, including in the homozygous state in a Chinese patient with classic PKU (plasma Phe not noted), in another patient with PKU (phenotype not further specified) in presumed trans with the c.611A>G (p.Ex6-96A>G) variant (Pathogenic by ClinGen PAH VCEP), in presumed trans with the p.V399V variant (Pathogenic by ClinGen PAH VCEP) in another Chinese patient with mild PKU, and in presumed trans with the p.Y356* variant (Pathogenic by ClinGen PAH VCEP) (PMID: 30050108). BH4 defect excluded with urine pterins and DHPR activity.  Single patient with this variant.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
3647,NM_001354304.2:c.920G>A,PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2022-06-12,PP4-Moderate,not_met,PubMed:26322415,BH4 defects excluded in all patients.  Single patient in this paper c.920G>A/C.331C>T (pathogenic) with mild PKU,BH4 defects excluded in all patients.  Single patient in this paper c.920G>A/C.331C>T (pathogenic) with mild PKU,BH4 defects excluded in all patients.  Single patient in this paper c.920G>A/C.331C>T (pathogenic) with mild PKU BH4 defects excluded in all patients.  Single patient in this paper c.920G>A/C.331C>T (pathogenic) with mild PKU,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
621,NM_000277.2(PAH):c.823C>T (p.Pro275Ser),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-05,PP4-Moderate,not_met,PubMed:24705691,BH4 defect excluded in all patients,"BH4 defect excluded in all patients (PMID: 24705691,  PMID: 20123475). Phe = 380umol/L (Gassio 2010)","BH4 defect excluded in all patients (PMID: 24705691,  PMID: 20123475). Phe = 380umol/L (Gassio 2010) BH4 defect excluded in all patients",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,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. Demographic data, including age, consanguinity, family history, and geographical origin, and biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected. One patient had c.532G>A (p.E178K).","Detected in Chinese PKU patient, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading were assessed.  PMID: 26503515 Detected in a Danish patient with probable MHP. PMID: 26542770","Detected in Chinese PKU patient, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading were assessed.  PMID: 26503515 Detected in a Danish patient with probable MHP. PMID: 26542770 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. Demographic data, including age, consanguinity, family history, and geographical origin, and biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected. One patient had c.532G>A (p.E178K).",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:26503515,,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 ,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:24705691,"Seen in a individual with diagnosed PKU, no other information provided. From a 'core' family meaning a completed pedigree.  No consanguineous families were included in this study","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 a individual with diagnosed PKU, no other information provided. From a 'core' family meaning a completed pedigree.  No consanguineous families were included in this study",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
2641,NM_000277.1:c.1123C>G,PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2021-09-19,PP4-Moderate,not_met,PubMed:26503515,"Seen in 2 individuals with Classic PKU.  Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected.","Seen in 2 individuals with Classic PKU. Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected.  PMID: 26503515","Seen in 2 individuals with Classic PKU. Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected.  PMID: 26503515 Seen in 2 individuals with Classic PKU.  Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
2645,NM_000277.1(PAH):c.665A>G (p.Asp222Gly),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2021-09-19,PM3-Strong,not_met,PubMed:23842451,1 PKU patient had genotype c.1066-11G>A1/p.D222G,D222G found with A104D parental analysis not performed (PMID: 9429153); R408W parental analysis not reported (PMID: 15589814); c.1066-11G>A parental analysis not reported (PMID: 23842451); L48S parental analysis not reported  (PMID: 25757997); p.I65T parental analysis not reported (PMID: 16165389); p.S16* validation tests on parents were performed (All Pathogenic in ClinVar) 3.5 pts,D222G found with A104D parental analysis not performed (PMID: 9429153); R408W parental analysis not reported (PMID: 15589814); c.1066-11G>A parental analysis not reported (PMID: 23842451); L48S parental analysis not reported  (PMID: 25757997); p.I65T parental analysis not reported (PMID: 16165389); p.S16* validation tests on parents were performed (All Pathogenic in ClinVar) 3.5 pts 1 PKU patient had genotype c.1066-11G>A1/p.D222G,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:29316886,This variant was documented in one Han Chinese patient diagnosed with mild PKU who was a compound heterozygote with the p.Cys217Tyr VUS in trans (PMID: 29316886).  Parental analysis was 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 one Han Chinese patient diagnosed with mild PKU who was a compound heterozygote with the p.Cys217Tyr VUS in trans (PMID: 29316886).  Parental analysis was performed to confirm heterozygosity.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1504,NM_000277.2(PAH):c.1196T>C (p.Val399Ala),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2020-07-10,PM3-Strong,not_met,PubMed:26666653,,V399A detected with P281L (P) and E178G (P) PMID: 21147011 p.R408W (P 14 submitters)  PMID: 23062575 c.1066-11G>A (P 7 submitters)  PMID: 26666653 Parental analysis not performed.,V399A detected with P281L (P) and E178G (P) PMID: 21147011 p.R408W (P 14 submitters)  PMID: 23062575 c.1066-11G>A (P 7 submitters)  PMID: 26666653 Parental analysis not performed. ,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,PM3-Strong,not_met,PubMed:28982351,This variant was documented in 1 PKU patient with the pathogenic c.1197A>T (p.V399V) variant in trans. This study included 655 PKU patients and phenylalanine plasma concentrations >120 µmol/L were reported for all subjects. Tetrahydrobiopterin (BH4) deficiency was excluded through urinary pterin analysis. Parental analysis was performed to confirm compound heterozygosity.,"This variant was documented in trans with a pathogenic or likely pathogenic PAH variant in 4 patients diagnosed with PKU or Hyperphenylalaninemia (PMID: 16256386, 28982351, 25456745, 23932990).","This variant was documented in trans with a pathogenic or likely pathogenic PAH variant in 4 patients diagnosed with PKU or Hyperphenylalaninemia (PMID: 16256386, 28982351, 25456745, 23932990). This variant was documented in 1 PKU patient with the pathogenic c.1197A>T (p.V399V) variant in trans. This study included 655 PKU patients and phenylalanine plasma concentrations >120 µmol/L were reported for all subjects. Tetrahydrobiopterin (BH4) deficiency was excluded through urinary pterin analysis. Parental analysis was performed to confirm compound heterozygosity.",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:30050108,From supplemental table: patient genotype p.P147L/c.611A>G (p.EX6-96A>G). The validation tests on parents were performed using Sanger 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 From supplemental table: patient genotype p.P147L/c.611A>G (p.EX6-96A>G). The validation tests on parents were performed using Sanger sequencing.",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,PM3-Strong,not_met,PubMed:28982351,found in trans with p.Gln419Arg (classified LP by Counsyl in ClinVar) allele in 1 case with mild hyperphenylalanemia,"It was found in two cases in trans with other P/LP alleles: one case with classic PKU (assessed via plasma Phe measurement in trans with the p.R158Q allele (PMID: 18956252) (PP4) and one case whose PKU sub-phenotype was not mentioned in trans with the p.R261Q allele (PMID: 23074961) (PM3_Strong). It has also been found in trans with the p.Gln419Arg, classified as Likely Pathogenic in ClinVar, in 1 case with mild hyperphenylalanemia (PMID 28982351).","It was found in two cases in trans with other P/LP alleles: one case with classic PKU (assessed via plasma Phe measurement in trans with the p.R158Q allele (PMID: 18956252) (PP4) and one case whose PKU sub-phenotype was not mentioned in trans with the p.R261Q allele (PMID: 23074961) (PM3_Strong). It has also been found in trans with the p.Gln419Arg, classified as Likely Pathogenic in ClinVar, in 1 case with mild hyperphenylalanemia (PMID 28982351). found in trans with p.Gln419Arg (classified LP by Counsyl in ClinVar) allele in 1 case with mild hyperphenylalanemia",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,PM3-Strong,not_met,PubMed:25757997,Subject 8 had mild PKU and genotype L48S/D222G,D222G found with A104D parental analysis not performed (PMID: 9429153); R408W parental analysis not reported (PMID: 15589814); c.1066-11G>A parental analysis not reported (PMID: 23842451); L48S parental analysis not reported  (PMID: 25757997); p.I65T parental analysis not reported (PMID: 16165389); p.S16* validation tests on parents were performed (All Pathogenic in ClinVar) 3.5 pts,D222G found with A104D parental analysis not performed (PMID: 9429153); R408W parental analysis not reported (PMID: 15589814); c.1066-11G>A parental analysis not reported (PMID: 23842451); L48S parental analysis not reported  (PMID: 25757997); p.I65T parental analysis not reported (PMID: 16165389); p.S16* validation tests on parents were performed (All Pathogenic in ClinVar) 3.5 pts Subject 8 had mild PKU and genotype L48S/D222G,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1563,NM_000277.2(PAH):c.932T>C (p.Leu311Pro),PAH,phenylketonuria,MONDO:0009861,Pathogenic,,Phenylketonuria,2020-02-22,PM3-Strong,not_met,PubMed:26666653,,L311P/I65T (pathogenic per ClinVar) p.Y386C (P/LP)  PMID: 22841515 p.R261Q (P 9 submitters)  PMID: 21871829 c.842+5G>A (P/LP)  PMID: 19609714 p.Gly257Asp (LP)  PMID: 26666653 parental analysis not reported in trans with c.842+1G>A (p 2 submitters)  PMID: 27121329,L311P/I65T (pathogenic per ClinVar) p.Y386C (P/LP)  PMID: 22841515 p.R261Q (P 9 submitters)  PMID: 21871829 c.842+5G>A (P/LP)  PMID: 19609714 p.Gly257Asp (LP)  PMID: 26666653 parental analysis not reported in trans with c.842+1G>A (p 2 submitters)  PMID: 27121329 ,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
688,NM_000277.2(PAH):c.504C>A (p.Tyr168Ter),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-05-26,PP4,met,PubMed:26666653,,The c.504C>A (p.Tyr168Ter) variant in PAH has been previously reported in one proband with mild hyperphenylalanemia (defined by the authors as plasma phenylalanine levels >180 umol/L and <600umol/L) (PMID: 26666653) (PP4).,The c.504C>A (p.Tyr168Ter) variant in PAH has been previously reported in one proband with mild hyperphenylalanemia (defined by the authors as plasma phenylalanine levels >180 umol/L and <600umol/L) (PMID: 26666653) (PP4). ,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
843,NM_000277.2(PAH):c.547_548delGAinsTT (p.Glu183Leu),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-08-11,PP4,met,PubMed:26666653,A compound heterozygous proband with this variant was described with the classic PKU phenotype and PHE >1200umol/L. Defects in BH4 cofactor metabolism were not excluded.,A compound heterozygous proband with this variant was described with the classic PKU phenotype and PHE >1200umol/L. Defects in BH4 cofactor metabolism were not excluded.,A compound heterozygous proband with this variant was described with the classic PKU phenotype and PHE >1200umol/L. Defects in BH4 cofactor metabolism were not excluded. A compound heterozygous proband with this variant was described with the classic PKU phenotype and PHE >1200umol/L. Defects in BH4 cofactor metabolism were not excluded.,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
715,NM_000277.2(PAH):c.887A>G (p.Asp296Gly),PAH,phenylketonuria,MONDO:0009861,Uncertain Significance,Autosomal recessive inheritance,Phenylketonuria,2019-07-14,PP4,met,PubMed:26666653,reported in a proband with classic PKU (plasma phenylalanine 1326 umol/L); BH4 deficiency does not appear to have been formally excluded,reported in a proband with classic PKU (plasma phenylalanine 1326 umol/L); BH4 deficiency does not appear to have been formally excluded (PP4).,reported in a proband with classic PKU (plasma phenylalanine 1326 umol/L); BH4 deficiency does not appear to have been formally excluded (PP4). reported in a proband with classic PKU (plasma phenylalanine 1326 umol/L); BH4 deficiency does not appear to have been formally excluded,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1575,NM_000277.2(PAH):c.441+1G>A,PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-06,PP4,met,PubMed:26503515,Recurrent mutation among Chinese cases with classic PKU.,"Found in multiple probands with classic PKU, although BH4 deficiency does not appear to have been formally excluded.","Found in multiple probands with classic PKU, although BH4 deficiency does not appear to have been formally excluded. Recurrent mutation among Chinese cases with classic PKU.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
76,NM_000277.1(PAH):c.926C>T (p.Ala309Val),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-05,PP4,met,PubMed:26666653,"Genotype-phenotype association in French patients with PKU.  364 patients, 24hr BH4 loading test.","Single patient with classic PKU (>1200umol/L), BH4 defect not excluded","Single patient with classic PKU (>1200umol/L), BH4 defect not excluded Genotype-phenotype association in French patients with PKU.  364 patients, 24hr BH4 loading test.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
718,NM_000277.2(PAH):c.837delC (p.Glu280Asnfs),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-07-14,PP4,met,PubMed:26666653,A compound heterozygous proband with the c.837del variant (misidentified in this publication as His280Asnfs*61) was described with the classic PKU phenotype and PHE >1200umol/L. Defects in BH4 cofactor metabolism were not excluded.,Two compound heterozygous probands have been described with the c.837del variant each with the classic PKU phenotype and PHE >1200umol/L. Defects in BH4 cofactor metabolism were not excluded.,Two compound heterozygous probands have been described with the c.837del variant each with the classic PKU phenotype and PHE >1200umol/L. Defects in BH4 cofactor metabolism were not excluded. A compound heterozygous proband with the c.837del variant (misidentified in this publication as His280Asnfs*61) 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
954,NM_000277.2(PAH):c.169G>T (p.Glu57Ter),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-10-02,PP4,met,PubMed:26666653,"The c.169G>T (p.Glu57Ter) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120268); the collection method is stated as “literature only” and no further information is provided. With respect to the published literature, it has been previously reported in one proband with classic PKU (defined by the authors as plasma phenylalanine levels > 1200umol/L) (PMID: 26666653) (PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic allele (per ClinGen PAH working group classification, see ClinVar ID 636) c.194T>C (p.Ile65Thr); however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence.","The c.169G>T (p.Glu57Ter) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120268); the collection method is stated as “literature only” and no further information is provided. With respect to the published literature, it has been previously reported in one proband with classic PKU (defined by the authors as plasma phenylalanine levels > 1200umol/L) (PMID: 26666653) (PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic allele (per ClinGen PAH working group classification, see ClinVar ID 636) c.194T>C (p.Ile65Thr); however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence.","The c.169G>T (p.Glu57Ter) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120268); the collection method is stated as “literature only” and no further information is provided. With respect to the published literature, it has been previously reported in one proband with classic PKU (defined by the authors as plasma phenylalanine levels > 1200umol/L) (PMID: 26666653) (PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic allele (per ClinGen PAH working group classification, see ClinVar ID 636) c.194T>C (p.Ile65Thr); however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence. The c.169G>T (p.Glu57Ter) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120268); the collection method is stated as “literature only” and no further information is provided. With respect to the published literature, it has been previously reported in one proband with classic PKU (defined by the authors as plasma phenylalanine levels > 1200umol/L) (PMID: 26666653) (PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic allele (per ClinGen PAH working group classification, see ClinVar ID 636) c.194T>C (p.Ile65Thr); however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
23,NM_000277.2(PAH):c.158G>A (p.Arg53His),PAH,phenylketonuria,MONDO:0009861,Uncertain Significance,Autosomal recessive inheritance,Phenylketonuria,2019-04-08,PM3,met,PubMed:26322415,"Patient genotype: c.[158G>A];[728G>A],p.[R53H];[R243Q]. 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.R243Q (P, 7 submitters)  PMID: 26322415","Detected in trans with p.R243Q (P, 7 submitters)  PMID: 26322415 Patient genotype: c.[158G>A];[728G>A],p.[R53H];[R243Q]. 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
718,NM_000277.2(PAH):c.837delC (p.Glu280Asnfs),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-07-14,PM3,met,PubMed:26666653,"The c.837del frameshift variant (in this publication misidentified as His280Asnfs*61) was observed in trans with the pathogenic variant c.1315+1G>A (ClinVar 576, Pathogenic).","The c.837del frameshift variant has been observed in trans with pathogenic variants Val388Met (ClinVar 619, Pathogenic) and c.1315+1G>A (ClinVar 576, Pathogenic).","The c.837del frameshift variant has been observed in trans with pathogenic variants Val388Met (ClinVar 619, Pathogenic) and c.1315+1G>A (ClinVar 576, Pathogenic). The c.837del frameshift variant (in this publication misidentified as His280Asnfs*61) was observed in trans with the pathogenic variant c.1315+1G>A (ClinVar 576, Pathogenic).",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
