ClinVar Miner

Submissions for variant NM_005670.4(EPM2A):c.488A>G (p.Asn163Ser) (rs141919651)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000765868 SCV000897265 uncertain significance Lafora disease 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000187386 SCV000240973 uncertain significance not provided 2017-12-20 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the EPM2A gene. The N163S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The N163S variant is observed in 41/126670 (0.03%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). The N163S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In addition, a different missense change at this residue (N163D) has been reported as pathogenic at GeneDx in association with epilepsy. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000696786 SCV000825365 uncertain significance Progressive myoclonic epilepsy 2018-08-08 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 163 of the EPM2A protein (p.Asn163Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs141919651, ExAC 0.03%). This variant has not been reported in the literature in individuals with EPM2A-related disease. ClinVar contains an entry for this variant (Variation ID: 205426). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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