ClinVar Miner

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

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Total submissions: 8
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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 ( 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

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