Submissions for variant NM_000258.3(MYL3):c.466G>T (p.Val156Leu)

dbSNP: rs199474707

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154477	SCV000204146	uncertain significance	not specified	2018-11-30	criteria provided, single submitter	clinical testing	The p.Val156Leu variant in MYL3 has been identified in 1 individual with HCM (LM M data). It has also been reported by other clinical laboratories in ClinVar (Va riation ID # 177841) and has been identified in 3/113668 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Another variant (c.466G>C) resulting in the same amino acid change has been identified in 2 individuals with HCM (Wa ng 2014, Walsh 2017). In addition, another variant at this position (p.Val156Me t) has been identified in 2 individuals with increased left ventricular wall thi ckness and 5 individuals with HCM, one of whom with infantile-onset-disease (Mo rita 2006, Berge 2014, LMM data), suggesting that changes at this position may n ot be tolerated. Computational prediction tools and conservation analysis sugges t that this variant may not impact the protein, though this information is not p redictive enough to rule out pathogenicity. In summary, the clinical significanc e of the p.Val156Leu variant is uncertain. ACMG/AMP Criteria applied: BP4, PS4_S upporting.
GeneDx	RCV000766488	SCV000208888	uncertain significance	not provided	2017-09-08	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the MYL3 gene. The V156L (c.466 G>T) variant has been reported previously in association with HCM; however, clinical data was not provided and segregation studies were not performed (Walsh et al., 2017). Additionally, while a different nucleotide substitution (c.466 G>C) that also results in the V156L missense substitution and a missense variant in the same residue (V156M) were previously reported in association with HCM (Morita et al., 2006; Wang et al., 2014), the pathogenicity of these variants has not been definitively determined. Furthermore, the V156L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Nevertheless, the V156L (c.466 G>T) variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Finally, missense variants in nearby residues (H155D, E152K) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein.
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000201472	SCV000256195	uncertain significance	Hypertrophic cardiomyopathy 8		criteria provided, single submitter	clinical testing
Phosphorus, Inc.	RCV000201472	SCV000679803	likely pathogenic	Hypertrophic cardiomyopathy 8	2017-08-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769164	SCV000900539	likely pathogenic	Cardiomyopathy	2023-04-19	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000845401	SCV000987465	uncertain significance	Primary familial hypertrophic cardiomyopathy		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000201472	SCV001309350	uncertain significance	Hypertrophic cardiomyopathy 8	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001309098	SCV001498581	pathogenic	Hypertrophic cardiomyopathy	2024-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 156 of the MYL3 protein (p.Val156Leu). This variant is present in population databases (rs199474707, gnomAD 0.002%). This missense change has been observed in individuals with clinical features of autosomal dominant hypertrophic cardiomyopathy (PMID: 25132132, 25611685, 27532257, 31737537; internal data). ClinVar contains an entry for this variant (Variation ID: 177841). 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: 16754800, 23549607, 24111713, 27532257; internal data). 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.
AiLife Diagnostics, AiLife Diagnostics	RCV000766488	SCV002502423	uncertain significance	not provided	2021-12-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000769164	SCV006064149	likely pathogenic	Cardiomyopathy	2024-02-28	criteria provided, single submitter	clinical testing	This missense variant replaces valine with leucine at codon 156 in the EF-hand domain of the MYL3 protein. Computational prediction suggests that this variant may have a 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, in combination with c.466G>C (p.Val156Leu), has been reported in over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 25132132, 27532257, 31737537, 33495596, 35026164; communication with external laboratories; ClinVar SCV001498581.2, SCV000204146.3). It has also been reported in an individual affected with dilated cardiomyopathy and ventricular tachycardia (PMID: 30630173). This variant has been identified in 3/251364 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.