ClinVar

Description

The p.A57D variant (also known as c.170C>A), located in coding exon 3 of the MYL3 gene, results from a C to A substitution at nucleotide position 170. The alanine at codon 57 is replaced by aspartic acid, an amino acid with dissimilar properties. This alteration has been detected in individuals from hypertrophic cardiomyopathy (HCM) cohorts (Fokstuen S et al. J Med Genet. 2011;48:572-6; Almaas VM et al. Europace. 2013;15:1319-27; Berge KE et al. Clin Genet. 2014;86:355-60; Rubattu S et al. Int J Mol Sci, 2016 Jul;17:1239). This variant has also been identified in two unrelated homozygous individuals with HCM, both of whom had consanguineous parents and family histories of sudden death; heterozygous family members were reportedly unaffected, and one proband had three homozygous young children who had normal echocardiograms at the time of evaluation (Jaafar N et al. Genet Test Mol Biomarkers. 2016;20:674-679; Osborn DPS et al. Genet Med, 2021 Apr;23:787-792). In addition, multiple probands with this variant have had additional pathogenic variants in other HCM-associated genes (Ambry internal data; Broendberg AK et al. Eur J Hum Genet, 2018 03;26:303-313). Furthermore, this variant did not demonstrate a deleterious impact in several functional assays performed in human induced pluripotent stem cells heterozygous or homozygous for this alteration, although zebrafish models showed only partial rescue; given that the molecular mechanisms underlying HCM are not fully understood, the physiological significance of these results is unclear (Ma N et al. Circulation. 2018;138:2666-2681; Osborn DPS et al. Genet Med, 2021 Apr;23:787-792). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.