ClinVar Miner

Submissions for variant NM_000258.2(MYL3):c.454G>A (p.Glu152Lys) (rs199474705)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000024473 SCV000582170 likely pathogenic not provided 2018-08-09 criteria provided, single submitter clinical testing The E152K likely pathogenic variant in the MYL3 gene has been reported previously in one individual with pre-adolescent HCM, and was absent in 400 control alleles (Kaski et al., 2009). Furthermore, the E152K variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In addition, the E152K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Located in the calcium binding EF-hand domain, this substitution occurs at a position that is conserved across species (Kaski et al., 2009). Consequently, in silico analysis predicts this variant is probably damaging to the protein structure/function. Moreover, missense variants in nearby residues (M149V, M149T, M149I, R154C, R154H) have been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014), supporting the functional importance of this region of the protein.Therefore, this variant is likely pathogenic. In order to definitively determine its clinical significance, additional data is required.
Invitae RCV000628893 SCV000749801 uncertain significance Hypertrophic cardiomyopathy 2019-01-21 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 152 of the MYL3 protein (p.Glu152Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 20031618, 27532257). ClinVar contains an entry for this variant (Variation ID: 31782). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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.
Leiden Muscular Dystrophy (MYL3) RCV000024473 SCV000045777 not provided not provided 2012-03-18 no assertion provided curation

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