655,NM_000277.2(PAH):c.386A>G (p.Asp129Gly),PAH,phenylketonuria,MONDO:0009861,Likely Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-05,PM3,met,PubMed:26666653,Patient genotype: c.194T>C;c.386A>G / p.(Ile65Thr);p.(Asp129Gly). Parental segregation not reported/performed.,Detected in trans with c.1066-11G>A PMID:27121329,Detected in trans with c.1066-11G>A PMID:27121329 Patient genotype: c.194T>C;c.386A>G / p.(Ile65Thr);p.(Asp129Gly). Parental segregation not reported/performed.,ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
76,NM_000277.1(PAH):c.926C>T (p.Ala309Val),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-05,PM3,met,PubMed:26666653,"Genotype-phenotype association in French patients with PKU.  364 patients, 24hr BH4 loading test.","Single patient with classic PKU, c.842C>T (pathogenic in ClinVar) / c.926C>T","Single patient with classic PKU, c.842C>T (pathogenic in ClinVar) / c.926C>T Genotype-phenotype association in French patients with PKU.  364 patients, 24hr BH4 loading test.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
1010,NM_000277.2(PAH):c.913-8A>G,PAH,phenylketonuria,MONDO:0009861,Uncertain Significance,Autosomal recessive inheritance,Phenylketonuria,2019-11-08,PM3,met,PubMed:26666653,"The c.913-8A>G intronic variant has been observed in trans with the previously assessed pathogenic variant c.1315+1G>A (ClinVar 576, Pathogenic).","The c.913-8A>G intronic variant has been observed in trans with the previously assessed pathogenic variant c.1315+1G>A (ClinVar 576, Pathogenic).","The c.913-8A>G intronic variant has been observed in trans with the previously assessed pathogenic variant c.1315+1G>A (ClinVar 576, Pathogenic). The c.913-8A>G intronic variant has been observed in trans with the previously assessed pathogenic variant c.1315+1G>A (ClinVar 576, Pathogenic).",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
615,NM_000277.2(PAH):c.632delC (p.Pro211Hisfs),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-08-17,PM3,met,PubMed:26666653,in trans,"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) in trans",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
2071,NM_000277.3(PAH):c.529G>C (p.Val177Leu),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2021-04-09,PM3-Very Strong,not_met,PubMed:26666653,c. [529G>C]; [561G>A] p.[Val177Leu];[Trp187*]. parental testing not reported.,"Detected with pathogenic variants F39L, L48S, F39del, R408W, R261Q, F55fs, R158Q, Trp187*. Parental testing not reported.  PMID: 8659548,  PMID: 16879198,  PMID: 19609714,  PMID: 23430918,  PMID: 22391997, PMID: 22513348,  PMID: 26666653","Detected with pathogenic variants F39L, L48S, F39del, R408W, R261Q, F55fs, R158Q, Trp187*. Parental testing not reported.  PMID: 8659548,  PMID: 16879198,  PMID: 19609714,  PMID: 23430918,  PMID: 22391997, PMID: 22513348,  PMID: 26666653 c. [529G>C]; [561G>A] p.[Val177Leu];[Trp187*]. parental testing not reported.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
4824,NM_000277.2(PAH):c.199T>C (p.Ser67Pro),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2023-03-16,PM3-Very Strong,not_met,PubMed:26351554,"A total of 218 alleles from109 individuals from 40 PKU families (40 PKU patients and their parents) were tested for S67P. Observed mutations in the patients were inherited from their parents. s67p/s67p; 2 patients, s67p/ivs10nt-11: 7 patients; s67p/r261q: 3 patients; r408q/s67p: 1 patient; s67p/r252w: 1 patient.","Detected in trans with: L48S (PMID: 8592329, parental testing performed), IVS10-11G>A, R408Q (P), R261Q, R252W (P/LP)  (PMID: 26351554, parental testing performed). p.R408W(c.1222C>T) (3 patients), p.R252W(c.754C>T) (2 patients) parental testing not reported PMID: 24350308","Detected in trans with: L48S (PMID: 8592329, parental testing performed), IVS10-11G>A, R408Q (P), R261Q, R252W (P/LP)  (PMID: 26351554, parental testing performed). p.R408W(c.1222C>T) (3 patients), p.R252W(c.754C>T) (2 patients) parental testing not reported PMID: 24350308 A total of 218 alleles from109 individuals from 40 PKU families (40 PKU patients and their parents) were tested for S67P. Observed mutations in the patients were inherited from their parents. s67p/s67p; 2 patients, s67p/ivs10nt-11: 7 patients; s67p/r261q: 3 patients; r408q/s67p: 1 patient; s67p/r252w: 1 patient.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
8,NM_000277.2(PAH):c.331C>T (p.Arg111Ter),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-04-09,PM3-Very Strong,not_met,PubMed:26322415,"Detected in 13 patients with: c.611A>G, p.E280K, p.Y356*,  p.V399V, p.Y154H, p.R158Q, p.R241C, p.R243Q, p.G307D, p.A322T, p.I324N, p.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 with: p.R158Q (P, 11 submitters); p.R241C (P, 7 submitters); p.R243Q (P, 7 submitters); p.E280K (P, 9 submitters); p.Y356* (P, 5 submitters); p.R413P (P, 6 submitters)","Detected with: p.R158Q (P, 11 submitters); p.R241C (P, 7 submitters); p.R243Q (P, 7 submitters); p.E280K (P, 9 submitters); p.Y356* (P, 5 submitters); p.R413P (P, 6 submitters) Detected in 13 patients with: c.611A>G, p.E280K, p.Y356*,  p.V399V, p.Y154H, p.R158Q, p.R241C, p.R243Q, p.G307D, p.A322T, p.I324N, p.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
5922,NM_000277.1:c.971T>A,PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2023-12-30,PM3-Very Strong,not_met,PubMed:26322415,"Single patient with this allele c.971T>A / c.331C>T (R111*) pathogenic with ""classic PKU"", but no specific Phe levels listed.","It has been previously reported in at least 12 patients with PKU and BH4 deficiency formally excluded, including in confirmed trans with Pathogenic or Likely Pathogenic variants (PM3_VeryStrong (7.5 points total); PP4_Moderate). It was reported in presumed trans with p.R241C (Pathogenic per ClinGen PAH VCEP) in a Chinese proband with mild PKU (plasma Phe 760 μmol/L) and BH4 deficiency was said to be excluded (PMID: 28982351); in presumed trans with p.R111* (Pathogenic by ClinGen PAH VCEP) in a Chinese proband with classic PKU and in presumed trans with c.509+1G>A (Pathogenic by ClinGen PAH VCEP) in a Chinese proband with classic PKU (plasma Phe levels not specified; BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes). It has also been reported in confirmed trans with c.1066-11G>A (Pathogenic by ClinGen PAH VCEP) in a Chinese proband with PKU and BH4 deficiency excluded by sequencing of genes in the BH4 cofactor metabolism pathway) (PMID: 24705691); in a Chinese proband with PKU in confirmed trans with the c.442–1G>A variant (Pathogenic by ClinGen PAH VCEP) and in another Chinese proband with PKU in confirmed trans with the p.G247R variant (Likely Pathogenic by ClinGen PAH VCEP) (PMID: 29353259). It has been noted in a patient with PKU in presumed trans with p.T418P variant (Pathogenic by ClinGen PAH VCEP) (plasma Phe levels not noted; BH4 deficiency excluded by sequencing of genes in the BH4 cofactor metabolism pathway) (PMID: 29731766); in a Chinese patient with mild PKU (plasma Phe 780 umol/L) in presumed trans with the p.R243Q variant (Pathogenic by ClinGen PAH VCEP) and BH4 deficiency excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PMID: 28754886). Finally, it has been noted among multiple Chinese PKU patients with BH4 deficiency excluded by urinary pterin analysis, including in the homozygous state in a Chinese patient with classic PKU (plasma Phe not noted), in another patient with PKU (phenotype not further specified) in presumed trans with the c.611A>G (p.Ex6-96A>G) variant (Pathogenic by ClinGen PAH VCEP), in presumed trans with the p.V399V variant (Pathogenic by ClinGen PAH VCEP) in another Chinese patient with mild PKU, and in presumed trans with the p.Y356* variant (Pathogenic by ClinGen PAH VCEP) (PMID: 30050108).","It has been previously reported in at least 12 patients with PKU and BH4 deficiency formally excluded, including in confirmed trans with Pathogenic or Likely Pathogenic variants (PM3_VeryStrong (7.5 points total); PP4_Moderate). It was reported in presumed trans with p.R241C (Pathogenic per ClinGen PAH VCEP) in a Chinese proband with mild PKU (plasma Phe 760 μmol/L) and BH4 deficiency was said to be excluded (PMID: 28982351); in presumed trans with p.R111* (Pathogenic by ClinGen PAH VCEP) in a Chinese proband with classic PKU and in presumed trans with c.509+1G>A (Pathogenic by ClinGen PAH VCEP) in a Chinese proband with classic PKU (plasma Phe levels not specified; BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes). It has also been reported in confirmed trans with c.1066-11G>A (Pathogenic by ClinGen PAH VCEP) in a Chinese proband with PKU and BH4 deficiency excluded by sequencing of genes in the BH4 cofactor metabolism pathway) (PMID: 24705691); in a Chinese proband with PKU in confirmed trans with the c.442–1G>A variant (Pathogenic by ClinGen PAH VCEP) and in another Chinese proband with PKU in confirmed trans with the p.G247R variant (Likely Pathogenic by ClinGen PAH VCEP) (PMID: 29353259). It has been noted in a patient with PKU in presumed trans with p.T418P variant (Pathogenic by ClinGen PAH VCEP) (plasma Phe levels not noted; BH4 deficiency excluded by sequencing of genes in the BH4 cofactor metabolism pathway) (PMID: 29731766); in a Chinese patient with mild PKU (plasma Phe 780 umol/L) in presumed trans with the p.R243Q variant (Pathogenic by ClinGen PAH VCEP) and BH4 deficiency excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PMID: 28754886). Finally, it has been noted among multiple Chinese PKU patients with BH4 deficiency excluded by urinary pterin analysis, including in the homozygous state in a Chinese patient with classic PKU (plasma Phe not noted), in another patient with PKU (phenotype not further specified) in presumed trans with the c.611A>G (p.Ex6-96A>G) variant (Pathogenic by ClinGen PAH VCEP), in presumed trans with the p.V399V variant (Pathogenic by ClinGen PAH VCEP) in another Chinese patient with mild PKU, and in presumed trans with the p.Y356* variant (Pathogenic by ClinGen PAH VCEP) (PMID: 30050108). Single patient with this allele c.971T>A / c.331C>T (R111*) pathogenic with ""classic PKU"", but no specific Phe levels listed.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
687,NM_000277.2(PAH):c.196G>T (p.Glu66Ter),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-05-26,PM3-Supporting,not_met,PubMed:26666653,"Detected with c.1315+1G>A; however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing.","Detected with c.1315+1G>A; however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing.","Detected with c.1315+1G>A; however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Detected with c.1315+1G>A; however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
688,NM_000277.2(PAH):c.504C>A (p.Tyr168Ter),PAH,phenylketonuria,MONDO:0009861,Pathogenic,Autosomal recessive inheritance,Phenylketonuria,2019-05-26,PM3-Supporting,not_met,PubMed:26666653,"The proband was said to be heterozygous for the variant and also harbor the known pathogenic allele (per ClinGen PAH working group classification, see ClinVar ID 92751) c. 898G > T (p.Ala300Ser) variant; however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing.","Detected with c.898G>T (p.Ala300Ser), however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing.","Detected with c.898G>T (p.Ala300Ser), however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. The proband was said to be heterozygous for the variant and also harbor the known pathogenic allele (per ClinGen PAH working group classification, see ClinVar ID 92751) c. 898G > T (p.Ala300Ser) variant; however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing.",ClinGenPhenylketonuriaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPAHVersion2.0.0_version=2.0.0.csv
646,NM_000441.1(SLC26A4):c.412G>T (p.Val138Phe),SLC26A4,Pendred syndrome,MONDO:0010134,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,BP2,not_met,PubMed:21551164,"This study identified a 46 year old Caucasian female who was diagnosed with Pendred syndrome. ""This case illustrates that, although pendrin is not usually required to maintain acid–base
homeostasis under ambient condition, loss of renal bicarbonate excretion by pendrin during a
metabolic alkalotic challenge may contribute to life-threatening acid–base disturbances in patients
with Pendred syndrome"".  This patient was homzoygous for the variant. Sequencing of the SLC26A4 gene revealed the genoytype. Consanguinity was not discussed.",," This study identified a 46 year old Caucasian female who was diagnosed with Pendred syndrome. ""This case illustrates that, although pendrin is not usually required to maintain acid–base
homeostasis under ambient condition, loss of renal bicarbonate excretion by pendrin during a
metabolic alkalotic challenge may contribute to life-threatening acid–base disturbances in patients
with Pendred syndrome"".  This patient was homzoygous for the variant. Sequencing of the SLC26A4 gene revealed the genoytype. Consanguinity was not discussed.","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,BP2,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)",," 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"
638,NM_004004.5(GJB2):c.71G>A (p.Trp24Ter),GJB2,nonsyndromic genetic deafness,MONDO:0019497,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,BP2,not_met,PubMed:15070423,W24* was found in trans with GJB2 35delG variant in one deaf individual. Also found in trans in unaffected individuals with R127H variant.,, W24* was found in trans with GJB2 35delG variant in one deaf individual. Also found in trans in unaffected individuals with R127H variant.,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
730,NM_004004.6(GJB2):c.107T>C (p.Leu36Pro),GJB2,nonsyndromic genetic deafness,MONDO:0019497,Likely Pathogenic,Autosomal recessive inheritance,Hearing Loss,2024-03-28,BP2,not_met,PubMed:26043044,"The p.Leu36Pro variant was found in trans with a c.79G>A (p.Val27Ile) and a c.341A>G (p.Glu114Gly) variant, in a Han Chinese hearing loss patient. Both variants found in trans are at high frequency in gnomAD and have been repeatedly reported as Benign in ClinVar.",," The p.Leu36Pro variant was found in trans with a c.79G>A (p.Val27Ile) and a c.341A>G (p.Glu114Gly) variant, in a Han Chinese hearing loss patient. Both variants found in trans are at high frequency in gnomAD and have been repeatedly reported as Benign in ClinVar.","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: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"
646,NM_000441.1(SLC26A4):c.412G>T (p.Val138Phe),SLC26A4,Pendred syndrome,MONDO:0010134,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,BP2,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.,, 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"
141,NM_004004.5(GJB2):c.35delG (p.Gly12Valfs),GJB2,nonsyndromic genetic deafness,MONDO:0019497,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PS4,met,PubMed:26969326,"3.2% (72/2238) of alleles reported in this study harbored 35delG. Compared this to the European population in gnomAD (0.969%) since this is the highest frequency population.  Ran a 2x2 contingency table using this data, and the two-tailed P value is <0.0001.","In 1 large study (Sloan-Heggen 2015) and in 1 review article/meta-analysis (Tsukada 2015), the allele frequency of the c.35delG variant was statistically higher in individuals with hearing loss compared with individuals in the general population.","In 1 large study (Sloan-Heggen 2015) and in 1 review article/meta-analysis (Tsukada 2015), the allele frequency of the c.35delG variant was statistically higher in individuals with hearing loss compared with individuals in the general population. 3.2% (72/2238) of alleles reported in this study harbored 35delG. Compared this to the European population in gnomAD (0.969%) since this is the highest frequency population.  Ran a 2x2 contingency table using this data, and the two-tailed P value is <0.0001.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
968,NM_004004.5(GJB2):c.516G>C (p.Trp172Cys),GJB2,nonsyndromic genetic deafness,MONDO:0019497,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-10-17,PS4,met,PubMed:31195736,"220 Tuvinians (Southern Siberia, Russia) with hearing loss were tested for variants in GJB2. The p.Trp172Cys accounted for 62.9% of all mutant GJB2 alleles. It was present in 25 homozygous individuals, 7 compound heterozygous individuals (with c.-23+1G>A, and in 9 heterozygotes. This variant was not found to be biallelic in any of the 157 ethnically-matched controls, but it was observed in 6 carriers.","A 2x2 conttingency analysis of total variant alleles in cases v controls was performed. The variant is present in 66/440 case alleles and 6/314 control alleles. With a fisher exact test, the p value is <0.0001. which is highly significant.","A 2x2 conttingency analysis of total variant alleles in cases v controls was performed. The variant is present in 66/440 case alleles and 6/314 control alleles. With a fisher exact test, the p value is <0.0001. which is highly significant. 220 Tuvinians (Southern Siberia, Russia) with hearing loss were tested for variants in GJB2. The p.Trp172Cys accounted for 62.9% of all mutant GJB2 alleles. It was present in 25 homozygous individuals, 7 compound heterozygous individuals (with c.-23+1G>A, and in 9 heterozygotes. This variant was not found to be biallelic in any of the 157 ethnically-matched controls, but it was observed in 6 carriers.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
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:15790391,"51 probands (76 individuals) with hearing loss from different regions in Russia (Altaians, n= 40; Russians, n = 17; Kazakhs, n = 3; mixed or other ethnicity, n = 16)
130 unrelated subjects of Altaian origin with no familial history of hearing problems were used as controls.
Phe191Leu was identified in 0.4% (1/260) of controls 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 51 probands (76 individuals) with hearing loss from different regions in Russia (Altaians, n= 40; Russians, n = 17; Kazakhs, n = 3; mixed or other ethnicity, n = 16)
130 unrelated subjects of Altaian origin with no familial history of hearing problems were used as controls.
Phe191Leu was identified in 0.4% (1/260) of controls chromosomes","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
142,NM_004004.6(GJB2):c.34G>T (p.Gly12Cys),GJB2,nonsyndromic genetic deafness,MONDO:0019497,Likely Pathogenic,Autosomal recessive inheritance,Hearing Loss,2023-02-02,PS4,not_met,PubMed:26969326,"One patient with congenital SNHL, reported inheritance was AD, as the variant was in trans with a p.Tyr68Cys variant that is thought to be LB. Cohort is multiethnic","attempted to use case-control as there are 10 reported alleles in HL cases in the literature out of 21004 total alleles screened

