ClinVar Genomic variation as it relates to human health

Identified in several unrelated patients with HCM or other cardiac findings (PMID: 16754800, 23594557, 24111713, 25637381, 27532257, 23549607); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 24111713, 16754800, 23594557, 27532257, 23549607, 35653365, 30665703, 37652022)

Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MYL3 related disorder (PMID:16754800, PS1_P). A different missense change at the same codon has been reported to be associated with MYL3 related disorder (PMID:25132132, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.926, 3CNET: 0.975, 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: 0.000021, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 156 of the MYL3 protein (p.Val156Met). This variant is present in population databases (rs199474707, gnomAD 0.004%). This missense change has been observed in individuals with clinical features of hypertrophic cardiomyopathy (PMID: 16754800, 23549607, 24111713, 27532257; Invitae). ClinVar contains an entry for this variant (Variation ID: 31778). 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.Met156 amino acid residue in MYL3. Other variant(s) that disrupt this residue have been observed in individuals with MYL3-related conditions (PMID: 25132132), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

This missense variant replaces valine with methionine at codon 156 of the MYL3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 23549607, 24111713, 27532257, 33495597) and in an individual showing early signs of left ventricular wall thickening (PMID 16754800). This variant has been identified in 6/282752 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

This missense variant replaces valine with methionine at codon 156 of the MYL3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 23549607, 24111713, 27532257, 33495597) and in an individual showing early signs of left ventricular wall thickening (PMID 16754800). This variant has been identified in 6/282752 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in one individual with HCM (Berge 2014) and two FHS offspring, neither of whom had LVWT >13 mm, but one had left atrial enlargement and enhanced fractional shortening (Morita 2006). Clinvar: VUS (GeneDx, Invitae, CSER, Ambry, Montreal Heart Institute). Gnomad: 0.004% (1 AFR allele, 5 NFE alleles).

The p.V156M variant (also known as c.466G>A), located in coding exon 4 of the MYL3 gene, results from a G to A substitution at nucleotide position 466. The valine at codon 156 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in individuals with hypertrophic cardiomyopathy (HCM) (Berge KE et al. Clin Genet, 2014 Oct;86:355-60; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Oktay V et al. Anatol J Cardiol. 2023 Nov 1;27(11):628-638; external communication; Ambry internal data). 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.

The MYL3 c.466G>A variant is predicted to result in the amino acid substitution p.Val156Met. This variant was reported in individuals with increased left ventricular wall thickness (Morita et al. 2006. PubMed ID: 16754800) and individuals with hypertrophic cardiomyopathy (Supplemental Table, Ho et al. 2013. PubMed ID: 23549607; Berge and Leren. 2014. PubMed ID: 24111713; Table S1B, Walsh et al. 2017. PubMed ID: 27532257). However, no functional studies were performed to support the pathogenicity of this variant. This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD and is interpreted as uncertain significance by the majority of laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/31778/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.