Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000793437 | SCV000932789 | likely pathogenic | Progressive myoclonic epilepsy | 2024-02-22 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 253 of the EPM2A protein (p.His253Leu). This variant is present in population databases (rs749937487, gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of EPM2A-related conditions (PMID: 30947044). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 640416). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on EPM2A protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Ambry Genetics | RCV002388420 | SCV002668670 | uncertain significance | Inborn genetic diseases | 2018-08-08 | criteria provided, single submitter | clinical testing | The p.H253L variant (also known as c.758A>T), located in coding exon 4 of the EPM2A gene, results from an A to T substitution at nucleotide position 758. The histidine at codon 253 is replaced by leucine, an amino acid with some similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |