Submissions for variant NM_000702.4(ATP1A2):c.1474G>A (p.Glu492Lys)

gnomAD frequency: 0.00055  dbSNP: rs142348542

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000727278	SCV000240359	uncertain significance	not provided	2023-10-10	criteria provided, single submitter	clinical testing	Reported previously in a five-year-old male with hemiplegic migraine and his mother who had a history of migraines with aura but no hemiplegic attacks (PMID: 18056581); Published in vitro functional studies suggest this variant results in partial loss of function due to reduced cell survival when transfected into HeLa cells (PMID: 18056581); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18957371, 18184292, 34426522, 36044383, 18056581)
Illumina Laboratory Services, Illumina	RCV000265061	SCV000349892	likely benign	Alternating hemiplegia of childhood 1	2017-04-27	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001093838	SCV000349893	likely benign	Migraine, familial hemiplegic, 2	2017-04-27	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Invitae	RCV000324860	SCV000632361	benign	Familial hemiplegic migraine	2024-01-30	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000727278	SCV000707185	uncertain significance	not provided	2017-04-13	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000727278	SCV001147478	uncertain significance	not provided	2024-01-01	criteria provided, single submitter	clinical testing
Mendelics	RCV002247601	SCV002516775	likely benign	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000727278	SCV002541284	uncertain significance	not provided	2021-06-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002390486	SCV002700681	likely benign	Inborn genetic diseases	2018-01-23	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Revvity Omics, Revvity	RCV000727278	SCV003832797	uncertain significance	not provided	2020-04-29	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003407685	SCV004115966	uncertain significance	ATP1A2-related condition	2023-02-06	criteria provided, single submitter	clinical testing	The ATP1A2 c.1474G>A variant is predicted to result in the amino acid substitution p.Glu492Lys. This variant was reported in an individual with hemiplegic migraines and also in his mother who presented with migraines lacking hemiplegia. In vitro studies indicated that this variant may partially impact protein function (de Vries et al. 2007. PubMed ID: 18056581). However, this variant is reported on 0.081% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-160099904-G-A), which is significantly more common than any established pathogenic variant in this gene. Additionally, this variant was not statistically more prevalent in affected individuals compared to presumably asymptomatic controls (Markel et al. 2022. PubMed ID: 36044383). Although we suspect c.1474G>A (p.Glu492Lys) may be benign, the clinical significance of this variant is currently classified as uncertain due to the absence of conclusive functional and genetic evidence.
Athena Diagnostics Inc	RCV000727278	SCV004229406	uncertain significance	not provided	2023-07-07	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). This variant is statistically more frequent in migraine-affected individuals than in the general population and/or healthy controls, suggesting in may be a risk factor for migraines. This variant has been identified in at least one individual with familial hemiplegic migraine. Assessment of experimental evidence suggests this variant results in abnormal protein function, although it shows a milder decrease in function than other known pathogenic variants. (PMID:18056581)