The c.1046T>C (p.Met349Thr) variant in MYH7 has been reported in at least 6 individuals with HCM (PS4_Supporting; Jeschke 1998 PMID:9544842; GeneDx: pers comm., Ambry: pers comm, Invitae: pers comm), 1 of whom also had additional variants in other HCM-associated genes (Ambry pers comm;). Additionally, one of these individuals also had severe, early-onset (<20 yo) presentation of HCM and carried a second de novo MYH7 variant on the second allele that was classified as pathogenic by this expert panel (p.Arg719Trp, ClinVar variation ID:14104). This variant has also been reported in 1 individual with unspecified heart disease, 1 with LVH, and 1 with arrhythmia, and 1 with LVNC with atrial and ventricular septal defect (Ambry pers comm.; GeneDX pers comm.; Invitae pers comm.; OMGL pers comm.). This variant has also been identified in 0.007% (1/15378) of European chromosomes, in gnomAD (v2.1.1; http://gnomad.broadinstitute.org). This represents only a fraction of the total European chromosomes, suggesting low coverage at this locus. Therefore, data from large population studies are insufficient to assess the frequency of this variant and apply PM2. Additionally, since the MYH7 specifications state that PS4 is only applicable if the variant is absent or rare in large population studies, the PS4 criterion was not applied (Kelly 2018 PMID:29300372). 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). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM1.