ClinVar

Description

The MYH7 c.1396G>C; p.Glu466Gln variant (rs4981473), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 430376). According to data provided to ARUP Laboratories from GeneDx, this variant was identified in two individuals with personal diagnoses and family histories of cardiomyopathy. This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glutamate at codon 466 is highly conserved, and it occurs in a highly conserved switch II domain involved in ATP binding and hydrolysis, activities necessary for myosin motor function (Furch 1999, Llinas 2015, Sasaki 1998). Biochemical characterization of Dictyostelium myosin-2 indicates that the orthologous glutamate is involved in a functionally important salt bridge, and substitution to either arginine or alanine significantly reduces ATP hydrolysis and disrupts myosin motility along actin filaments (Furch 1999, Sasaki 1998). Consistent with functional studies of orthologous proteins, computational predictors (SIFT, PolyPhen-2) predict that the MYH7 p.Glu466Gln variant is deleterious (Kumar 2013). Based on available information, this variant is considered to be likely pathogenic. References: Furch M et al. Role of the salt-bridge between switch-1 and switch-2 of Dictyostelium myosin. J Mol Biol. 1999 Jul 16;290(3):797-809. Kumar A et al. Roadmap to determine the point mutations involved in cardiomyopathy disorder: a Bayesian approach. Gene. 2013 Apr 25;519(1):34-40. Llinas P et al. How actin initiates the motor activity of Myosin. Dev Cell. 2015 May 26;33(4):401-12. Sasaki N et al. Mutational analysis of the switch II loop of Dictyostelium myosin II. J Biol Chem. 1998 Aug 7;273(32):20334-40.