ClinVar Miner

Submissions for variant NM_005670.4(EPM2A):c.776G>A (p.Gly259Glu) (rs200641543)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000427841 SCV000536080 uncertain significance not provided 2017-01-13 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the EPM2A gene. The G259E variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G259E variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G259E 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. Additionally, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000813908 SCV000954290 uncertain significance Progressive myoclonic epilepsy 2018-09-17 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 259 of the EPM2A protein (p.Gly259Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is present in population databases (rs200641543, ExAC 0.06%). This variant has not been reported in the literature in individuals with EPM2A-related disease. ClinVar contains an entry for this variant (Variation ID: 392758). 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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