ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3408C>A (p.Tyr1136Ter) (rs193922383)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000549683 SCV000059237 pathogenic Hypertrophic cardiomyopathy 2011-09-21 criteria provided, single submitter clinical testing The Tyr1136X variant leads to a premature stop at codon 1136, which is predicted to lead to a truncated or absent protein. Loss of function variants are an esta blished mechanism of disease for the MYBPC3 gene. Therefore, Tyr1136X variant me ets our criteria for pathogenicity (http://pcpgm.partners.org/LMM).
Ambry Genetics RCV000253851 SCV000318293 pathogenic Cardiovascular phenotype 2013-01-23 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000426587 SCV000515917 pathogenic not provided 2015-08-27 criteria provided, single submitter clinical testing The Y1136X pathogenic variant in the MYBPC3 gene has been reported in a two-month-old male withLVNC who also harbors the c.2373dupG variant in the MYPBC3 gene (Haberer et al., 2014). TheY1136X variant was inherited from his mother who has a diagnosis of HCM, and the c.2373dupG variantwas inherited from his unaffected father (Haberer et al., 2014). Additionally, the Y1136X variant wasclassified as a pathogenic variant by one other clinical laboratory in ClinVar (Landrum et al., 2014).Y1136X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other pathogenic nonsense variants in the MYBPC3 gene have been reported inthe Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014).Furthermore, the Y1136X pathogenic variant was not observed in approximately 6,200 individuals ofEuropean and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not acommon benign variant in these populations. In summary, Y1136X in the MYBPC3 gene is interpreted as a pathogenic variant.
Invitae RCV000549683 SCV000623594 pathogenic Hypertrophic cardiomyopathy 2019-08-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr1136*) 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 the literature in individuals with hypertrophic cardiomyopathy (PMID: 25262865, 24111713, 27532257, 28408708). ClinVar contains an entry for this variant (Variation ID: 36611). Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV000426587 SCV000927757 pathogenic not provided 2018-06-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000030289 SCV000052956 pathogenic Primary familial hypertrophic cardiomyopathy 2015-05-26 no assertion criteria provided clinical testing
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000549683 SCV001430862 pathogenic Hypertrophic cardiomyopathy 2019-12-11 no assertion criteria provided research The MYBPC3 Tyr1136Ter variant has been reported in a compound heterozygous infant born with an ventricular septal defect and LVNC, and a family history of HCM on both sides of the family. The Tyr1136Ter segregated on it's own in the probands mother who had a diagnosis of HCM (Haberer K, et al., 2014). It has also been reported in 4 HCM probands (Alfares AA, et al., 2015; Walsh R, et al., 2017). This variant is absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We have identified this variant in a HCM proband and this variant was found to segregate to an affected family member (Ingles et al., 2017). Based on the adapted ACMG guidelines (Kelly MA, et al., 2018) this variant results in loss of function of MYBPC3 (PVS1), is rare in the general population (PM2) and has been reported in at least two HCM probands (PS4_supporting), therefore we classify MYBPC3 Tyr1136Ter as "pathogenic".

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