ClinVar Miner

Submissions for variant NM_005670.4(EPM2A):c.157G>A (p.Ala53Thr) (rs763719276)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187390 SCV000240977 uncertain significance not specified 2015-11-05 criteria provided, single submitter clinical testing p.Ala53Thr (GCC>ACC): c.157 G>A in exon 1 of the EPM2A gene (NM_005670.3). The A53T variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 2,900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A53T 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. A missense mutation in a nearby residue (E56K) has been reported in association with Lafora disease. However, this substitution occurs at a position that is not conserved across species. 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 mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Invitae RCV000706648 SCV000835713 uncertain significance Progressive myoclonic epilepsy 2018-05-11 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 53 of the EPM2A protein (p.Ala53Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. While this variant is present in population databases (rs763719276), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with EPM2A-related disease. ClinVar contains an entry for this variant (Variation ID: 205430). 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 tolerated, 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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