There are 130/271738 alleles in gnomAD with the variant (used the total because all reports were multiethnic) but the graphpad software only allows a denominator of 123456, therefore, 10/21004 was compared to the frequency in the general population equal to that of 130/271738 but with a denominator of 123456. Which equals 59/123456.

The frequency differential between cases and the general population was NOT significant.","attempted to use case-control as there are 10 reported alleles in HL cases in the literature out of 21004 total alleles screened

There are 130/271738 alleles in gnomAD with the variant (used the total because all reports were multiethnic) but the graphpad software only allows a denominator of 123456, therefore, 10/21004 was compared to the frequency in the general population equal to that of 130/271738 but with a denominator of 123456. Which equals 59/123456.

The frequency differential between cases and the general population was NOT significant. One patient with congenital SNHL, reported inheritance was AD, as the variant was in trans with a p.Tyr68Cys variant that is thought to be LB. Cohort is multiethnic","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:21738395,Variant was identified in 2 heterozygotes with Usher syndrome after screening of 75 unrelated Italian patinets.One of the patients also carried a p.E767fs variant in USH2A in a het state.,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%. Variant was identified in 2 heterozygotes with Usher syndrome after screening of 75 unrelated Italian patinets.One of the patients also carried a p.E767fs variant in USH2A in a het state.,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
638,NM_004004.5(GJB2):c.71G>A (p.Trp24Ter),GJB2,nonsyndromic genetic deafness,MONDO:0019497,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PM3-Very Strong,not_met,PubMed:15070423,W24* was found in trans with GJB2 35delG variant in one deaf individual. Also found in trans in unaffected individuals with R127H variant.,Many examples of the W24* variant found in trans with other nonsense or frameshifting GJB2 alleles.,Many examples of the W24* variant found in trans with other nonsense or frameshifting GJB2 alleles. W24* was found in trans with GJB2 35delG variant in one deaf individual. Also found in trans in unaffected individuals with R127H variant.,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
639,NM_000441.1(SLC26A4):c.919-2A>G,SLC26A4,Pendred syndrome,MONDO:0010134,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PM3-Very Strong,not_met,PubMed:23151025,Retrospective review of 1065 Chinese probands with moderate-to-profound bilateral sensorineural hearing loss found 53 homozygous and 80 heterozygous for the c.919-2A>G variant. 16 individuals were compound het. for the pathogenic p.H723R variant in SLC26A4.,16 Chinese SNHL probands are compound heterozygous for the c.919-2A>G and p.H723R variants in SLC26A4.,16 Chinese SNHL probands are compound heterozygous for the c.919-2A>G and p.H723R variants in SLC26A4. Retrospective review of 1065 Chinese probands with moderate-to-profound bilateral sensorineural hearing loss found 53 homozygous and 80 heterozygous for the c.919-2A>G variant. 16 individuals were compound het. for the pathogenic p.H723R variant in SLC26A4.,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
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:21551164,"This study identified a 46 year old Caucasian female who was diagnosed with Pendred syndrome. ""This case illustrates that, although pendrin is not usually required to maintain acid–base
homeostasis under ambient condition, loss of renal bicarbonate excretion by pendrin during a
metabolic alkalotic challenge may contribute to life-threatening acid–base disturbances in patients
with Pendred syndrome"".  This patient was homzoygous for the variant. Sequencing of the SLC26A4 gene revealed the genoytype. Consanguinity was not discussed.",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. This study identified a 46 year old Caucasian female who was diagnosed with Pendred syndrome. ""This case illustrates that, although pendrin is not usually required to maintain acid–base
homeostasis under ambient condition, loss of renal bicarbonate excretion by pendrin during a
metabolic alkalotic challenge may contribute to life-threatening acid–base disturbances in patients
with Pendred syndrome"".  This patient was homzoygous for the variant. Sequencing of the SLC26A4 gene revealed the genoytype. Consanguinity was not discussed.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
730,NM_004004.6(GJB2):c.107T>C (p.Leu36Pro),GJB2,nonsyndromic genetic deafness,MONDO:0019497,Likely Pathogenic,Autosomal recessive inheritance,Hearing Loss,2024-03-28,PM3-Very Strong,not_met,PubMed:26043044,"The p.Leu36Pro variant was found in trans with a c.79G>A (p.Val27Ile) and a c.341A>G (p.Glu114Gly) variant, in a Han Chinese hearing loss patient. Both variants found in trans are at high frequency in gnomAD and have been repeatedly reported as Benign in ClinVar."," This variant has been detected in trans with a pathogenic variant in three patients with hearing loss (4 points, PM3_VeryStrong; PMID:16125251, 16467727, 29605365, 31246659, Invitae internal date (SCV002241983.2))."," This variant has been detected in trans with a pathogenic variant in three patients with hearing loss (4 points, PM3_VeryStrong; PMID:16125251, 16467727, 29605365, 31246659, Invitae internal date (SCV002241983.2)). The p.Leu36Pro variant was found in trans with a c.79G>A (p.Val27Ile) and a c.341A>G (p.Glu114Gly) variant, in a Han Chinese hearing loss patient. Both variants found in trans are at high frequency in gnomAD and have been repeatedly reported as Benign in ClinVar.","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:24164807,Identified heterozygous in three affected siblings who also had a heterozygous PCDH15 variant.,"1 point from homozygotes
PM3_Strong (3.75 points scored)","1 point from homozygotes
PM3_Strong (3.75 points scored) Identified heterozygous in three affected siblings who also had a heterozygous PCDH15 variant.","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:22899989,12 probands cmpound het with rare VUS. Patients with phase confirmed reported in Wagatsuma 2007.,"1 point from homozygotes
PM3_Strong (3.75 points scored)","1 point from homozygotes
PM3_Strong (3.75 points scored) 12 probands cmpound het with rare VUS. Patients with phase confirmed reported in Wagatsuma 2007.","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: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.,"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. 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"
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:22135276,Indian proband diagnosed with Usher type 2 --> 0.5 points (phase unknown) - other variant is p.Glu767Serfs*21,"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. Indian proband diagnosed with Usher type 2 --> 0.5 points (phase unknown) - other variant is p.Glu767Serfs*21","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
745,NM_004004.5(GJB2):c.109G>A (p.Val37Ile),GJB2,nonsyndromic genetic deafness,MONDO:0019497,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PM3,met,PubMed:31160754,>120 compound hets with the p.V37I variant,"Shen et al 2019 demonstrated in the combined analysis of at least 10 clinical sites that there were >120 compound heterozygotes with the p.Val37Ile variant. However, because the variant is also very frequent in the general population, the HL group decided to only apply this criteria at the usual strength of Moderate.","Shen et al 2019 demonstrated in the combined analysis of at least 10 clinical sites that there were >120 compound heterozygotes with the p.Val37Ile variant. However, because the variant is also very frequent in the general population, the HL group decided to only apply this criteria at the usual strength of Moderate. >120 compound hets with the p.V37I variant","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
143,NM_206933.2(USH2A):c.12295-?_14133+?del,USH2A,Usher syndrome,MONDO:0019501,Likely Pathogenic,Autosomal recessive inheritance,Hearing Loss,2023-10-05,PM3,met,PubMed:26969326,"1 proband compound het with c.2276G>T, p.Cys759Phe. Unsure of phase.","3 LMM probands:
1 homozygote with Usher (0.5 points)
1 cmp het (VUS phase unknown) with hearing loss and light sensitivity (teens, 0.25 points)
1 cmp het (p.Tyr3747X, phase unknown) with hearing loss (<5 years old, 0.5 points)","3 LMM probands:
1 homozygote with Usher (0.5 points)
1 cmp het (VUS phase unknown) with hearing loss and light sensitivity (teens, 0.25 points)
1 cmp het (p.Tyr3747X, phase unknown) with hearing loss (<5 years old, 0.5 points) 1 proband compound het with c.2276G>T, p.Cys759Phe. Unsure of phase.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
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: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"
643,NM_206933.2(USH2A):c.5581G>A (p.Gly1861Ser),USH2A,Usher syndrome,MONDO:0019501,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,BS4,not_met,PubMed:26310143,This is a case report of a Chinese family with pseudo-dominant Usher syndrome. The proband is compound het for p.Gly1861Ser and p.C934W. There is also an affected brother who has this genotype.,, This is a case report of a Chinese family with pseudo-dominant Usher syndrome. The proband is compound het for p.Gly1861Ser and p.C934W. There is also an affected brother who has this genotype.,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
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,BS4,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.",," 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"
649,NM_206933.2(USH2A):c.8559-2A>G,USH2A,Usher syndrome,MONDO:0019501,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-07-17,PP1-Strong,not_met,PubMed:19023448,"2 Usher affected families:

