Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000635222 | SCV000756605 | likely pathogenic | Familial hemiplegic migraine | 2020-01-27 | criteria provided, single submitter | clinical testing | 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. 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. 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. |