Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000686981 | SCV000814527 | uncertain significance | Progressive myoclonic epilepsy | 2018-04-05 | criteria provided, single submitter | clinical testing | This sequence change replaces tryptophan with arginine at codon 32 of the EPM2A protein (p.Trp32Arg). The tryptophan residue is moderately conserved and there is a moderate physicochemical difference between tryptophan and arginine. 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. 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: "Probably Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Trp32Gly) has been determined to be pathogenic (PMID: 10932264, 11739371, 12019207, 14532330). This suggests that the tryptophan residue is critical for EPM2A protein function and that other missense substitutions at this position may also be pathogenic. 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. |