ClinVar

Description

A variant of uncertain significance has been identified in the MYH7 gene. The M1248K variant has not been published as pathogenic or been reported as benign to our knowledge. However, it is classified as a variant of uncertain significance in ClinVar by a different clinical laboratory in association with HCM (ClinVar SCV000546191.1; Landrum et al., 2016). The M1248K variant is also not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Additionally, M1248K is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Furthermore, this substitution occurs at a position that is conserved in mammals and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, this variant has not been observed in a significant number of affected individuals and it lacks both segregation and functional studies which would further clarify its pathogenicity.