ClinVar Miner

Submissions for variant NM_005670.4(EPM2A):c.235G>C (p.Gly79Arg) (rs374826256)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724166 SCV000224497 uncertain significance not provided 2014-11-11 criteria provided, single submitter clinical testing
GeneDx RCV000724166 SCV000240985 uncertain significance not provided 2017-05-16 criteria provided, single submitter clinical testing p.Gly79Arg (GGC>CGC): c.235 G>C in exon 1 of the EPM2A gene (NM_005670.3). The G79R variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed with any significant frequency in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The G79R 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 alters a conserved position in the carbohydrate binding domain of the protein, and multiple other missense mutations in this domain have been reported in a gene specific database in association with Lafora disease, supporting the functional importance of this region of the protein. However, this position is not well conserved in related proteins throughout evolution, and in silico analysis predicts the G79R 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 mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Invitae RCV000700602 SCV000829362 uncertain significance Progressive myoclonic epilepsy 2020-01-05 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 79 of the EPM2A protein (p.Gly79Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs374826256, ExAC 0.3%). This variant has not been reported in the literature in individuals with EPM2A-related disease. ClinVar contains an entry for this variant (Variation ID: 193326). 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.
Ambry Genetics RCV000718070 SCV000848932 uncertain significance Seizures 2018-08-01 criteria provided, single submitter clinical testing Insufficient evidence
Fulgent Genetics,Fulgent Genetics RCV000765869 SCV000897266 uncertain significance Lafora disease 2018-10-31 criteria provided, single submitter clinical testing

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