The NM_000257.4(MYH7):c.1969A>C (p.Lys657Gln) variant in MYH7 has been reported in at least 1 individual with HCM and segregated with HCM in at least 3 affected relatives (PP1; Hill 2015 PMID:26337809; Walsh 2017 PMID:26337809; LMM pers. comm.). Due to potential overlap in the individuals reported, PS4_Supporting criteria is not met. This variant was absent from large population studies (PM2_Supporting; http://gnomad.broadinstitute.org, v2.1.1). Following the ClinGen Sequence Variant Interpretation (SVI) working group recommendation for weight adjustment of the PM2 criterion due to concerns that rarity in the general population may not meet the relative odds of pathogenicity for moderate evidence, the PM2 criterion was downgraded to PM2_Supporting. 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 associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, this variant meets criteria to be classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. ACMG/AMP Criteria applied: PP1, PM2_Supporting, PM1, PP3.