ClinVar Miner

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

dbSNP: rs397516398
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Total submissions: 4
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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 RCV000626688 SCV000060040 likely pathogenic Hypertrophic cardiomyopathy 2011-02-17 criteria provided, single submitter clinical testing The Glu65Lys variant has not been reported in the literature nor detected in iso lation by our laboratory. This variant was not identified in either parent of th is individual, indicating that this variant likely arose de novo in this individ ual. In addition, glutamic acid (Glu) at position 65 is highly conserved across several evolutionary distant species, increasing the likelihood that the change is pathogenic. Furthermore, this variant was predicted to be pathogenic using a novel computational tool (a customized sarcomere-specific PolyPhen tool, which w as validated using a set of cardiomyopathy variants with well-established clinic al significance). This tool's pathogenic prediction is estimated to be correct 9 4% of the time. Therefore, this variant is likely to be pathogenic.
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)
Invitae RCV002513380 SCV003441207 uncertain significance Hypertrophic cardiomyopathy 10 2022-07-21 criteria provided, single submitter clinical testing 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. 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).

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