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

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

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

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

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

F3: Variant was inherited in trans with a p.T3936P variant in USH2A in other family. This individual has an unaffected sib with only the p.T3936P variant and experienced HL onset at age 10 while other individuals had congenital HL.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
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:27623246,"A homozygous knock-in mouse model of c.109G>A in Gjb2 was reported to
have progressive mild hearing loss, more pronounced at higher sound frequencies. However, because the codon for p.Val37 in mouse (GTG) was different from that in human (GTT), c.109G>A in mouse would translate into p.Val37Met, so it was not counted toward strong functional evidence.","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. A homozygous knock-in mouse model of c.109G>A in Gjb2 was reported to
have progressive mild hearing loss, more pronounced at higher sound frequencies. However, because the codon for p.Val37 in mouse (GTG) was different from that in human (GTT), c.109G>A in mouse would translate into p.Val37Met, so it was not counted toward strong functional evidence.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
968,NM_004004.5(GJB2):c.516G>C (p.Trp172Cys),GJB2,nonsyndromic genetic deafness,MONDO:0019497,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-10-17,PM3-Supporting,not_met,PubMed:15790391,"76 Altaian (South Siberia, Russia) individuals with NSHL were tested for variants in GJB2, GJB6 deletions, and mitochondrial variants. The p.Trp172Cys variant was identified in one individual who was compound het for the c.235delC variant. It was absent from 130 unrelated Altaian controls.","With the new specifications (and this variant meeting BA1), these two cases would only count as 0.1 points each, 0.2 points total. PM3 is not met. However, after group discussion, we felt that the Tuvinian population is too small to use the new PM3 rule, but decided to downgrade it to PM3_supporting because of the frequency in Tuvinian controls.","With the new specifications (and this variant meeting BA1), these two cases would only count as 0.1 points each, 0.2 points total. PM3 is not met. However, after group discussion, we felt that the Tuvinian population is too small to use the new PM3 rule, but decided to downgrade it to PM3_supporting because of the frequency in Tuvinian controls. 76 Altaian (South Siberia, Russia) individuals with NSHL were tested for variants in GJB2, GJB6 deletions, and mitochondrial variants. The p.Trp172Cys variant was identified in one individual who was compound het for the c.235delC variant. It was absent from 130 unrelated Altaian controls.","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
707,NM_004004.5(GJB2):c.101T>C (p.Met34Thr),GJB2,nonsyndromic genetic deafness,MONDO:0019497,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2019-06-28,BS1,not_met,PubMed:31160754,Showed this variant is statistically enriched in affected populations therefore BA1 should not be applied,see BA1,see BA1 Showed this variant is statistically enriched in affected populations therefore BA1 should not be applied,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
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,BS2,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 (Wu 2017), suggesting an age-related penetrance. Therefore, BS2 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 (Wu 2017), suggesting an age-related penetrance. Therefore, BS2 is not met. ","ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
985,NM_206933.3(USH2A):c.12295-3T>A,USH2A,Usher syndrome,MONDO:0019501,Pathogenic,Autosomal recessive inheritance,Hearing Loss,2023-02-06,PP4,met,PubMed:22135276,Patient diagnosed with Usher syndrome type 2 and found to have variants in only USH2A.,, Patient diagnosed with Usher syndrome type 2 and found to have variants in only USH2A.,"ClinGenHearingLossExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforCDH23,COCH,GJB2,KCNQ4,MYO6,MYO7A,SLC26A4,TECTAandUSH2AVersion2_version=2.0.0.csv"
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,PP1,met,PubMed:31160754,This paper described 16 segregations of the p.Met34Thr variant in homozygous/compound het occurrences in Supplementary table S2,This paper described 16 segregations of the p.Met34Thr variant in homozygous/compound het occurrences in Supplementary table S2,This paper described 16 segregations of the p.Met34Thr variant in homozygous/compound het occurrences in Supplementary table S2 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"
124,NM_000314.6(PTEN):c.395G>A (p.Gly132Asp),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2021-10-29,PS3,met,PubMed:32350270,LOF for multiple assays c/w Mighell results,, LOF for multiple assays c/w Mighell results,ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
545,NM_000314.6(PTEN):c.331T>C (p.Trp111Arg),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Likely Pathogenic,Autosomal dominant inheritance,PTEN,2022-09-30,PS3,met,PubMed:29785012,"Protein abundance score 0.09, ""low"" abundance category.",," Protein abundance score 0.09, ""low"" abundance category.",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,PS3,not_met,PubMed:29785012,Variant showed WT-like protein stability (score = 1.37) but only 2 experimental replicates.,, Variant showed WT-like protein stability (score = 1.37) but only 2 experimental replicates.,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:19457929,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.,"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. 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.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
747,NM_000314.6(PTEN):c.370T>C (p.Cys124Arg),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2019-07-23,PS3,met,PubMed:29785012,"Appears to show decreased stability (score 0.28) but EP still figuring out cutoff for this publication, and PS3 already applied for other literature.",I agree (FH),"I agree (FH) Appears to show decreased stability (score 0.28) but EP still figuring out cutoff for this publication, and PS3 already applied for other literature.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
1539,NM_001304717.5(PTEN):c.730-2_731del,PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2019-12-04,BS3,not_met,PubMed:28677221,Nomenclature c.210-4_c.210-1delTTAG: variant resulted in exon 4 skipping in pt cells.,, Nomenclature c.210-4_c.210-1delTTAG: variant resulted in exon 4 skipping in pt cells.,ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
777,NM_000314.6(PTEN):c.364A>G (p.Ile122Val),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Uncertain Significance,Autosomal dominant inheritance,PTEN,2022-09-30,BS3,met,PubMed:29785012,Variant demonstrated WT-like abundance on high-throughput VAMPseq assay.,"PMID 21828076: demonstrated that missense change does not affect PTEN PIP3 phosphatase activity.

I agree (FH)","PMID 21828076: demonstrated that missense change does not affect PTEN PIP3 phosphatase activity.

