ClinVar Miner

Submissions for variant NM_000432.4(MYL2):c.193G>A (p.Glu65Lys)

dbSNP: rs397516398
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV001588846 SCV000060040 uncertain significance not provided 2023-02-16 criteria provided, single submitter clinical testing The p.Glu65Lys variant in MYL2 has been identified in 1 individual with hypertrophic cardiomyopathy (HCM) who also had a likely pathogenic variant in a gene associated with DCM (Ho 2013 PMID: 23549607, Alfares 2015 PMID: 25611685, Walsh 2017 PMID:27532257, LMM data, Invitae pers. comm.). This variant was identified as a de novo occurrence in this individual, though maternity and paternity was not confirmed. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 43459) and was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PM6, PP3.
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000626688 SCV000747391 likely pathogenic Hypertrophic cardiomyopathy 2017-01-01 criteria provided, single submitter clinical testing
GeneDx RCV001588846 SCV001823494 uncertain significance not provided 2020-10-01 criteria provided, single submitter clinical testing Reported in association with cardiomyopathy (Ho et al., 2013; Alfares et al., 2015); Not observed in large population cohorts (Lek et al., 2016); 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: 23549607, 27532257, 25611685)
Labcorp Genetics (formerly Invitae), Labcorp RCV002513380 SCV003441207 uncertain significance Hypertrophic cardiomyopathy 10 2022-07-21 criteria provided, single submitter clinical testing Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 43459). This missense change has been observed in individual(s) with clinical features of hypertrophic cardiomyopathy (PMID: 23549607, 25611685, 27532257). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 65 of the MYL2 protein (p.Glu65Lys). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Juno Genomics, Hangzhou Juno Genomics, Inc RCV002513380 SCV005416377 uncertain significance Hypertrophic cardiomyopathy 10 criteria provided, single submitter clinical testing PM2_Supporting+PP3+PS4_Supporting

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