ClinVar Genomic variation as it relates to human health

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 149 of the MYL3 protein (p.Met149Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 23283745, 27532257; Invitae). ClinVar contains an entry for this variant (Variation ID: 43123). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Met149 amino acid residue in MYL3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8673105, 16267253, 22131351). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

The Met149Thr variant in MYL3 has been reported in 1 Asian individual with HCM ( Zou 2013) and has been identified by our laboratory in 1 Asian adult with HCM, b ut has also been identified in 1/200 of Southern Han Chinese chromosomes by the 1000 Genomes Project (dbSNP rs202141423). Another pathogenic variant at the same position has been reported (Met149Val; Poetter 1996, Arad 2005) suggesting a ch ange at this residue may not be tolerated. Computational prediction tools and co nservation analysis do not provide strong support for or against an impact to th e protein. In summary, the clinical significance of the Met149Thr variant is unc ertain.

Different missense changes at the same codon have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000014061,VCV000181444, PMID:8673105,25132132, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.671, 3CNET: 0.928, PP3_P). A missense variant is a common mechanism associated with Cardiomyopathy (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MYL3 related disorder (PMID:23283745, PS1_P). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

The p.M149T variant (also known as c.446T>C), located in coding exon 4 of the MYL3 gene, results from a T to C substitution at nucleotide position 446. The methionine at codon 149 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in individuals with hypertrophic cardiomyopathy (HCM) (Zou Y et al. Mol Biol Rep, 2013 Jun;40:3969-76; Olfson E et al. PLoS One, 2015 Sep;10:e0135193; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Harper AR et al. Nat Genet, 2021 Feb;53:135-142; external communications; Ambry internal data). Another variant at the same codon, p.M149V (c.445A>G), has been detected in individuals with HCM and reported to segregate with disease in multiple affected family members (Poetter K et al. Nat. Genet., 1996 May;13:63-9; Arad M et al. Circulation, 2005 Nov;112:2805-11). 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.