I agree (FH) Variant demonstrated WT-like abundance on high-throughput VAMPseq assay.",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:29785012,Possibly_wt-like 0.83 protein abundance,"Phosphatase activity, stability, pAKT, and subcellular localization similar to WT","Phosphatase activity, stability, pAKT, and subcellular localization similar to WT Possibly_wt-like 0.83 protein abundance",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
1035,NM_000314.7(PTEN):c.579G>A (p.Leu193=),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Likely Benign,Autosomal dominant inheritance,PTEN,2019-12-04,PS4,not_met,PubMed:25669429,,Please also see comment for criteria PP4 below.,Please also see comment for criteria PP4 below. ,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:25669429,Variant listed as identified in this study in Supplementary Table 4. No additional patient specific information reported.,"If BS1 met, PS4/PP4 cannot apply","If BS1 met, PS4/PP4 cannot apply Variant listed as identified in this study in Supplementary Table 4. No additional patient specific information reported.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
124,NM_000314.6(PTEN):c.395G>A (p.Gly132Asp),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2021-10-29,PS4,met,PubMed:25288137,4yo M with autism and OFC +5.9SD. Peds score = 5 = 1 phenotype specificity point.,"2.5 phenotype specificity points from literature, additional 1.5 points from internal laboratory case.","2.5 phenotype specificity points from literature, additional 1.5 points from internal laboratory case. 4yo M with autism and OFC +5.9SD. Peds score = 5 = 1 phenotype specificity point.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
553,NM_000314.6(PTEN):c.755A>G (p.Asp252Gly),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2023-10-19,PS3-Moderate,not_met,PubMed:25527629,"Variant demonstrated decreased protein expression, pAKT closer to WT than pos control C124S.  Also showed decreased protein stability.","Massively parallel functional assay interrogating phosphatase activity in Mighell et al. 2018 (PMID: 29706350) showed reduced phosphatase activity (Column I=TRUE; Column G=-2.1; PS3_Moderate).   
","Massively parallel functional assay interrogating phosphatase activity in Mighell et al. 2018 (PMID: 29706350) showed reduced phosphatase activity (Column I=TRUE; Column G=-2.1; PS3_Moderate).   
 Variant demonstrated decreased protein expression, pAKT closer to WT than pos control C124S.  Also showed decreased protein stability.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
1059,NM_000314.7(PTEN):c.112C>T (p.Pro38Ser),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Uncertain Significance,Autosomal dominant inheritance,PTEN,2024-03-01,PS3-Moderate,not_met,PubMed:29785012,WT-like protein abundance score 1.136,Functional studies supportive of a damaging effect on the gene or gene product. Score of this variant = -1.515 (≤ -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 = -1.515 (≤ -1.11) on a high throughput phosphatase assay (PMID:29706350).  WT-like protein abundance score 1.136,ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
98,NM_000314.6(PTEN):c.50_51delAA (p.Gln17Argfs),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2018-12-10,PS4-Supporting,not_met,PubMed:20223021,Proband(s) with phenotype specificity score of 1-1.5,, Proband(s) with phenotype specificity score of 1-1.5,ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
751,NM_000314.6(PTEN):c.284C>T (p.Pro95Leu),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Pathogenic,Autosomal dominant inheritance,PTEN,2019-07-23,PS4-Supporting,not_met,PubMed:25669429,Likely is the same patient as Heald et al. and Tan et al.,"Heald B et al. in a prospective series of PTEN mutation carriers reported subject 1515 has having > 50 hamartomas.  The Herman Laboratory Nationwide Children's Hospital reported clinical data into Clinvar.  The patient had macrocephaly (+6.4 SD) and > 40 colon polyps and 15 were > 1cm and all were juvenile polyps.  It is unclear whether this patient is the same as the patient reported in Heald B et al. Tan et. al reported individual 20 as meeting relaxed International Consortium operational criteria for PTHS. Could meet PS4_S but need more phenotype information. Entry by MPerpich. KS: GeneDx internal data:  male child with macrocephaly, penile freckling, developmental delay  and pediatric proband score = 7.  This case is also de novo, and reaches 1 phenotype specificity point. A second case of a female in her 40's with breast cancer and 3 colon polyps (adenomatous and hyperplastic). PTEN study data: Very likely this is the same patient as Heald et al., OFC = 60 cm, GI hamartomas (6), and GI poylps NOS (44), and CC score = 22.","Heald B et al. in a prospective series of PTEN mutation carriers reported subject 1515 has having > 50 hamartomas.  The Herman Laboratory Nationwide Children's Hospital reported clinical data into Clinvar.  The patient had macrocephaly (+6.4 SD) and > 40 colon polyps and 15 were > 1cm and all were juvenile polyps.  It is unclear whether this patient is the same as the patient reported in Heald B et al. Tan et. al reported individual 20 as meeting relaxed International Consortium operational criteria for PTHS. Could meet PS4_S but need more phenotype information. Entry by MPerpich. KS: GeneDx internal data:  male child with macrocephaly, penile freckling, developmental delay  and pediatric proband score = 7.  This case is also de novo, and reaches 1 phenotype specificity point. A second case of a female in her 40's with breast cancer and 3 colon polyps (adenomatous and hyperplastic). PTEN study data: Very likely this is the same patient as Heald et al., OFC = 60 cm, GI hamartomas (6), and GI poylps NOS (44), and CC score = 22. Likely is the same patient as Heald et al. and Tan et al.",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,PP4,not_met,PubMed:28677221,Variant reported in two adults with CC scores of 11 and 2 respectively. No PP4 criteria met.,, Variant reported in two adults with CC scores of 11 and 2 respectively. No PP4 criteria met.,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,PP4,not_met,PubMed:25669429,Reported in a pt with features of PHTS; no specifics provided. Would also be in Chen 2017 paper. Omit.,, Reported in a pt with features of PHTS; no specifics provided. Would also be in Chen 2017 paper. Omit.,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:29785012,"variant abundance in “possibly WT-like” range, indicating no striking impact on protein stability",PS3_supporting applied following functional subgroup discussion.,"PS3_supporting applied following functional subgroup discussion. variant abundance in “possibly WT-like” range, indicating no striking impact on protein stability",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
782,NM_000314.8(PTEN):c.892C>G (p.Gln298Glu),PTEN,PTEN hamartoma tumor syndrome,MONDO:0017623,Likely Benign,Autosomal dominant inheritance,PTEN,2023-10-19,BS3-Supporting,not_met,PubMed:29785012,Variant abundance measured by massively parallel sequencing; in possibly wt-like abundance class (results 0.77).,Mighell WT-like (0.30) results. Matreyek possibly wt-like (0.77) abundance class.,Mighell WT-like (0.30) results. Matreyek possibly wt-like (0.77) abundance class. Variant abundance measured by massively parallel sequencing; in possibly wt-like abundance class (results 0.77).,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:25418537,"Seen de novo in 4yo M with autism and macrocephaly +3.44SD, no other features noted. No phenotype points.","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. Seen de novo in 4yo M with autism and macrocephaly +3.44SD, no other features noted. No phenotype points.",ClinGenPTENExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTENVersion3.1.0_version=3.1.0.csv
1178,NM_000152.4(GAA):c.2140delC (p.His714Thrfs),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-05-26,PM3,not_met,PubMed:30564623,,"This variant has been reported in two patients who also carry a second variant in GAA. One of these cases meets the ClinGen LSD VCEP’s specifications for PP4 and is compound heterozygous for p.His714Thrfs and a missense variant, c.1561G>A (p.Glu521Lys); the phase is unknown (PMID 17723315). The in trans data from this patient will be used in the assessment of p.Glu521Lys and, therefore, was not included here in order to avoid circular logic. The second case is compound heterozygous for the variant and c.-32-13T>G (PMID 30564623) but the GAA activity was not reported and PP4 cannot be assessed.",,ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1347,NM_000152.5(GAA):c.1352C>G (p.Pro451Arg),GAA,glycogen storage disease II,MONDO:0009290,Likely Benign,Autosomal recessive inheritance,Lysosomal Diseases,2023-05-26,PM3,not_met,PubMed:29149851,"Patient 21, with limb girdle muscular dystrophy, is compound heterozygous for c.1352C>G (p.Pro451Arg) and an intronic variant, c.1438-7_1438-5delTGT. The phase of the variants is unknown. No GAA activity is provided for the patient. The authors stated that this combination of variants was not thought to be causative of the patient’s phenotype.","A patient with limb-girdle muscle weakness has been reported to be compound heterozygous for  c.1352C>G (p.Pro451Arg) and an intronic variant, c.1438-7_1438-5delTGT (PMID 29149851). The phase of the variants is unknown and no GAA activity was provided for the patient. The authors stated that this combination of variants was not thought to be causative of the patient’s phenotype. Therefore, this criterion is not met.","A patient with limb-girdle muscle weakness has been reported to be compound heterozygous for  c.1352C>G (p.Pro451Arg) and an intronic variant, c.1438-7_1438-5delTGT (PMID 29149851). The phase of the variants is unknown and no GAA activity was provided for the patient. The authors stated that this combination of variants was not thought to be causative of the patient’s phenotype. Therefore, this criterion is not met. Patient 21, with limb girdle muscular dystrophy, is compound heterozygous for c.1352C>G (p.Pro451Arg) and an intronic variant, c.1438-7_1438-5delTGT. The phase of the variants is unknown. No GAA activity is provided for the patient. The authors stated that this combination of variants was not thought to be causative of the patient’s phenotype.",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
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:27708273,"Patient 1117 is compound heterozygous for c.1841C>A (p.Thr614Lys) and the known pathogenic variant, c.-32-13T>G identified by exome sequencing. The patient had a clinical diagnosis of limb girdle muscular dystrophy.","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 1117 is compound heterozygous for c.1841C>A (p.Thr614Lys) and the known pathogenic variant, c.-32-13T>G identified by exome sequencing. The patient had a clinical diagnosis of limb girdle muscular dystrophy.",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1189,NM_000152.4(GAA):c.1687C>T (p.Gln563Ter),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-05-26,PM3,met,PubMed:25741864,,"This variant was found in compound heterozygosity with a unique pathogenic variant in GAA, c.722_723delTT, in one patient with Pompe disease who also meets the ClinGen LSD VCEP's PP4 specifications. The phase was confirmed as in trans. Based on the ClinGen LSD VCEP's guidelines, this data was given a total of 1 point, which meets PM3.","This variant was found in compound heterozygosity with a unique pathogenic variant in GAA, c.722_723delTT, in one patient with Pompe disease who also meets the ClinGen LSD VCEP's PP4 specifications. The phase was confirmed as in trans. Based on the ClinGen LSD VCEP's guidelines, this data was given a total of 1 point, which meets PM3. ",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:27408821,"c.1128_1129delGGinsC was found in compound heterozygosity with a pathogenic variant, -32-13T>G (a known pathogenic variant), 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.","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 (a known pathogenic variant), 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.",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1735,NM_000152.5(GAA):c.1075G>T (p.Gly359Ter),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-11-12,PM3-Supporting,not_met,PubMed:25741864,,"One patient has been reported who is homozygous for this variant (19775921, 25741864, 29122469) and meets PP4.  0.5 points were given, meeting PM3_Supporting.","One patient has been reported who is homozygous for this variant (19775921, 25741864, 29122469) and meets PP4.  0.5 points were given, meeting PM3_Supporting. ",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:32802993,,"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
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,PM3-Supporting,not_met,PubMed:22676651,This variant was found in patient 4 with c.-32-13T>G. c.-32-13T>G is a well known pathogenic variant. The phase of the variants was not confirmed. This patient meets PP4 criteria. No points were awarded since in trans data for c.-32-13T>G has already been scored and the variants were not confirmed in trans.,"This variant has been reported in three individuals with Pompe disease and residual GAA activating meeting PP4 specifications (PMIDs 20033296, 20817528, 22676651). Two of these individuals are compound heterozygous for the variant and c.-32-13T>G, phase unknown (PMIDs 20817528, 22676651) (0.5 points). The other individual is compound heterozygous for the variant and c.1655T>C (p.Leu552Pro) (PMID 20033296), however, this in trans data will be used in the classification of p.Leu552Pro and is 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 provided and therefore PP4 cannot be assessed (PMID 24923245, 25455803). In total, 0.5 points were given for PM3, meeting PM3_Supporting.","This variant has been reported in three individuals with Pompe disease and residual GAA activating meeting PP4 specifications (PMIDs 20033296, 20817528, 22676651). Two of these individuals are compound heterozygous for the variant and c.-32-13T>G, phase unknown (PMIDs 20817528, 22676651) (0.5 points). The other individual is compound heterozygous for the variant and c.1655T>C (p.Leu552Pro) (PMID 20033296), however, this in trans data will be used in the classification of p.Leu552Pro and is 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 provided and therefore PP4 cannot be assessed (PMID 24923245, 25455803). In total, 0.5 points were given for PM3, meeting PM3_Supporting. This variant was found in patient 4 with c.-32-13T>G. c.-32-13T>G is a well known pathogenic variant. The phase of the variants was not confirmed. This patient meets PP4 criteria. No points were awarded since in trans data for c.-32-13T>G has already been scored and the variants were not confirmed in trans.",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,PP4,met,PubMed:30022036,,"Two  individuals have been reported with this variant and GAA activity in the affected range when compared to the laboratory’s control range (PMIDs 17056254, 30778879) . This meets the criteria for PP4.","Two  individuals have been reported with this variant and GAA activity in the affected range when compared to the laboratory’s control range (PMIDs 17056254, 30778879) . This meets the criteria for PP4. ",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1323,NM_000152.4(GAA):c.2662G>T (p.Glu888Ter),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-05-27,PP4,met,PubMed:25526786,,"At least 6 patients have been reported with have been reported with this variant and GAA activity <10% normal in lymphocytes, leukocytes, or muscle samples, or <30% normal activity in cultured fibroblasts, or in the affected range in a GAA activity assay (PMIDs 16531044, 17723315, 18458862, 21232767, 25526786). This meets the specifications for PP4.","At least 6 patients have been reported with have been reported with this variant and GAA activity <10% normal in lymphocytes, leukocytes, or muscle samples, or <30% normal activity in cultured fibroblasts, or in the affected range in a GAA activity assay (PMIDs 16531044, 17723315, 18458862, 21232767, 25526786). This meets the specifications for PP4. ",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1179,NM_000152.3(GAA):c.1548G>A (p.Trp516Ter),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-05-26,PM3-Strong,not_met,PubMed:29181627,Patient 16 is compound heterozygous for c.1548G>A (p.Trp516Ter) and c.1470G>A (p.Phe490Leu). The phase of the variants is unknown. Residual GAA activity was not provided and therefore this data will not be included for PM3. The patient is on enzyme replacement therapy.,"This variant is reported to be in compound heterozygosity with a unique pathogenic variant (c.-32-13T>G, c.525delT, or c.2481+1022_646+31del) in three patients who also meet the ClinGen LSD VCEP’s specifications for PP4 (PMID 20826098, 22237443, 25243733). In one of these patients, the variants were confirmed to be in trans (PMID 25243733). Additional cases have been reported but were not included for PM3 either because the residual GAA activity was not provided (and therefore PP4 cannot be assessed) (PMIDs 24715333, 29181627, 30155607), full HGVS nomenclature was not provided (PMID 25626711), a case with the same variant (not confirmed in trans) had already been included (PMID 29122469), or the second variant is a variant of unknown significance (PMID 26873529). Based on the ClinGen LSD VCEP's specifications, this data was given a total of 2 points which meets PM3_Strong.","This variant is reported to be in compound heterozygosity with a unique pathogenic variant (c.-32-13T>G, c.525delT, or c.2481+1022_646+31del) in three patients who also meet the ClinGen LSD VCEP’s specifications for PP4 (PMID 20826098, 22237443, 25243733). In one of these patients, the variants were confirmed to be in trans (PMID 25243733). Additional cases have been reported but were not included for PM3 either because the residual GAA activity was not provided (and therefore PP4 cannot be assessed) (PMIDs 24715333, 29181627, 30155607), full HGVS nomenclature was not provided (PMID 25626711), a case with the same variant (not confirmed in trans) had already been included (PMID 29122469), or the second variant is a variant of unknown significance (PMID 26873529). Based on the ClinGen LSD VCEP's specifications, this data was given a total of 2 points which meets PM3_Strong. Patient 16 is compound heterozygous for c.1548G>A (p.Trp516Ter) and c.1470G>A (p.Phe490Leu). The phase of the variants is unknown. Residual GAA activity was not provided and therefore this data will not be included for PM3. The patient is on enzyme replacement therapy.",ClinGenLysosomalStorageDisordersVariantCurationExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
1179,NM_000152.3(GAA):c.1548G>A (p.Trp516Ter),GAA,glycogen storage disease II,MONDO:0009290,Pathogenic,Autosomal recessive inheritance,Lysosomal Diseases,2020-05-26,PM3-Strong,not_met,PubMed:24715333,"Patient 11 is compound heterozygous for c.1548G>A (p.Trp516Ter) and c.1913G>T (p.Gly638Val). The phase of the variants is unknown. No residual GAA activity data is available, and therefore this data will not be included for PM3.","This variant is reported to be in compound heterozygosity with a unique pathogenic variant (c.-32-13T>G, c.525delT, or c.2481+1022_646+31del) in three patients who also meet the ClinGen LSD VCEP’s specifications for PP4 (PMID 20826098, 22237443, 25243733). In one of these patients, the variants were confirmed to be in trans (PMID 25243733). Additional cases have been reported but were not included for PM3 either because the residual GAA activity was not provided (and therefore PP4 cannot be assessed) (PMIDs 24715333, 29181627, 30155607), full HGVS nomenclature was not provided (PMID 25626711), a case with the same variant (not confirmed in trans) had already been included (PMID 29122469), or the second variant is a variant of unknown significance (PMID 26873529). Based on the ClinGen LSD VCEP's specifications, this data was given a total of 2 points which meets PM3_Strong.","This variant is reported to be in compound heterozygosity with a unique pathogenic variant (c.-32-13T>G, c.525delT, or c.2481+1022_646+31del) in three patients who also meet the ClinGen LSD VCEP’s specifications for PP4 (PMID 20826098, 22237443, 25243733). In one of these patients, the variants were confirmed to be in trans (PMID 25243733). Additional cases have been reported but were not included for PM3 either because the residual GAA activity was not provided (and therefore PP4 cannot be assessed) (PMIDs 24715333, 29181627, 30155607), full HGVS nomenclature was not provided (PMID 25626711), a case with the same variant (not confirmed in trans) had already been included (PMID 29122469), or the second variant is a variant of unknown significance (PMID 26873529). Based on the ClinGen LSD VCEP's specifications, this data was given a total of 2 points which meets PM3_Strong. Patient 11 is compound heterozygous for c.1548G>A (p.Trp516Ter) and c.1913G>T (p.Gly638Val). The phase of the variants is unknown. No residual GAA activity data is available, and therefore this data will not be included for PM3.",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:29946513,,"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
182,NM_000257.3(MYH7):c.2722C>G (p.Leu908Val),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
254,NM_000257.3(MYH7):c.1207C>T (p.Arg403Trp),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
249,NM_000257.3(MYH7):c.1750G>C (p.Gly584Arg),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
183,NM_000257.3(MYH7):c.2717A>G (p.Asp906Gly),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
193,NM_000257.3(MYH7):c.2207T>C (p.Ile736Thr),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PM1,met,PubMed:27532257,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated Variants in head region of the protein (aa 181-937) are statistically more likely to be disease-associated,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
176,NM_000257.3(MYH7):c.3286G>T (p.Asp1096Tyr),MYH7,cardiomyopathy,MONDO:0004994,Likely Benign,Autosomal dominant inheritance,Cardiomyopathy,2021-08-25,PS4,not_met,PubMed:27532257,Variant identified in 1 proband with HCM,4 probands with HCM (including SHaRe and ClinVar SCV000256636.2) however PS4 not applied since PM2 not met,4 probands with HCM (including SHaRe and ClinVar SCV000256636.2) however PS4 not applied since PM2 not met Variant identified in 1 proband with HCM,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
185,NM_000257.3(MYH7):c.5704G>C (p.Glu1902Gln),MYH7,cardiomyopathy,MONDO:0004994,Likely Benign,Autosomal dominant inheritance,Cardiomyopathy,2021-08-25,PS4,not_met,PubMed:27532257,Variant identified in proband with HCM,"5 probands with HCM total (including ClinVar SCV000059629.5 and SHaRe data) - but PS4 not applied as PM2 criterion was not met

INDIVIDUAL DATA:
Invitae: No proband count provided since LB
OMGL: 1 proband with HCM, likely same as Walsh 2017 (PMID: 27532257)
Ingles: Seen in 1 family (assumed to be HCM)
Ambry: Seen in 1 proband with HCM
CHEO: 1 proband with HCM
GeneDx: 1 proband who also had MYBPC3 nonsense variant","5 probands with HCM total (including ClinVar SCV000059629.5 and SHaRe data) - but PS4 not applied as PM2 criterion was not met

INDIVIDUAL DATA:
Invitae: No proband count provided since LB
OMGL: 1 proband with HCM, likely same as Walsh 2017 (PMID: 27532257)
Ingles: Seen in 1 family (assumed to be HCM)
Ambry: Seen in 1 proband with HCM
CHEO: 1 proband with HCM
GeneDx: 1 proband who also had MYBPC3 nonsense variant Variant identified in proband with HCM",ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
229,NM_000257.3(MYH7):c.5326A>G (p.Ser1776Gly),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Uncertain Significance,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PS4,not_met,PubMed:27532257,Variant identified in probands with HCM,"Variant identified in 12 probands with HCM, but PS4 criterion not applied since PM2 was not met","Variant identified in 12 probands with HCM, but PS4 criterion not applied since PM2 was not met Variant identified in probands with HCM",ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
178,NM_000257.4(MYH7):c.3158G>A (p.Arg1053Gln),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2021-12-09,PS4,met,PubMed:27532257,Variant identified in probands with HCM,"SUMMARY: This variant has been reported in >35 individuals with hypertrophic cardiomyopathy, and a large proportion are of Finnish ancestry (PS4; Kärkkäinen 2004 PMID:15556047; Jääskeläinen 2014 PMID:24888384; Walsh 2017 PMID:27532257; Ambry pers. comm.; GeneDx pers. comm., Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.). 

Kärkkäinen 2004 (PMID:15556047) - 1 family with a proband with HCM->DCM and segregated in 5 relatives with HCM
Jääskeläinen 2014 (PMID:24888384) - 17 probands with HCM
Walsh 2017 (PMID:27532257) - 6 probands with HCM from OMGL data
LMM Data - 1 proband with HCM
SHaRe - 2 probands with HCM (lab not specified, may overlap with other sources)
Invitae - 5 probands with HCM
Ambry - 2 probands with HCM
GeneDx - 4 probands with HCM
OMGL - 10 probands with HCM (only considering 4 additional from Walsh paper), 13 segregations from 6 families

Literature from ClinVar, HGMD, and Google Scholar from Alamut search string","SUMMARY: This variant has been reported in >35 individuals with hypertrophic cardiomyopathy, and a large proportion are of Finnish ancestry (PS4; Kärkkäinen 2004 PMID:15556047; Jääskeläinen 2014 PMID:24888384; Walsh 2017 PMID:27532257; Ambry pers. comm.; GeneDx pers. comm., Invitae pers. comm.; LMM pers. comm.; OMGL pers. comm.). 

