ClinVar Miner

Submissions for variant NM_000258.2(MYL3):c.451G>A (p.Ala151Thr) (rs869025486)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000208495 SCV000264108 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-12-11 criteria provided, single submitter clinical testing
GeneDx RCV000426551 SCV000513823 likely pathogenic not provided 2016-12-12 criteria provided, single submitter clinical testing A variant that is likely pathogenic was identified in the MYL3 gene. The A151T variant has not been published as a pathogenic or been reported as a benign to our knowledge. This variant has been identified independently in an individual referred for HCM genetic testing at GeneDx and the variant was found to segregate with disease (>7 meioses) in this family. The A151T variant has not been observed in large population cohorts (Lek et al., 2016; McVean et al., 2012; Exome Variant Server). Additionally, the A151T 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. This substitution occurs at a position that is conserved across species. Lastly, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic. In order to definitively determine its clinical significance, additional data is required.
Invitae RCV000817802 SCV000958385 uncertain significance Hypertrophic cardiomyopathy 2019-09-23 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 151 of the MYL3 protein (p.Ala151Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MYL3-related disease. ClinVar contains an entry for this variant (Variation ID: 222737). 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 C0"). 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.

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