Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000445082 | SCV000533400 | uncertain significance | not provided | 2016-10-28 | criteria provided, single submitter | clinical testing | A variant of uncertain significance has been identified in the ATP1A2 gene. The H207Y variant has not been published as a pathogenic variant, nor has it been reported as a benign variant 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 H207Y 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 in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A missense variant in a nearby residue (R202Q) has been reported in the Human Gene Mutation Database in association with Hemiplegic migraine 2 (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. |
| Invitae | RCV002522582 | SCV003035206 | uncertain significance | Familial hemiplegic migraine | 2022-03-18 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 390538). This variant has not been reported in the literature in individuals affected with ATP1A2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 207 of the ATP1A2 protein (p.His207Tyr). 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. 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. |