ClinVar Miner

Submissions for variant NM_005670.4(EPM2A):c.644A>T (p.Asp215Val) (rs144565191)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000726261 SCV000343249 uncertain significance not provided 2016-07-19 criteria provided, single submitter clinical testing
GeneDx RCV000726261 SCV000240976 uncertain significance not provided 2016-11-28 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the EPM2A gene. The D215V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The D215V variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or in the 1000 Genomes Project. The D215V 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 where amino acids with similar properties to Aspartic acid are tolerated across species. Missense variants in nearby residues (E210K, L220Q) have been reported in the Human Gene Mutation Database in association with Lafora disease (Stenson et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000638310 SCV000759804 uncertain significance Progressive myoclonic epilepsy 2018-08-14 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 215 of the EPM2A protein (p.Asp215Val). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is present in population databases (rs144565191, ExAC 0.04%). This variant has not been reported in the literature in individuals with EPM2A-related disease. ClinVar contains an entry for this variant (Variation ID: 205429). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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