Submissions for variant NM_000702.4(ATP1A2):c.1244C>T (p.Thr415Met)

gnomAD frequency: 0.00001  dbSNP: rs121918618

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000547097	SCV000632358	uncertain significance	Familial hemiplegic migraine	2023-04-20	criteria provided, single submitter	clinical testing	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. Experimental studies have shown that this missense change affects ATP1A2 function (PMID: 17473835). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ATP1A2 protein function. ClinVar contains an entry for this variant (Variation ID: 12928). This missense change has been observed in individual(s) with clinical features of ATP1A2-related conditions (PMID: 17473835; Invitae). This variant is present in population databases (rs121918618, gnomAD 0.006%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 415 of the ATP1A2 protein (p.Thr415Met).
Illumina Laboratory Services, Illumina	RCV000013791	SCV001254236	uncertain significance	Migraine, familial hemiplegic, 2	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001097906	SCV001254237	uncertain significance	Alternating hemiplegia of childhood 1	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
PreventionGenetics, part of Exact Sciences	RCV003398497	SCV004105177	uncertain significance	ATP1A2-related condition	2023-05-01	criteria provided, single submitter	clinical testing	The ATP1A2 c.1244C>T variant is predicted to result in the amino acid substitution p.Thr415Met. This variant was reported in the compound heterozygous state, and showed partial segregation with the phenotype in a single family with ATP1A2 related disorders (Vanmolkot et al. 2007. PubMed ID: 17473835). This variant is reported in 0.0089% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-160098797-C-T). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
OMIM	RCV000013791	SCV000034038	pathogenic	Migraine, familial hemiplegic, 2	2007-08-01	no assertion criteria provided	literature only