ClinVar Miner

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

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Total submissions: 3
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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 2018-11-29 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

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