ClinVar

Description

The p.R495W variant (also known as c.1483C>T), located in coding exon 17 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 1483. The arginine at codon 495 is replaced by tryptophan, an amino acid with dissimilar properties. In one family, this variant was detected in a proband and maternal grandfather both reported to have hypertrophy, and was also detected in the proband's unaffected mother (García-Castro M et al. Rev Esp Cardiol, 2009 Jan;62:48-56). This variant has also been detected in other probands reported to have hypertrophic cardiomyopathy (HCM) and in HCM cohorts where, in some cases, clinical detail was limited or another variant was also detected (Zou Y et al. Mol. Biol. Rep., 2013 Jun;40:3969-76; Berge KE et al. Clin. Genet., 2014 Oct;86:355-60; Lopes LR et al. Heart. 2015 Feb;101(4):294-301; Rubattu S et al. Int J Mol Sci, 2016 Jul;17(8); Walsh R et al. Genet. Med., 2017 02;19:192-203;Lipari M et al. Pol Arch Intern Med, 2020 02;130:89-99). This alteration was also reported in one individual from a dilated cardiomyopathy (DCM) cohort (Mazzarotto F et al. Circulation, 2020 02;141:387-398). Another alteration at the same codon, p.R495Q (c.1484G>A), has been reported in association with HCM (Niimura H et al. N. Engl. J. Med. 1998 Apr;338(18):1248-57). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.