ClinVar

Description

The p.E1426K variant (also known as c.4276G>A), located in coding exon 29 of the MYH7 gene, results from a G to A substitution at nucleotide position 4276. The glutamic acid at codon 1426 is replaced by lysine, an amino acid with similar properties, and is located in the tail domain. This alteration was detected in two individuals with dilated cardiomyopathy (DCM) and presumed present in an affected obligate carrier in one family (Villard E et al. Eur. Heart J., 2005 Apr;26:794-803). In another family, this alteration was detected in a patient with cardiomegaly, non-dilated LV, impaired systolic function, and syncope, however, this individual had undergone chemotherapy and radiotherapy. The alteration was also detected on post mortem testing in her daughter with reported history of DCM and sudden death, although clinical details were limited (Shipman KE et al. J. Clin. Oncol., 2011 Jun;29:e537-8). This alteration was also detected in a cohort of individuals undergoing genetic testing for hypertrophic cardiomyopathy (Walsh R et al. Genet. Med., 2017 Feb;19:192-203). One in vitro functional study of cardiac myofibrils from a patient sample indicated this alteration to result in decreased passive stiffness and possible altered calcium sensitivity (Vikhorev PG et al. Sci Rep, 2017 Nov;7:14829). Furthermore, ClinGen's Inherited Cardiomyopathy Expert Panel classifies this alteration as a variant of unknown significance (Kelly MA et al. Genet. Med., 2018 03;20:351-359). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.