Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002003780 | SCV002268708 | uncertain significance | Familial hemiplegic migraine | 2023-08-04 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 72 of the ATP1A2 protein (p.Arg72Gln). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 1486680). 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. |
| Victorian Clinical Genetics Services, |
RCV004785434 | SCV005400026 | uncertain significance | Developmental and epileptic encephalopathy 98 | 2022-09-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies (MIM#619602). While functional studies have demonstrated loss of function for variants associated with autosomal dominant alternating hemiplegia of childhood 1 (AHC; MIM#104290), familial basilar migraine, (MIM#602481), familial hemiplegic migraine 2 (FHM2; MIM#602481) and developmental and epileptic encephalopathy 98 (MIM#619605), dominant negative has not been definitively ruled out (PMID: 27445835, 33880529). (I) 0108 - This gene is associated with both recessive and dominant disease. However, the genotype-phenotype correlation in terms of location or variant types is currently unestablished (PMID: 19455354, 33880529). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 1 heterozygote, 0 homozygotes). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated cation_ATPase_N domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been classified as a VUS by a diagnostic laboratory in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |