NM_000257.4(MYH7):c.5647G>A (p.Glu1883Lys) The c.5647G>A (p.Glu1883Lys) variant in MYH7 has been reported in the homozygous state in 1 individual from a consanguineous family with myosin storage myopathy, HCM and a family history consistent with recessive inheritance (Tajharghi 2007 PMID 17372140) and in 4 individuals with HCM from testing laboratories (PS4_Supporting; Walsh 2017 PMID:27532257; GeneDx pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant has been identified in 0.01% (1/18716) of African/African American chromosomes by gnomAD v2.1.1 (https://gnomad.broadinstitute.org), but absent from all other populations (PM2). In vitro functional studies provide conflicting evidence on the impact of this on protein function, with some suggesting a potential impact (Viswanathan 2017 PMID: 28973424; Armel 2009 PMID: 19336582), while another suggests that it has a similar function as its wild time counterpart (Dahl-Halvarsson PMID 28125727). Therefore, this data is currently insufficient to establish functional impact and apply PS3. Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient evidence, 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): PS4_Supporting, PM2, PP3.