Submissions for variant NM_000258.3(MYL3):c.466G>A (p.Val156Met)

gnomAD frequency: 0.00004  dbSNP: rs199474707

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000024469	SCV000059678	uncertain significance	not provided	2019-04-04	criteria provided, single submitter	clinical testing	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).
GeneDx	RCV000024469	SCV000208887	uncertain significance	not provided	2024-11-06	criteria provided, single submitter	clinical testing	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000196294	SCV000254449	pathogenic	Hypertrophic cardiomyopathy	2024-12-17	criteria provided, single submitter	clinical testing	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 autosomal dominant hypertrophic cardiomyopathy (PMID: 16754800, 23549607, 24111713, 27532257; internal data). 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.Val156 amino acid residue in MYL3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25132132, 25611685, 27532257, 31737537). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000617202	SCV000739969	likely pathogenic	Cardiovascular phenotype	2024-06-10	criteria provided, single submitter	clinical testing	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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000624899	SCV000740626	uncertain significance	Primary familial hypertrophic cardiomyopathy	2016-12-22	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769165	SCV000900540	likely pathogenic	Cardiomyopathy	2023-03-21	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000024469	SCV000927847	uncertain significance	not provided	2018-08-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000769165	SCV001344277	uncertain significance	Cardiomyopathy	2022-11-17	criteria provided, single submitter	clinical testing	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.
3billion, Medical Genetics	RCV001807740	SCV002058425	likely pathogenic	Hypertrophic cardiomyopathy 8	2022-01-03	criteria provided, single submitter	clinical testing	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.
All of Us Research Program, National Institutes of Health	RCV000196294	SCV004843320	uncertain significance	Hypertrophic cardiomyopathy	2023-08-15	criteria provided, single submitter	clinical testing	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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001807740	SCV005397129	uncertain significance	Hypertrophic cardiomyopathy 8	2024-10-02	criteria provided, single submitter	clinical testing	Criteria applied: PM5,PP3
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV001807740	SCV005417732	likely pathogenic	Hypertrophic cardiomyopathy 8		criteria provided, single submitter	clinical testing	PM2_Supporting+PP3_Moderate+PS4_Moderate+PM5_Supporting
Leiden Muscular Dystrophy (MYL3)	RCV000024469	SCV000045772	not provided	not provided	2012-03-18	no assertion provided	curation
CSER _CC_NCGL, University of Washington	RCV000148717	SCV000190449	uncertain significance	Increased left ventricular wall thickness	2014-06-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004730856	SCV005336650	uncertain significance	MYL3-related disorder	2024-05-08	no assertion criteria provided	clinical testing	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.