The c.1357C>A (p.Arg453Ser) variant in MYH7 has been identified in 3 individuals with HCM, including 1 individual with early onset HCM (<20 yo; PS4_Supporting; Frazier 2008 PMID:18175163; Walsh 2017 PMID:27532257; Centenary Institute Sydney pers. comm.; LMM pers. comm.) and segregated with disease in 9 affected relatives with HCM from 2 families (PP1_Strong; Centenary Institute Sydney pers. comm.; LMM pers. comm.). This variant was absent from large population studies (PM2; http:/gnomad.broadinstitute.org, v2.1.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). Two different missense variants that have been classified as pathogenic by this expert panel have been previously identified at this codon, which indicate that this residue may be critical to the function of the protein (PM5; c.1358G>T, p.Arg453His - Variation ID 42838 and c.1357C>T, p.Arg453Cys - Variation ID 14089). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; Walsh 2017 PMID:27532257); however, because the other pathogenic variants at this codon were used to establish this enrichment, PM1 cannot be used in combination with PM5. In summary, this variant meets criteria to be classified as likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting; PP1_Strong; PM2; PP3; PM5.