ClinVar Miner

Submissions for variant NM_005670.4(EPM2A):c.143G>A (p.Gly48Asp) (rs946076987)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000434593 SCV000512937 uncertain significance not provided 2018-05-15 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the EPM2A gene. The G48D variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. Although the G48D variant is not observed in large population cohorts, the data is noted to have reduced depth of sequencing reads and therefore may be unreliable. (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G48D 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. This substitution occurs at a position where amino acids with similar properties to Glycine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000536343 SCV000636472 uncertain significance Progressive myoclonic epilepsy 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 48 of the EPM2A protein (p.Gly48Asp). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. 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 a EPM2A-related disease. ClinVar contains an entry for this variant (Variation ID: 377829). 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768208 SCV000898672 uncertain significance Lafora disease 2018-02-05 criteria provided, single submitter clinical testing EPM2A NM_005670.3 exon 1 p.Gly48Asp (c.143G>A):This variant has not been reported in the literature but is present in 8/29388 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is present in ClinVar (Variation ID:377829). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Athena Diagnostics Inc RCV000434593 SCV001143864 uncertain significance not provided 2018-09-18 criteria provided, single submitter clinical testing

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