Submissions for variant NM_000258.3(MYL3):c.466G>T (p.Val156Leu) (rs199474707)

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine,Partners HealthCare 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	Familial hypertrophic cardiomyopathy 8		criteria provided, single submitter	clinical testing
Phosphorus, Inc.	RCV000201472	SCV000679803	likely pathogenic	Familial hypertrophic cardiomyopathy 8	2017-08-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario	RCV000769164	SCV000900539	uncertain significance	Cardiomyopathy	2017-03-21	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 Clinical Services Laboratory,Illumina	RCV000201472	SCV001309350	uncertain significance	Familial 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.
Color	RCV000769164	SCV001346147	uncertain significance	Cardiomyopathy	2019-11-08	criteria provided, single submitter	clinical testing