ClinVar Miner

Submissions for variant NM_005670.4(EPM2A):c.241G>A (p.Val81Met) (rs747386643)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187399 SCV000240986 uncertain significance not provided 2012-12-31 criteria provided, single submitter clinical testing p.Val81Met (GTG>ATG): c.241 G>A in exon 1 of the EPM2A gene (NM_005670.3). The Val81Met missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Val81Met in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. The amino acid substitution is conservative, as Valine and Methionine are both uncharged, non-polar amino acids. It alters a poorly conserved position in the CBM20 domain, and multiple in silico algorithms predict it may be benign. However, other missense mutations have been reported at nearby codons in association with Lafora disease. Therefore, the currently available evidence suggests that Val81Met may be a benign variant, but the possibility that it is a disease-causing mutation cannot be excluded. The variant is found in EPILEPSY panel(s).
Invitae RCV000696730 SCV000825304 uncertain significance Progressive myoclonic epilepsy 2018-02-21 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 81 of the EPM2A protein (p.Val81Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs747386643, ExAC 0.1%). This variant has not been reported in the literature in individuals with EPM2A-related disease. ClinVar contains an entry for this variant (Variation ID: 205437). 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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