ClinVar

Description

This MYBPC3 Arg495Gly variant has previously been identified in multiple unrelated HCM cases and absent from >1500 control chromosomes, collectively (Alfares AA, et al., 2015; Morita H, et al., 2008; Frisso G, et al., 2009; Millat G, et al., 2010; Calore C, et al., 2015; Oxford genetics, https://cardiodb.org.uk/ACGV/acgv_variant.php?id=4185). This variant is also absent from the 1000 genomes project (http://www.1000genomes.org/), as well as the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). Familial evaluation by Page SP, et al. (2012) identified Arg495Gly in 3 affected HCM cases (2 families) with fully penetrant disease. Similarly, Frisso G, et al. (2009) found the MYBPC3 Arg495Gly variant in 2 affected family members albeit with different disease phenotypes - one individual was diagnosed with childhood HCM, and his father with LVNC. Incomplete penetrance and/or asymptomatic carriers of this variant has been reported in the literature where familial screening is available (Christiaans I, et al., 2010; Morita H, et al., 2008). We identified this variant in 1 HCM proband with a family history of disease, however segregation was not possible. Interestingly, other amino acid substitutions at codon 495 (Arg495Trp, Arg495Gln) have also been idenitifed in HCM cases, and the Arg495Gln variant has been classified as a pathogenic variant, which provides strong support that that an amino acid substitution at this position is not tolerated. Structurally, Arg495 is located in a positively charged region of the C3 domain, where it is exposed on the protein surface of MYBPC3. It is predicted that amino acid substitutions in this domain will likely perturb the surface charge and disrupt the interaction of MYBPC3 with other proteins (Zhang XL, et al., 2014). In silico tools (SIFT, PolyPhen-2, MutationTaster) predict MYBPC3 Arg495Gly to be disease-causing. In summary, based on rarity in general populations, reports of multiple HCM probands with the variant, segregation data and the pathogenic classification of a different amino acid substitution at this position, we classify the MYBPC3 Arg495Gly variant as "pathogenic".