ClinVar Miner

Submissions for variant NM_005670.4(EPM2A):c.815G>A (p.Arg272His) (rs958366800)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000493798 SCV000613261 uncertain significance not specified 2016-12-21 criteria provided, single submitter clinical testing
GeneDx RCV000766646 SCV000582797 uncertain significance not provided 2017-04-24 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the EPM2A gene. The R272H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R272H variant is observed in 5/11,558 (0.04%) alleles from individuals of East Asian background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R272H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably 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 RCV000793406 SCV000932757 uncertain significance Progressive myoclonic epilepsy 2018-12-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 272 of the EPM2A protein (p.Arg272His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs958366800, 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: 430074). 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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