Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000186803 | SCV000240372 | uncertain significance | not provided | 2019-01-16 | criteria provided, single submitter | clinical testing | p.Arg51Leu (CGC>CTC): c.152 G>T in exon 3 of the ATP1A2 gene (NM_000702.3). The R51L variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R51L 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 that is conserved across species. However, missense mutations in nearby residues have not been reported in association with ATP1A2-related disorders. 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 mutation or a rare benign variant. The variant is found in EPILEPSY panel(s). |
| Labcorp Genetics |
RCV001045545 | SCV001209405 | uncertain significance | Familial hemiplegic migraine | 2023-12-08 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 51 of the ATP1A2 protein (p.Arg51Leu). This variant is present in population databases (rs144106169, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with ATP1A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 204901). 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) performed at Invitae indicates that this missense variant is not expected to disrupt ATP1A2 protein function with a negative predictive value of 80%. 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. |