Kärkkäinen 2004 (PMID:15556047) - 1 family with a proband with HCM->DCM and segregated in 5 relatives with HCM
Jääskeläinen 2014 (PMID:24888384) - 17 probands with HCM
Walsh 2017 (PMID:27532257) - 6 probands with HCM from OMGL data
LMM Data - 1 proband with HCM
SHaRe - 2 probands with HCM (lab not specified, may overlap with other sources)
Invitae - 5 probands with HCM
Ambry - 2 probands with HCM
GeneDx - 4 probands with HCM
OMGL - 10 probands with HCM (only considering 4 additional from Walsh paper), 13 segregations from 6 families

Literature from ClinVar, HGMD, and Google Scholar from Alamut search string Variant identified in probands with HCM",ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
193,NM_000257.3(MYH7):c.2207T>C (p.Ile736Thr),MYH7,hypertrophic cardiomyopathy,MONDO:0005045,Pathogenic,Autosomal dominant inheritance,Cardiomyopathy,2018-11-16,PS4,met,PubMed:27532257,Variant identified in 6 probands with HCM,>20 probands with HCM including SHaRe data; ClinVar SCV000199207.4; ClinVar SCV000212631.2,>20 probands with HCM including SHaRe data; ClinVar SCV000199207.4; ClinVar SCV000212631.2 Variant identified in 6 probands with HCM,ClinGenCardiomyopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYH7Version2.0.0_version=2.0.0.csv
381,NM_002880.3(RAF1):c.1472C>T (p.Thr491Ile),RAF1,RASopathy,MONDO:0021060,Pathogenic,Autosomal dominant inheritance,RASopathy,2018-12-10,PM1,met,PubMed:29493581,"Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581).","Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581).","Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581).",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
1215,NM_002834.4(PTPN11):c.215C>T (p.Ala72Val),PTPN11,RASopathy,MONDO:0021060,Pathogenic,Autosomal dominant inheritance,RASopathy,2020-03-25,PM1,met,PubMed:26619011,Describes this region as a hotspot,"Directly interacting residues between N-SH2 and PTPN domains: 4, 7-9, 58-63, 69-77, 247, 251, 255, 256, 258, 261, 265, 278-281, 284 (Gelb et al. 2018).","Directly interacting residues between N-SH2 and PTPN domains: 4, 7-9, 58-63, 69-77, 247, 251, 255, 256, 258, 261, 265, 278-281, 284 (Gelb et al. 2018). Describes this region as a hotspot",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
311,NM_002880.3(RAF1):c.775T>A (p.Ser259Thr),RAF1,RASopathy,MONDO:0021060,Pathogenic,Autosomal dominant inheritance,RASopathy,2020-04-13,PM1,met,PubMed:29493581,"Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581).",The variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581).,"The variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581).",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
1215,NM_002834.4(PTPN11):c.215C>T (p.Ala72Val),PTPN11,RASopathy,MONDO:0021060,Pathogenic,Autosomal dominant inheritance,RASopathy,2020-03-25,PM1,met,PubMed:29493581,RAS VCEP outlines hotspot regions,"Directly interacting residues between N-SH2 and PTPN domains: 4, 7-9, 58-63, 69-77, 247, 251, 255, 256, 258, 261, 265, 278-281, 284 (Gelb et al. 2018).","Directly interacting residues between N-SH2 and PTPN domains: 4, 7-9, 58-63, 69-77, 247, 251, 255, 256, 258, 261, 265, 278-281, 284 (Gelb et al. 2018). RAS VCEP outlines hotspot regions",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
309,NM_007373.3(SHOC2):c.4A>G (p.Ser2Gly),SHOC2,Noonan syndrome-like disorder with loose anagen hair 1,MONDO:0054637,Pathogenic,Autosomal dominant inheritance,RASopathy,2018-12-10,PS3,met,PubMed:19684605,In vitro functional studies provide some evidence that the p.Ser2Gly variant may impact protein function (PS3; PMID: 19684605).,In vitro functional studies provide some evidence that the p.Ser2Gly variant may impact protein function (PS3; PMID: 19684605).,In vitro functional studies provide some evidence that the p.Ser2Gly variant may impact protein function (PS3; PMID: 19684605). In vitro functional studies provide some evidence that the p.Ser2Gly variant may impact protein function (PS3; PMID: 19684605).,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforSHOC2Version2.3.0_version=2.3.0.csv
392,NM_002755.3(MAP2K1):c.389A>G (p.Tyr130Cys),MAP2K1,cardiofaciocutaneous syndrome,MONDO:0015280,Pathogenic,Autosomal dominant inheritance,RASopathy,2018-12-10,PS3,met,PubMed:23093928,"In vitro functional studies provide some evidence that the p.Tyr130Cys variant may impact protein function (PS3; PMID 18413255, 23093928, 17981815).","In vitro functional studies provide some evidence that the p.Tyr130Cys variant may impact protein function (PS3; PMID 18413255, 23093928, 17981815).","In vitro functional studies provide some evidence that the p.Tyr130Cys variant may impact protein function (PS3; PMID 18413255, 23093928, 17981815). In vitro functional studies provide some evidence that the p.Tyr130Cys variant may impact protein function (PS3; PMID 18413255, 23093928, 17981815).",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,PS4,met,PubMed:24767283,1 proband,"Added this code since the Gelb 2018 paper. There are more than 5 independent occurrences of the variant in NSML patients. PMIDs: 20883402, 15520399, 17935252, 24767283, 12058348, 15520399","Added this code since the Gelb 2018 paper. There are more than 5 independent occurrences of the variant in NSML patients. PMIDs: 20883402, 15520399, 17935252, 24767283, 12058348, 15520399 1 proband",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,PS4,met,PubMed:24219368,1 proband with Noonan syndrome and a mature cataract,6 probands have been identified with NS/ NSML; this code was not applied in the Gelb 2018 paper,6 probands have been identified with NS/ NSML; this code was not applied in the Gelb 2018 paper 1 proband with Noonan syndrome and a mature cataract,ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforPTPN11Version2.3.0_version=2.3.0.csv
377,NM_005633.3(SOS1):c.508A>G (p.Lys170Glu),SOS1,Noonan syndrome,MONDO:0018997,Pathogenic,Autosomal dominant inheritance,RASopathy,2018-12-10,PM6,met,PubMed:21387466,"The c.508A>G (p.Lys170Glu) variant in SOS1 has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID 19020799, 21387466)","The c.508A>G (p.Lys170Glu) variant in SOS1 has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID 19020799, 21387466)","The c.508A>G (p.Lys170Glu) variant in SOS1 has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID 19020799, 21387466) The c.508A>G (p.Lys170Glu) variant in SOS1 has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID 19020799, 21387466)",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
696,NM_004333.4(BRAF):c.735A>T (p.Leu245Phe),BRAF,RASopathy,MONDO:0021060,Pathogenic,Autosomal dominant inheritance,RASopathy,2019-06-28,PS4-Supporting,not_met,PubMed:30820351,"p.Leu245Phe variant was identified in this melanoma cohort, but this should not be counted for Mendelian inheritance of RASopathies.","LMM: Patient with Noonan syndrome was found to have this c.735A>T p.Leu245Phe variant. The parents were not sequenced.

GeneDx: observed in one case, no detailed pheno information


Invitae: c.735A>T variant detected in female in 30's with short stature. No further phenotypic information

SarkozyDiglio: identified one pateint with CFC PMID: 19206169, 22190897.","LMM: Patient with Noonan syndrome was found to have this c.735A>T p.Leu245Phe variant. The parents were not sequenced.

GeneDx: observed in one case, no detailed pheno information


Invitae: c.735A>T variant detected in female in 30's with short stature. No further phenotypic information

SarkozyDiglio: identified one pateint with CFC PMID: 19206169, 22190897. p.Leu245Phe variant was identified in this melanoma cohort, but this should not be counted for Mendelian inheritance of RASopathies.",ClinGenRASopathyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_version=1.0.0.csv
1301,NM_002880.3(RAF1):c.776C>A (p.Ser259Tyr),RAF1,RASopathy,MONDO:0021060,Pathogenic,Autosomal dominant inheritance,RASopathy,2020-05-21,PS4-Moderate,not_met,PubMed:31030682,,"Identified in a patient with Hypertrophic cardiomyopathy, dysmorphic features. Clinically diagnosed with Noonan syndrome. No parental carrier testing. (GeneDx internal data). 

Identified in 3 month old baby with NS, variant listed as VOUS in ClinVar but LMM is in the process of reclassifying (SCV000061364.6) may be the same case described in PMID 26918529.","Identified in a patient with Hypertrophic cardiomyopathy, dysmorphic features. Clinically diagnosed with Noonan syndrome. No parental carrier testing. (GeneDx internal data). 

