Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000623208 | SCV000847540 | likely pathogenic | Inborn genetic diseases | 2017-02-22 | criteria provided, single submitter | clinical testing | The p.R937H variant (also known as c.2810G>A), located in coding exon 20 of the ATP1A2 gene, results from a G to A substitution at nucleotide position 2810. The arginine at codon 937 is replaced by histidine, an amino acid with highly similar properties. This variant has been determined to be the result of a de novo mutation or germline mosaicism in one family with an isolated case of ATP1A2-related epilepsy. This alteration is located in the cation ATPase C domain and is indicated to be structurally deleterious (Ambry internal data; Shinoda T et al. Nature, 2009 May;459:446-50; Spiller S et al. World J Biol Chem, 2014 May;5:240-53). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Labcorp Genetics |
RCV000716697 | SCV002282948 | likely pathogenic | Familial hemiplegic migraine | 2024-02-24 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 937 of the ATP1A2 protein (p.Arg937His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of familial hemiplegic migraine (Invitae). ClinVar contains an entry for this variant (Variation ID: 521207). 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 expected to disrupt ATP1A2 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg937 amino acid residue in ATP1A2. Other variant(s) that disrupt this residue have been observed in individuals with ATP1A2-related conditions (PMID: 16088919, 29867740), which suggests that this may be a clinically significant amino acid residue. 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. |