ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3286G>T (p.Glu1096Ter) (rs121909377)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621059 SCV000740203 pathogenic Cardiovascular phenotype 2017-08-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Center for Human Genetics,University of Leuven RCV000628863 SCV000886769 pathogenic Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000158223 SCV000208158 pathogenic not provided 2018-08-14 criteria provided, single submitter clinical testing The E1096X pathogenic variant in the MYBPC3 gene has previously been reported in association with HCM (Richard et al., 1999; Richard et al., 2003; Marsiglia et al., 2013). The E1096X variant was first reported in a French Caribbean family with HCM in which two affected individuals harbored E1096X, two affected individuals were double heterozygous for E1096X and a missense variant in the MYH7 gene, and four affected individuals harbored only the MYH7 variant (Richard et al., 1999). Richard et al. (1999) reported that patients who were double heterozygous exhibited marked left ventricular hypertrophy, which was significantly greater than in the individuals who harbored only one variant. Marsiglia et al. (2013) also reported the E1096X pathogenic variant in one Brazilian patient with HCM. E1096X has been observed in other unrelated individuals referred for cardiomyopathy genetic testing at GeneDx, and has been classified in ClinVar as a pathogenic or likely pathogenic variant by other clinical laboratories (ClinVar SCV000059223.4; SCV000256169.1; Landrum et al., 2016). Furthermore, the E1096X variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. E1096X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Moreover, multiple downstream nonsense variants in the MYBPC3 gene have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014).
Gharavi Laboratory,Columbia University RCV000158223 SCV000809464 pathogenic not provided 2018-09-16 no assertion criteria provided research
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000009147 SCV000840019 pathogenic Familial hypertrophic cardiomyopathy 4 2018-04-25 criteria provided, single submitter clinical testing This c.3286G>T (p.Glu1096*) variant in the MYBPC3 gene has been reported in multiple hypertrophic cardiomyopathy (HMC) patients [PMID: 7786104, 10424815, 12707239] while observed with extremely low allele frequency in general population according to gnomad database. It has been demonstrated that this variant was co-segregated with disease in a HCM family [PMID: 10424815]. This variant has been reported by multiple clinical test center as disease-causing according to ClinVar database. This variant is predicted to cause loss of function of normal protein through mRNA decay or producing a truncated protein, which is a known disease mechanism for this gene. Based on current evidences, this c.3286G>T (p.Glu1096*) variant in the MYBPC3 gene is classified as pathogenic.
Invitae RCV000628863 SCV000749771 pathogenic Hypertrophic cardiomyopathy 2018-07-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Glu1096*) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy and to segregate with disease in a single family (PMID: 10424815, 27532257). ClinVar contains an entry for this variant (Variation ID: 8616). Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000628863 SCV000059223 pathogenic Hypertrophic cardiomyopathy 2018-07-03 criteria provided, single submitter clinical testing The p.Glu1096X variant in MYBPC3 has been reported in 7 individuals with HCM, in cluding 1 individual with HCM who also carries a variant in MYH7 (Richard 1999, Richard 2003, Marsiglia 2013, Walsh 2016, LMM data). The p.Glu1096X variant was observed in isolation in 3 affected relatives (including an obligate carrier) an d in combination with the MYH7 variant in 1 affected relative. The proband and t he relative, who both carry the MYH7 and this variant, exhibited more severe dis ease compared with the other affected relatives. This variant has been identifie d in 1/11,964 African chromosomes by the Genome Aggregation Database (gnomAD, ht tp://gnomad.broadinstitute.org/; dbSNP rs121909377). This nonsense variant leads to a premature termination codon at position 1096, which is predicted to lead t o a truncated or absent protein. In summary, this variant meets criteria to be c lassified as pathogenic for HCM in an autosomal dominant manner based upon the p redicted impact of the variant, segregation studies, and absence from controls. ACMG/AMP Criteria applied: PVS1; PM2; PS4_Moderate; PP1.
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000009147 SCV000256169 likely pathogenic Familial hypertrophic cardiomyopathy 4 criteria provided, single submitter clinical testing
OMIM RCV000009147 SCV000029364 pathogenic Familial hypertrophic cardiomyopathy 4 1999-07-01 no assertion criteria provided literature only

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