ClinVar

Description

The p.E143K variant (also known as c.427G>A), located in coding exon 4 of the MYL3 gene, results from a G to A substitution at nucleotide position 427. The glutamic acid at codon 143 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in the homozygous state in multiple unrelated individuals with early onset cardiomyopathy with restrictive physiology and/or hypertrophic cardiomyopathy (HCM) and has segregated with disease in affected homozygous siblings, while tested heterozygous family members were unaffected (Olson TM et al. Circulation. 2002;105(20):2337-40; Caleshu C et al. Am J Med Genet. A 2011;155A(9):2229-35; Ambry internal data; external communication). This alteration has also been detected in the heterozygous state in numerous individuals with HCM or who were referred for HCM genetic testing (McNamara JW et al. PLoS ONE. 2017;12(6):e0180064; Walsh R et al. Genet. Med. 2017;19:192-203; Ambry internal data; external communication). The vast majority of reported cases are of Hispanic ethnicity, and based on data from gnomAD, this alteration is present at a low frequency of 0.01% (4/35436) in the Latino sub-population. Functional studies suggest this alteration impacts a variety of mechanistic properties of myosin, and transgenic mice overexpressing E143K exhibit a phenotype consistent with restrictive cardiomyopathy; however, the clinical relevance of these results is unclear (Lossie J et al. Cardiovasc Res. 2012;93(3):390-6; Yuan CC et al. Cardiovasc Res. 2017;113(10):1124-1136; Wang Y et al. Open Biol. 2018;8(4):170240). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic; however, in the heterozygous state, this variant may have reduced penetrance.