Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000635222 | SCV000756605 | likely pathogenic | Familial hemiplegic migraine | 2020-01-27 | criteria provided, single submitter | clinical testing | Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported to segregate with ATP1A2-related disease in a family (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with glutamic acid at codon 855 of the ATP1A2 protein (p.Gly855Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. Different missense substitutions at this codon (p.Gly855Arg, p.Gly855Val) have been determined to be pathogenic (PMID: 19874388, 20837964, 24921013). This suggests that the glycine residue is critical for ATP1A2 protein function and that other missense substitutions at this position may also be pathogenic. 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. |
| Victorian Clinical Genetics Services, |
RCV004593985 | SCV005086411 | pathogenic | Migraine, familial hemiplegic, 2 | 2022-02-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with alternating hemiplegia of childhood 1 (MIM#104290), familial basilar migraine (MIM#602481) and familial hemiplegic migraine, 2 (MIM#602481). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Incomplete penetrance has been reported for familial hemiplegic migraine, 2 (MIM#602481) (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to glutamic acid. It should be noted that this variant also affects a splice region. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a moderate amino acid change. Additionally, in silico predictions for abnormal splicing are conflicting. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. The p.(Gly855Arg) variant has been classified as pathogenic by clinical diagnostic laboratories and has been reported in individuals in hemiplegic migraine, febrile seizures, epilepsy or intellectual or developmental disabilities while the p.(Gly855Val) variant has been reported in one individual with hemiplegic migraine without epilepsy (ClinVar; PMIDs: 19874388, 26544041, 20837964). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been classified as likely pathogenic by a clinical diagnostic laboratory (ClinVar). (SP) 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 |