ClinVar Miner

Submissions for variant NM_005670.4(EPM2A):c.148G>A (p.Gly50Arg) (rs753397854)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000720477 SCV000851354 uncertain significance Seizures 2016-11-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000426321 SCV000511022 uncertain significance not provided 2017-01-26 criteria provided, single submitter clinical testing Converted during submission to Uncertain significance.
GeneDx RCV000426321 SCV000240971 uncertain significance not provided 2017-11-22 criteria provided, single submitter clinical testing The G50R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G50R variant is not observed at a significant frequency in large population cohorts; however, limited data are available (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G50R 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, this substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to 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 RCV000638309 SCV000759803 uncertain significance Progressive myoclonic epilepsy 2018-09-07 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 50 of the EPM2A protein (p.Gly50Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs753397854, ExAC 0.02%). This variant has not been reported in the literature in individuals with EPM2A-related disease. ClinVar contains an entry for this variant (Variation ID: 205424). 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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