ClinVar Miner

Submissions for variant NM_005670.4(EPM2A):c.208G>C (p.Glu70Gln) (rs550455609)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000720467 SCV000851344 uncertain significance Seizures 2016-11-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000255450 SCV000321603 uncertain significance not provided 2018-11-20 criteria provided, single submitter clinical testing The E70Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is observed in24/51428 (0.05%) alleles from individuals of European background, in large population cohorts (Lek et al., 2016). The E70Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure asthese residues differ in some properties. This substitution occurs at a position that is conserved in mammals. However, in silico analysis predicts this variant likely does not alter 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 RCV000524852 SCV000636474 uncertain significance Progressive myoclonic epilepsy 2018-09-21 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 70 of the EPM2A protein (p.Glu70Gln). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and glutamine. While this variant is present in population databases (rs550455609), 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: 265122). 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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