ClinVar Miner

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

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770365 SCV000901806 likely pathogenic Cardiomyopathy 2016-07-12 criteria provided, single submitter clinical testing
Invitae RCV000543508 SCV000623527 pathogenic Hypertrophic cardiomyopathy 2018-05-08 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000151132 SCV000198913 uncertain significance not specified 2014-11-24 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg495Trp variant in MYBPC3 has been previously reported in at least 4 individuals with HCM (García-Castro 2009, Rodríguez-García 2010, Coto 2012, Martin 2013) and has been identified by our laboratory in 4 individuals with HCM (2 Caucasian adults, 1 Asian adult, and 1 African American infant). It was absent from large population studies. Computational prediction tools and conservation analysis suggest that the p.Arg495Trp variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In addition, our lab has identified two additional variants at this position (p.Arg495Gly and p.Arg495Gln) in individuals with HCM, raising the possibility that changes at this position may play a role in disease. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Arg495Trp variant is uncertain.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.