ClinVar Miner

Submissions for variant NM_005670.4(EPM2A):c.136G>A (p.Ala46Thr) (rs374338349)

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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 RCV000765870 SCV000897267 uncertain significance Lafora disease 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000187406 SCV000240993 uncertain significance not provided 2018-03-27 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the EPM2A gene. The A46T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A46T variant is observed in 4/1760 (0.2%) alleles from individuals of Latino background in large population cohorts (Lek et al., 2016). The A46T 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. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter 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 RCV000528451 SCV000636471 uncertain significance Progressive myoclonic epilepsy 2018-09-17 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 46 of the EPM2A protein (p.Ala46Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. While this variant is not present in population databases, 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: 205444). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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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