ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1483C>T (p.Arg495Trp) (rs397515905)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000543508 SCV000198913 likely pathogenic Hypertrophic cardiomyopathy 2019-03-11 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Invitae RCV000543508 SCV000623527 pathogenic Hypertrophic cardiomyopathy 2020-08-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 495 of the MYBPC3 protein (p.Arg495Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 19150014, 22765922, 27532257). ClinVar contains an entry for this variant (Variation ID: 164114). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Two different missense substitutions at this codon (p.Arg495Gly and p.Arg495Gln) have been determined to be pathogenic (PMID: 11499718, 18403758, 19659763, 20019025, 20624503, 22857948, 23396983, 24093860, 27532257). This suggests that the arginine residue is critical for MYBPC3 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770365 SCV000901806 likely pathogenic Cardiomyopathy 2016-07-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193929 SCV001363106 likely pathogenic Primary familial hypertrophic cardiomyopathy 2019-05-13 criteria provided, single submitter clinical testing Variant summary: MYBPC3 c.1483C>T (p.Arg495Trp) results in a non-conservative amino acid change located in the Immunoglobulin subtype 2 (IPR003598) domain and Immunoglobulin I-set (IPR013098) domain of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249906 control chromosomes (gnomAD) but has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy (Garcia-Castro_2009, Coto_2012, Rodriguez-Garcia_2010, Walsh_2017). These data indicate that the variant may be associated with disease. However, this variant was also found in two asymptomatic family members (Garcia-Castro_2009), suggesting incomplete penetrance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Another missense change at this codon has been classified as pathogenic by our laboratory (p.Arg495Gly). Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV001265564 SCV001443721 pathogenic Familial hypertrophic cardiomyopathy 4 2019-10-22 criteria provided, single submitter clinical testing This variant has been previously reported as a heterozygous change in patients with hypertrophic cardiomyopathy or dilated cardiomyopathy (PMID: 19150014, 22765922, 27532257). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.1483C>T (p.Arg495Trp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1483C>T (p.Arg495Trp) variant is classified as Pathogenic.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000543508 SCV001430846 likely pathogenic Hypertrophic cardiomyopathy 2019-12-06 no assertion criteria provided research The MYBPC3 Arg495Trp variant has been reported in at least >10 HCM cases (see literature), and was found to segregate in one family (García-Castro M, et al., 2009). We have identified this variant in a HCM proband of East Asian descent, with no family history of disease. The variant is present at a low frequency in the Genome Aggregation Database (AF=0.000007; http://gnomad.broadinstitute.org/). In silico tools SIFT, PolyPhen-2 and MutationTaster predict this variant to be deleterious. Furthermore different rare variants at this position (Arg495Gln and Arg495Gly) have been reported as pathogenic, suggesting that an amino acid substitution at this site may not be tolerated. Based on the adapted ACMG criteria (Kelly MA, et al., 2018) the variant has been reported in more than 10 HCM probands (PS4_supporting), is rare in the general population (PM2), other amino acid changes at this position have been classified as pathogenic (PM5) and multiple in silico tools predict that this variant is deleterious (PP3), therefore we classify MYBPC3 Arg495Trp as 'likely pathogenic'.

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