Identified in 3 month old baby with NS, variant listed as VOUS in ClinVar but LMM is in the process of reclassifying (SCV000061364.6) may be the same case described in PMID 26918529. ",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,PS2-Very Strong,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,, 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
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,PS4,met,PubMed:25315765,One family from the US that meets HDGC clinical criteria,"Six families that meet HDGC clinical criteria (PMID: 18391748, 23709761, 25315765, 26072394, SCV000665426.2). Three families that do not meet HDGC clinical criteria due to lack of information (SCV000665426.2)","Six families that meet HDGC clinical criteria (PMID: 18391748, 23709761, 25315765, 26072394, SCV000665426.2). Three families that do not meet HDGC clinical criteria due to lack of information (SCV000665426.2) One family from the US that meets HDGC clinical criteria",ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
522,NM_004360.4(CDH1):c.1679C>G (p.Thr560Arg),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Pathogenic,Autosomal dominant inheritance,CDH1,2023-08-29,PS4,met,PubMed:27880784,Shows multiple family members with the CDH1 mutation and all 3 have gastric cancer,Four published families plus internal lab data (SCV000580704.2),Four published families plus internal lab data (SCV000580704.2) Shows multiple family members with the CDH1 mutation and all 3 have gastric cancer,ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
932,NM_004360.4(CDH1):c.2549_2550delCC (p.Ser850Phefs),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Uncertain Significance,Autosomal dominant inheritance,CDH1,2023-08-04,PS4,not_met,PubMed:29798843,"Family does not meet HDGC clinical criteria. Proband with bilateral/contralateral DCIS and IDC/ILC <50, and adenomatous polyps. Same case that has been submitted to ClinVar (SCV000185568.5).",No reported cases that meet HDGC clinical criteria.,"No reported cases that meet HDGC clinical criteria. Family does not meet HDGC clinical criteria. Proband with bilateral/contralateral DCIS and IDC/ILC <50, and adenomatous polyps. Same case that has been submitted to ClinVar (SCV000185568.5).",ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
523,NM_004360.4(CDH1):c.670C>T (p.Arg224Cys),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Likely Benign,Autosomal dominant inheritance,CDH1,2023-08-17,BS3,not_met,PubMed:27582386,Found variant weakly activates E-cadherin induced cell adhesion.,Two functional studies suggest little or no impact on cell adhesion.,Two functional studies suggest little or no impact on cell adhesion. Found variant weakly activates E-cadherin induced cell adhesion.,ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
878,NM_004360.4(CDH1):c.8C>G (p.Pro3Arg),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Likely Benign,Autosomal dominant inheritance,CDH1,2023-08-17,BS3,not_met,PubMed:20921021,This variant is located in the signal peptide of the E-cadherin pre-protein and would be predicted to impact membrane localization. Localization to the plasma membrane was not affected when this variant was expressed in cells lacking endogenous expression E-cadherin.,This variant is located in the signal peptide of the E-cadherin pre-protein and would be predicted to impact membrane localization. Localization to the plasma membrane was not affected when this variant was expressed in cells lacking endogenous expression E-cadherin (PMID: 20921021).,This variant is located in the signal peptide of the E-cadherin pre-protein and would be predicted to impact membrane localization. Localization to the plasma membrane was not affected when this variant was expressed in cells lacking endogenous expression E-cadherin (PMID: 20921021). This variant is located in the signal peptide of the E-cadherin pre-protein and would be predicted to impact membrane localization. Localization to the plasma membrane was not affected when this variant was expressed in cells lacking endogenous expression E-cadherin.,ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
523,NM_004360.4(CDH1):c.670C>T (p.Arg224Cys),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Likely Benign,Autosomal dominant inheritance,CDH1,2023-08-17,PS3,not_met,PubMed:27582386,Found variant weakly activates E-cadherin induced cell adhesion.,Two functional studies suggest little or no impact on cell adhesion.,Two functional studies suggest little or no impact on cell adhesion. Found variant weakly activates E-cadherin induced cell adhesion.,ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
878,NM_004360.4(CDH1):c.8C>G (p.Pro3Arg),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Likely Benign,Autosomal dominant inheritance,CDH1,2023-08-17,PS3,not_met,PubMed:20921021,This variant is located in the signal peptide of the E-cadherin pre-protein and would be predicted to impact membrane localization. Localization to the plasma membrane was not affected when this variant was expressed in cells lacking endogenous expression E-cadherin.,, This variant is located in the signal peptide of the E-cadherin pre-protein and would be predicted to impact membrane localization. Localization to the plasma membrane was not affected when this variant was expressed in cells lacking endogenous expression E-cadherin.,ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
898,NM_004360.4(CDH1):c.220C>T (p.Arg74Ter),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Pathogenic,Autosomal dominant inheritance,CDH1,2023-08-29,PS4-Supporting,not_met,PubMed:25123297,"Found in one individual (76 yo) with gastric adenocarcinoma with suspected family history of gastric cancer (mother, brother), but NOT germline.","Found in one individual (76 yo) with gastric adenocarcinoma with suspected family history of gastric cancer (mother, brother), but NOT germline.
SCV000288456.3 - one proband meet IGCLC HDGC criteria.
- one proband does not meet IGCLC HDGC criteria.
SCV000661607.2 - 3 cases do not meet HDGC criteria with unknown pathology.","Found in one individual (76 yo) with gastric adenocarcinoma with suspected family history of gastric cancer (mother, brother), but NOT germline.
SCV000288456.3 - one proband meet IGCLC HDGC criteria.
- one proband does not meet IGCLC HDGC criteria.
SCV000661607.2 - 3 cases do not meet HDGC criteria with unknown pathology. Found in one individual (76 yo) with gastric adenocarcinoma with suspected family history of gastric cancer (mother, brother), but NOT germline.",ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
904,NM_004360.4(CDH1):c.2293C>T (p.Gln765Ter),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Pathogenic,Autosomal dominant inheritance,CDH1,2023-08-29,PS4-Supporting,not_met,PubMed:29156750,Somatic variant in a breast tumour from a white female,"One family that meets HDGC criteria (SCV000839094.1).
Proband with unknown whether family fulfills HDGC criteria (SCV000274004.4).","One family that meets HDGC criteria (SCV000839094.1).
Proband with unknown whether family fulfills HDGC criteria (SCV000274004.4). Somatic variant in a breast tumour from a white female",ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
881,NM_004360.3(CDH1):c.521dupA (p.Asn174Lysfs),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Pathogenic,Autosomal dominant inheritance,CDH1,2023-08-25,PS4-Moderate,not_met,PubMed:24763289,"Identified in a cohort of patients who underwent hereditary cancer predisposition testing, but no pathology or clinical history provided.","PMID: 17660459 - 2 LBC under 50 yo (variant published as 517insA). 
DOI: 10.1200/PO.16.00021 (Lowstuter et al, Unexpected CDH1 mutations identified on multi-gene panels pose clinical management challenges. J Precis Oncol doi:10.1200/PO.16.00021) - One proband with signet cell gastric cancer.","PMID: 17660459 - 2 LBC under 50 yo (variant published as 517insA). 
DOI: 10.1200/PO.16.00021 (Lowstuter et al, Unexpected CDH1 mutations identified on multi-gene panels pose clinical management challenges. J Precis Oncol doi:10.1200/PO.16.00021) - One proband with signet cell gastric cancer. Identified in a cohort of patients who underwent hereditary cancer predisposition testing, but no pathology or clinical history provided.",ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.csv
496,NM_004360.4(CDH1):c.2494G>A (p.Val832Met),CDH1,CDH1-related diffuse gastric and lobular breast cancer,MONDO:0007648,Benign,Autosomal dominant inheritance,CDH1,2023-08-10,PP4,not_met,PubMed:20921021,Patient with lobular breast cancer at 43 and the variant. Sister had a ductal breast cancer and maternal aunt had an unspecified breast cancer,Multiple families with the variant and either lobular breast cancer or diffuse gastric cancer,Multiple families with the variant and either lobular breast cancer or diffuse gastric cancer Patient with lobular breast cancer at 43 and the variant. Sister had a ductal breast cancer and maternal aunt had an unspecified breast cancer,ClinGenCDH1ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion3.1_version=3.1.0.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:30231930,"macrocephaly and right lateralized overgrowth, reported from birth, Magnetic Resonance Imaging that revealed ventriculomegaly, cerebellar tonsillar ectopia, a markedly thick corpus callosum, and white matter abnormalities",also present in 2 tumor samples in COSMIC Upgraded to very strong,"also present in 2 tumor samples in COSMIC Upgraded to very strong macrocephaly and right lateralized overgrowth, reported from birth, Magnetic Resonance Imaging that revealed ventriculomegaly, cerebellar tonsillar ectopia, a markedly thick corpus callosum, and white matter abnormalities",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,PS4,met,PubMed:28086757,"2 w/ OFC >2 SD, 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  2 w/ OFC >2 SD, ventriculomegaly and PMG",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,PS4,met,PubMed:27830187,"2 IIb, 1 IIa with somatic mutations (no functional assay)",19 tumor samples in COSMIC,"19 tumor samples in COSMIC 2 IIb, 1 IIa with somatic mutations (no functional assay)",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,PM6,not_met,PubMed:22729224,"13 MPPH (1 family w/ 3 affected sibs, parent was  inferred to have germline mosaicism)",," 13 MPPH (1 family w/ 3 affected sibs, parent was  inferred to have germline mosaicism)",ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2759,NM_006218.3(PIK3CA):c.2740G>A (p.Gly914Arg),PIK3CA,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Pathogenic,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-12,PM6,not_met,PubMed:22729224,"102/811 reads in LCL and 56/313 in saliva in individual LR11-070, 112/818 in blood and 103/171 saliva in individual LR06-341",," 102/811 reads in LCL and 56/313 in saliva in individual LR11-070, 112/818 in blood and 103/171 saliva in individual LR06-341",ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2767,NM_001386501.1:c.3127G>T,MTOR,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Uncertain Significance,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-11,PS2-Moderate,not_met,PubMed:27830187,This variant was detected at an allele frequency of 2.41% in brain and 1.3% in blood,, This variant was detected at an allele frequency of 2.41% in brain and 1.3% in blood,ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2747,NM_005027.4(PIK3R2):c.1117G>A (p.Gly373Arg),PIK3R2,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Pathogenic,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-17,PS3,not_met,PubMed:22729224,patient derived cell lines showed increased PI3K activity and S6 phosphorylation versus control cells,, patient derived cell lines showed increased PI3K activity and S6 phosphorylation versus control cells,ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2747,NM_005027.4(PIK3R2):c.1117G>A (p.Gly373Arg),PIK3R2,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Pathogenic,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-17,BS3,not_met,PubMed:22729224,patient derived cell lines showed increased PI3K activity and S6 phosphorylation versus control cells,, patient derived cell lines showed increased PI3K activity and S6 phosphorylation versus control cells,ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
2759,NM_006218.3(PIK3CA):c.2740G>A (p.Gly914Arg),PIK3CA,overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes,MONDO:0016054,Pathogenic,Autosomal dominant inheritance (mosaic),Brain Malformations,2022-02-12,PS2,met,PubMed:22729224,"102/811 reads in LCL and 56/313 in saliva in individual LR11-070, 112/818 in blood and 103/171 saliva in individual LR06-341",," 102/811 reads in LCL and 56/313 in saliva in individual LR11-070, 112/818 in blood and 103/171 saliva in individual LR06-341",ClinGenBrainMalformationsExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1.1.0_version=1.1.0.csv
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:28748566,"2 segregations - 3 individuals with chronic thrombocytopenia, no MDS",," 2 segregations - 3 individuals with chronic thrombocytopenia, no MDS",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:27112265,1 proband with secondary AML to MDS.,4 probands counted across publications.,4 probands counted across publications. 1 proband with secondary AML to MDS.,ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
5879,NM_001754.5(RUNX1):c.330G>C (p.Lys110Asn),RUNX1,hereditary thrombocytopenia and hematologic cancer predisposition syndrome,MONDO:0011071,Likely Pathogenic,Autosomal dominant inheritance,Myeloid Malignancy,2023-12-09,PS3,met,PubMed:22649608,"K83N was transduced into SC1 murine fibroblasts, and reduction of this variant's mRNA was seen upon transfection with short interfering-RNA (posttranscriptional silencing of target gene). K83N was transduced into HEK293T cells, and reduction of this variant's mRNA was seen upon transfection with short hairpin-RNA (longer-lasting gene silencing). These results were confirmed by RT-PCR and flow cytometry.","The variant in a transactivation assay using the M-CSF promoter exhibited a 70% reduction; the mutant protein was also unable to bind DNA whether or or not in the presence of the CBFβ subunit, without affecting CBFβ heterodimerization and nuclear localization (PMID: 10068652; PMID: 11830488). Additional studies of the mutant protein showed that it decreases the ratio of erythroid to myeloid colonies, results in immortalization of cells, and the accumulation of myeloblasts and dysplastic progenitors (PMID: 17234761).","The variant in a transactivation assay using the M-CSF promoter exhibited a 70% reduction; the mutant protein was also unable to bind DNA whether or or not in the presence of the CBFβ subunit, without affecting CBFβ heterodimerization and nuclear localization (PMID: 10068652; PMID: 11830488). Additional studies of the mutant protein showed that it decreases the ratio of erythroid to myeloid colonies, results in immortalization of cells, and the accumulation of myeloblasts and dysplastic progenitors (PMID: 17234761). K83N was transduced into SC1 murine fibroblasts, and reduction of this variant's mRNA was seen upon transfection with short interfering-RNA (posttranscriptional silencing of target gene). K83N was transduced into HEK293T cells, and reduction of this variant's mRNA was seen upon transfection with short hairpin-RNA (longer-lasting gene silencing). These results were confirmed by RT-PCR and flow cytometry.",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:28748566,"2 segregations - 3 individuals with chronic thrombocytopenia, no MDS",4 segregations counted additively across publications,"4 segregations counted additively across publications 2 segregations - 3 individuals with chronic thrombocytopenia, no MDS",ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
3859,NM_001754.5(RUNX1):c.496C>T (p.Arg166Ter),RUNX1,hereditary thrombocytopenia and hematologic cancer predisposition syndrome,MONDO:0011071,Pathogenic,Autosomal dominant inheritance,Myeloid Malignancy,2022-07-05,BS3,not_met,PubMed:33692461,"R139* shows Transactivation assays demonstrating altered transactivation (<20% of wt, and/or reduced to levels similar to well-established pathogenic variants such as R201Q or R166Q) in luciferase assay",: Transactivation assays demonstrating enhanced transactivation (>115% of wt) (PS3_Supporting; PMID: 33692461) Cannot be applied because meets PVS1,": Transactivation assays demonstrating enhanced transactivation (>115% of wt) (PS3_Supporting; PMID: 33692461) Cannot be applied because meets PVS1 R139* shows Transactivation assays demonstrating altered transactivation (<20% of wt, and/or reduced to levels similar to well-established pathogenic variants such as R201Q or R166Q) in luciferase assay",ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
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,PP1-Strong,not_met,PubMed:27112265,"3 affected individuals in Pedigree D with FPD/AML, 2 meioses in segregation.","This variant was found to co-segregate with disease in multiple affected family members, with seven meioses observed across 3 families.","This variant was found to co-segregate with disease in multiple affected family members, with seven meioses observed across 3 families. 3 affected individuals in Pedigree D with FPD/AML, 2 meioses in segregation.",ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
800,NM_001754.5(RUNX1):c.442_449del (p.Thr148fs),RUNX1,hereditary thrombocytopenia and hematologic cancer predisposition syndrome,MONDO:0011071,Pathogenic,Autosomal dominant inheritance,Myeloid Malignancy,2024-03-26,PS4-Supporting,not_met,PubMed:27112265,One family with FPD/AML.,One family with FPD/AML.,One family with FPD/AML. One family with FPD/AML.,ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.csv
7754,NM_001122607.2:c.403_404delinsGC,RUNX1,hereditary thrombocytopenia and hematologic cancer predisposition syndrome,MONDO:0011071,Uncertain Significance,Autosomal dominant inheritance,Myeloid Malignancy,2024-08-16,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).”","Located at a residue that directly contacts DNA (PMID: 11276260, 12377125, 12393679, 12807882, 19808697, 28231333) and is a defined hotspot (PMID: 31648317, 27294619, 23958918).","Located at a residue that directly contacts DNA (PMID: 11276260, 12377125, 12393679, 12807882, 19808697, 28231333) and is a defined hotspot (PMID: 31648317, 27294619, 23958918). “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:32943879,Scalable functional screening by sequencing displays decreased gene expression in this variant.,"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). Scalable functional screening by sequencing displays decreased gene expression in this variant.",ClinGenMyeloidMalignancyExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2_version=2.0.0.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,BS3,met,PubMed:30224644,No evidence of dominant negative effect or loss of function.,"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 evidence of dominant negative effect or loss of function.",ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
1591,NM_001126112.2(TP53):c.250G>A (p.Ala84Thr),TP53,Li-Fraumeni syndrome,MONDO:0018875,Likely 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
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,BS3,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
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,BS3,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
1595,NM_000546.5(TP53):c.1163A>C (p.Glu388Ala),TP53,Li-Fraumeni syndrome,MONDO:0018875,Likely Benign,Autosomal dominant inheritance,TP53,2022-01-10,BS3,met,PubMed:30224644,noDNE+noLOF (p53WTNutlin3 Z-score -0.248 (< 0.61) and Etoposide Z-score 1.239 (> -0.21 )),"Functional (Kato et al 2003, 100% mean transactivation activity (>75%)) 
noDNE+noLOF (Giacomelli et al. 2018, p53WTNutlin3 Z-score -0.248 (< 0.61) and Etoposide Z-score 1.239 (> -0.21 ))","Functional (Kato et al 2003, 100% mean transactivation activity (>75%)) 
noDNE+noLOF (Giacomelli et al. 2018, p53WTNutlin3 Z-score -0.248 (< 0.61) and Etoposide Z-score 1.239 (> -0.21 )) noDNE+noLOF (p53WTNutlin3 Z-score -0.248 (< 0.61) and Etoposide Z-score 1.239 (> -0.21 ))",ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
1587,NM_000546.6(TP53):c.329G>A (p.Arg110His),TP53,Li-Fraumeni syndrome,MONDO:0018875,Likely Benign,Autosomal dominant inheritance,TP53,2025-01-16,BS3-Supporting,not_met,PubMed:33051313,Report a deleterious effect of this variant using a functional assay from patient blood sample.,"In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation, and retained growth suppression activity indicating that this variant does not impact protein function
(BS3_Supporting; PMIDs: 12826609, 29979965, 30224644).","In vitro assays performed in yeast and/or human cell lines showed partially functional transactivation, and retained growth suppression activity indicating that this variant does not impact protein function
(BS3_Supporting; PMIDs: 12826609, 29979965, 30224644). Report a deleterious effect of this variant using a functional assay from patient blood sample.",ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
1597,NM_000546.5(TP53):c.396G>C (p.Lys132Asn),TP53,Li-Fraumeni syndrome,MONDO:0018875,Likely Pathogenic,Autosomal dominant inheritance,TP53,2022-03-18,PS3,met,PubMed:30224644,Shows DNE and LOF,"Experimental studies show this variant to be non-functional (Kato 2003) and to demonstrate both dominant negative effect (DNE) and loss of function (LOF) (Dearth 2007, Giacomelli 2018 and Kotler 2018).","Experimental studies show this variant to be non-functional (Kato 2003) and to demonstrate both dominant negative effect (DNE) and loss of function (LOF) (Dearth 2007, Giacomelli 2018 and Kotler 2018). Shows DNE and LOF",ClinGenTP53ExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforTP53Version2.3.0_version=2.3.0.csv
7655,NC_012920.1:m.14597A>G,,mitochondrial disease,MONDO:0044970,Likely Pathogenic,Mitochondrial inheritance,Mitochondrial Diseases,2024-08-12,PS3-Supporting,not_met,PubMed:34045482,"Analysis of three cybrid fibroblast cell lines demonstrated significantly reduced complex I activity, respiration rate, & ATP content.
","Cybrid studies support the functional impact of this variant (PS3_supporting; PMIDs: 34045482) as significantly reduced complex I activity, respiration rate, and ATP content in three cybrid fibroblast cell lines were demonstrated.","Cybrid studies support the functional impact of this variant (PS3_supporting; PMIDs: 34045482) as significantly reduced complex I activity, respiration rate, and ATP content in three cybrid fibroblast cell lines were demonstrated. Analysis of three cybrid fibroblast cell lines demonstrated significantly reduced complex I activity, respiration rate, & ATP content.
",ClinGenMitochondrialDiseaseNuclearandMitochondrialExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_mtDNA_version=1.0.0.csv
4263,NC_012920.1:m.3291T>C,MT-TL1,mitochondrial disease,MONDO:0044970,Likely Pathogenic,Mitochondrial inheritance,Mitochondrial Diseases,2022-10-13,PS3-Supporting,not_met,PubMed:23273904,"Single fiber testing showed greater abundance of mutant genomes in COX-deficient (89.1± 9.9%, n=18), than in COX-positive fibers (51.1±27.1%, n=17; P < 0.001; PS3_supporting, PMID: 23273904).","Single fiber testing showed greater abundance of mutant genomes in COX-deficient (89.1± 9.9%, n=18), than in COX-positive fibers (51.1±27.1%, n=17; P < 0.001; PS3_supporting, PMID: 23273904).
","Single fiber testing showed greater abundance of mutant genomes in COX-deficient (89.1± 9.9%, n=18), than in COX-positive fibers (51.1±27.1%, n=17; P < 0.001; PS3_supporting, PMID: 23273904).
 Single fiber testing showed greater abundance of mutant genomes in COX-deficient (89.1± 9.9%, n=18), than in COX-positive fibers (51.1±27.1%, n=17; P < 0.001; PS3_supporting, PMID: 23273904).",ClinGenMitochondrialDiseaseNuclearandMitochondrialExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_mtDNA_version=1.0.0.csv
5109,m.7497G>A,MT-TS1,mitochondrial disease,MONDO:0044970,Likely Pathogenic,Mitochondrial inheritance,Mitochondrial Diseases,2023-05-19,PS3-Supporting,not_met,PubMed:16199753,"Cybrid studies showed a correlation between higher heteroplasmy level and lower complex I and IV activity (PS3_supporting, PMID: 16199753).  ","Cybrid studies showed a correlation between higher heteroplasmy level and lower complex I and IV activity (PS3_supporting, PMID: 16199753).  ","Cybrid studies showed a correlation between higher heteroplasmy level and lower complex I and IV activity (PS3_supporting, PMID: 16199753).   Cybrid studies showed a correlation between higher heteroplasmy level and lower complex I and IV activity (PS3_supporting, PMID: 16199753).  ",ClinGenMitochondrialDiseaseNuclearandMitochondrialExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_mtDNA_version=1.0.0.csv
3115,NC_012920.1:m.9055G>A,MT-ATP6,mitochondrial disease,MONDO:0044970,Benign,Mitochondrial inheritance,Mitochondrial Diseases,2022-01-05,BA1,met,PubMed:24104924,Establishes haplogroup K as common in Ashkenazi Jews,"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.
 Establishes haplogroup K as common in Ashkenazi Jews",ClinGenMitochondrialDiseaseNuclearandMitochondrialExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion1_mtDNA_version=1.0.0.csv
4748,NC_012920.1(MT-CYB):m.3243A>T,MT-TL1,mitochondrial disease,MONDO:0044970,Likely Pathogenic,Mitochondrial inheritance,Mitochondrial Diseases,2023-03-13,PS3-Moderate,not_met,PubMed:32273537,Mitochondrial dysfunction in 3243T cybrids seemed to affect the response to IR and could change the response of cells to bystander signals during radiation damage.,"The m.3243A>T variant is at the same nucleotide position as a previously established pathogenic variant (m. 3243A>G; PM5_supporting). Several different functional studies have been performed on this variant that support its pathogenicity and show independent deleterious effects of the variant, including generation of cybrids, single fiber testing, and aminoacylation assays (PS3_moderate). Cybrids with high levels of this variant, when compared to wild type, showed lower oxygen consumption, higher glucose consumption and lactate production, increased motility and migration capacities associated with specific glycosylation patterns, lower growth rate, and altered cellular processes (PMIDs: 25504047, 32273537). Single fiber testing showed higher levels of the variant in COX-deficient fibers (95.8 ± 0.7%, n=9) than in COX-positive fibers (44.3 ± 8.8%, n=9; p < 0.001; PMID: 20471262). Structural and aminoacylation studies of in-vitro transcribed human tRNALeu(UUR) showed that the m.3243A>T variant was associated with a 300-fold loss of aminoacylation efficiency (PMID: 12729737).","The m.3243A>T variant is at the same nucleotide position as a previously established pathogenic variant (m. 3243A>G; PM5_supporting). Several different functional studies have been performed on this variant that support its pathogenicity and show independent deleterious effects of the variant, including generation of cybrids, single fiber testing, and aminoacylation assays (PS3_moderate). Cybrids with high levels of this variant, when compared to wild type, showed lower oxygen consumption, higher glucose consumption and lactate production, increased motility and migration capacities associated with specific glycosylation patterns, lower growth rate, and altered cellular processes (PMIDs: 25504047, 32273537). Single fiber testing showed higher levels of the variant in COX-deficient fibers (95.8 ± 0.7%, n=9) than in COX-positive fibers (44.3 ± 8.8%, n=9; p < 0.001; PMID: 20471262). Structural and aminoacylation studies of in-vitro transcribed human tRNALeu(UUR) showed that the m.3243A>T variant was associated with a 300-fold loss of aminoacylation efficiency (PMID: 12729737). Mitochondrial dysfunction in 3243T cybrids seemed to affect the response to IR and could change the response of cells to bystander signals during radiation damage.",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:31757951,"Assay: PALB2 variants introduced by RMCE system (FlpO expression vector + PALB2-RMCE exchange vector) in Palb2KO/Tp53KO mES cells, ~500 neomycin-resistant clones pooled & expanded, then 1x106 cells transfected with I-SceI & mCherry co-expression cell line, HDR assessed by %GFP+ cells among the mCherry+ cells by FACS. Material: Mouse embryonic stem (mES) cell line 129/Ola E14 IB10 (Palb2-/-; Trp53-/-) with stably integrated DR-GFP reporter & RMCE (recombination mediated cassette exchange) system; PALB2 variants made by site mutagenesis of cDNA constructs in RMCE exchange vector. Readout: Quantitative; Relative HR efficiency (mean % of WT GFP+ cells among mCherry+ cells) +/- SEM for 2 replicates. Controls: wild type cDNA, empty vector, 12 LP/P controls, 9 LB/B controls Threshold for normal readout: B/LB ctrls are ≥79.52% of WT Threshold for abnormal readout: <40% of WT HR efficency (HR >60% reduced) Assay result: 83.25% Assay result assertion: Normal Standard deviation: 5.27 Standard error mean: 3.73","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: PALB2 variants introduced by RMCE system (FlpO expression vector + PALB2-RMCE exchange vector) in Palb2KO/Tp53KO mES cells, ~500 neomycin-resistant clones pooled & expanded, then 1x106 cells transfected with I-SceI & mCherry co-expression cell line, HDR assessed by %GFP+ cells among the mCherry+ cells by FACS. Material: Mouse embryonic stem (mES) cell line 129/Ola E14 IB10 (Palb2-/-; Trp53-/-) with stably integrated DR-GFP reporter & RMCE (recombination mediated cassette exchange) system; PALB2 variants made by site mutagenesis of cDNA constructs in RMCE exchange vector. Readout: Quantitative; Relative HR efficiency (mean % of WT GFP+ cells among mCherry+ cells) +/- SEM for 2 replicates. Controls: wild type cDNA, empty vector, 12 LP/P controls, 9 LB/B controls Threshold for normal readout: B/LB ctrls are ≥79.52% of WT Threshold for abnormal readout: <40% of WT HR efficency (HR >60% reduced) Assay result: 83.25% Assay result assertion: Normal Standard deviation: 5.27 Standard error mean: 3.73","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: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 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   

