Submissions for variant NM_000702.4(ATP1A2):c.1133C>T (p.Thr378Ile)

dbSNP: rs28934002

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000429188	SCV000535365	uncertain significance	not specified	2016-12-22	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the ATP1A2 gene. The T378I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The T378I variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T378I 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. Additionally, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants at the same position (T378N) and in nearby residues (T376M, R383H) have been reported in the Human Gene Mutation Database in association with familial hemiplegic migraine 2 (FHM2) (Stenson et al., 2014), supporting the functional importance of this region of the protein. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000635223	SCV000756606	pathogenic	Familial hemiplegic migraine	2020-10-08	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with isoleucine at codon 378 of the ATP1A2 protein (p.Thr378Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant has been observed in individual(s) with clinical features of ATP1A2-related conditions (Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 392148). 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 disrupts the p.Thr378 amino acid residue in ATP1A2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15174025, 15286158). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV003456396	SCV004183607	likely pathogenic	not provided	2023-11-01	criteria provided, single submitter	clinical testing	ATP1A2: PM2, PM5, PP3, PS4:Supporting