ClinVar

Description

The p.E22K variant (also known as c.64G>A), located in coding exon 2 of the MYL2 gene, results from a G to A substitution at nucleotide position 64. The glutamic acid at codon 22 is replaced by lysine, an amino acid with similar properties. This alteration has been previously detected in numerous hypertrophic cardiomyopathy (HCM) cohorts and has been shown to segregate with HCM in several families (Poetter K et al. Nat. Genet., 1996 May;13:63-9; Kabaeva ZT et al. Eur. J. Hum. Genet., 2002 Nov;10:741-8; Lopes LR et al. Heart, 2015 Feb;101:294-301; Alejandra Restrepo-Cordoba M et al. J Cardiovasc Transl Res, 2017 Feb;10:35-46; Walsh R et al. Genet. Med., 2017 02;19:192-203). This variant is a founder mutation with shared haplotype in the Netherlands; however, the presence of this allele in unaffected relatives and the existence of additional risk factors in many of the affected carriers suggests this allele exhibits reduced penetrance and may not cause disease on its own (Claes GR et al. Eur. Heart J., 2016 06;37:1815-22). Multiple in vitro functional studies suggest this alteration may impact protein function, but adult transgenic mice expressing E22K do not exhibit detectable cardiac hypertrophy (Sanbe A et al. Circ. Res., 2000 Aug;87:296-302; Roopnarine O. Biophys. J., 2003 Apr;84:2440-9; Szczesna-Cordary D et al. J. Cell. Sci., 2005 Aug;118:3675-83; Farman GP et al. J. Appl. Physiol., 2014 Dec;117:1471-7). 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, it may represent a risk factor or a milder allele that presents with incomplete penetrance.