 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"
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:31757951,This variant had <40% homologous recombination efficiency relative to wildtype which is below the threshold for a non-functional variant (PMID 31757951; PS3_Moderate),"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 <40% homologous recombination efficiency relative to wildtype which is below the threshold for a non-functional variant (PMID 31757951; PS3_Moderate)","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: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 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  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"
3162,NM_000261.2:c.731G>T,MYOC,primary open angle glaucoma,MONDO:0007665,Uncertain Significance,Autosomal dominant inheritance,Glaucoma,2022-07-11,PS3,not_met,PubMed:27092720,"The G244V protein is secreted.
This study does not meet the OddsPath threshold for  BS3_Supporting (< 0.48).","Although the OddsPath threshold for BS3_Supporting was not met, no functional evidence indicating that this variant impacts protein function has been found.
","Although the OddsPath threshold for BS3_Supporting was not met, no functional evidence indicating that this variant impacts protein function has been found.
 The G244V protein is secreted.
This study does not meet the OddsPath threshold for  BS3_Supporting (< 0.48).",ClinGenGlaucomaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYOCVersion2.0.0_version=2.0.0.csv
4479,NM_000261.2:c.1037G>C,MYOC,primary open angle glaucoma,MONDO:0007665,Uncertain Significance,Autosomal dominant inheritance,Glaucoma,2022-12-14,PS3,not_met,PubMed:17615537,"The study reporting functional evidence (PMID: 17615537) demonstrated that the Arg346Thr
protein had reduced solubility levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (> 2.1) for PS3_Supporting to be applied.    ","The study reporting functional evidence (PMID: 17615537) demonstrated that the Arg346Thr
protein had reduced solubility levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (> 2.1) for PS3_Supporting to be applied.    
","The study reporting functional evidence (PMID: 17615537) demonstrated that the Arg346Thr
protein had reduced solubility levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (> 2.1) for PS3_Supporting to be applied.    
 The study reporting functional evidence (PMID: 17615537) demonstrated that the Arg346Thr
protein had reduced solubility levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (> 2.1) for PS3_Supporting to be applied.    ",ClinGenGlaucomaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYOCVersion2.0.0_version=2.0.0.csv
3161,NM_000261.2:c.624C>G,MYOC,primary open angle glaucoma,MONDO:0007665,Likely Benign,Autosomal dominant inheritance,Glaucoma,2022-07-11,BS3,not_met,PubMed:27092720,"The D208E protein is secreted.
This study does not meet the OddsPath threshold for  BS3_Supporting.","The studies reporting functional evidence (PMIDs: 27092720, 14688426) demonstrated that the Asp208Glu 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 studies reporting functional evidence (PMIDs: 27092720, 14688426) demonstrated that the Asp208Glu 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 D208E protein is secreted.
This study does not meet the OddsPath threshold for  BS3_Supporting.",ClinGenGlaucomaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYOCVersion2.0.0_version=2.0.0.csv
3162,NM_000261.2:c.731G>T,MYOC,primary open angle glaucoma,MONDO:0007665,Uncertain Significance,Autosomal dominant inheritance,Glaucoma,2022-07-11,BS3,not_met,PubMed:27092720,"The G244V protein is secreted.
This study does not meet the OddsPath threshold for  BS3_Supporting (< 0.48).","The study reporting functional evidence (PMID: 27092720) demonstrated that the Gly244Val protein had similar secretion levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (< 0.48) for BS3_Supporting to be applied.","The study reporting functional evidence (PMID: 27092720) demonstrated that the Gly244Val protein had similar secretion levels compared to wild type myocilin protein, but did not meet the OddsPath threshold (< 0.48) for BS3_Supporting to be applied. The G244V protein is secreted.
This study does not meet the OddsPath threshold for  BS3_Supporting (< 0.48).",ClinGenGlaucomaExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforMYOCVersion2.0.0_version=2.0.0.csv
1844,NM_000212.2:c.774_775del,ITGB3,Glanzmann's thrombasthenia,MONDO:0010119,Pathogenic,Autosomal recessive inheritance,Platelet Disorders,2021-01-28,PP4-Moderate,not_met,PubMed:25539746,,"From PMID: 25539746 The patient had a history of bleeding, normal platelet number and size, impaired aggregation to ADP and arachidonic acid but normal or only mildly reduced agglutination with ristocetin, and αIIbβ3 expression between 5% and 20% (measured by flow cytometry).",,ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2.1_version=2.1.0.csv
1851,NM_000419.4(ITGA2B):c.2944G>A (p.Val982Met),ITGA2B,Glanzmann's thrombasthenia,MONDO:0010119,Pathogenic,Autosomal recessive inheritance,Platelet Disorders,2021-01-28,PM3,met,PubMed:25539746,"GT-6 was described to have triple heterozygosity with a paternally inherited nonsense, Glu538Ter, pathogenic variant and both Val982Met and Ala958Thr occurring as de novo variants. However it was asserted that Ala989Thr was a polymorphism and Val982Met is the second variant of interest in this patient. No confirmation was reported that the variants are in trans phase. 0.5pt","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). GT-6 was described to have triple heterozygosity with a paternally inherited nonsense, Glu538Ter, pathogenic variant and both Val982Met and Ala958Thr occurring as de novo variants. However it was asserted that Ala989Thr was a polymorphism and Val982Met is the second variant of interest in this patient. No confirmation was reported that the variants are in trans phase. 0.5pt",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,PP4-Strong,not_met,PubMed:28748566,"Patient 1, homozygous for the Trp11Arg variant, had mild thrombocytopenia and absent aggregation with all agonists employed (which agonists were used was not specified). No mention was made of mucocutaneous bleeding, platelet size, or protein expression.","The Trp11Arg variant has been described in 3 probands in the literature, at least one of whom (PMID: 25728920) meets criteria for PP4_Strong; including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of  αIIbβ3 measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries.","The Trp11Arg variant has been described in 3 probands in the literature, at least one of whom (PMID: 25728920) meets criteria for PP4_Strong; including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of  αIIbβ3 measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries. Patient 1, homozygous for the Trp11Arg variant, had mild thrombocytopenia and absent aggregation with all agonists employed (which agonists were used was not specified). No mention was made of mucocutaneous bleeding, platelet size, or protein expression.",ClinGenPlateletDisordersExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesVersion2.1_version=2.1.0.csv
7216,NM_000551.4(VHL):c.500G>A (p.Arg167Gln),VHL,von Hippel-Lindau disease,MONDO:0008667,Pathogenic,Autosomal dominant inheritance,VHL,2024-06-25,PS3-Supporting,not_met,PubMed:19030229,"Hacker et al shows R167Q confers partial suppression of HIF2a , inability to bind Elongin C and retains the ability to ubiquitinate HIF1a, similar to WT VHL. ","Multiple publications support disruption of Elongin C binding with the Arg167Gln variant, as well as altered regulation of HIF2a and near wild type regulation via ubiquitination of HIF1a.","Multiple publications support disruption of Elongin C binding with the Arg167Gln variant, as well as altered regulation of HIF2a and near wild type regulation via ubiquitination of HIF1a. Hacker et al shows R167Q confers partial suppression of HIF2a , inability to bind Elongin C and retains the ability to ubiquitinate HIF1a, similar to WT VHL. ",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:30890701,Functional evaluation focuses more on RSUME (RWD domain-containing protein SUMO Enhancer) interaction with L188V. Assays with direct comparisons to WT show no significant difference in HIF interaction/regulation and VCB complex formation.,"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).  Functional evaluation focuses more on RSUME (RWD domain-containing protein SUMO Enhancer) interaction with L188V. Assays with direct comparisons to WT show no significant difference in HIF interaction/regulation and VCB complex formation.",ClinGenVHLExpertPanelSpecificationstotheACMGAMPVariantInterpretationGuidelinesforVHLVersion1.1.0_version=1.1.0.csv