Submissions for variant NM_000702.4(ATP1A2):c.889G>A (p.Ala297Thr)

dbSNP: rs181618883

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493825	SCV000583066	pathogenic	not provided	2023-07-14	criteria provided, single submitter	clinical testing	Also reported in one individual with post-traumatic hemiplegic migraine and another individual with dystonia in the published literature (Cobb-Pitstick et al., 2020; Graziola et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33794876, 31737037, 32345385, 35231114)
Invitae	RCV000533161	SCV000632377	pathogenic	Familial hemiplegic migraine	2023-06-02	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 297 of the ATP1A2 protein (p.Ala297Thr). For these reasons, this variant has been classified as Pathogenic. 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) performed at Invitae indicates that this missense variant is expected to disrupt ATP1A2 protein function. ClinVar contains an entry for this variant (Variation ID: 430293). This missense change has been observed in individual(s) with clinical features of ATP1A2-related conditions (PMID: 31737037; Invitae). In at least one individual the variant was observed to be de novo. This variant is present in population databases (rs181618883, gnomAD 0.007%).
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System	RCV000678349	SCV000804413	uncertain significance	Alternating hemiplegia of childhood 1; Migraine, familial hemiplegic, 2	2017-05-26	criteria provided, single submitter	provider interpretation	This 9 year old female with an intellectual disability was found to carry a missense variant in the ATP1A2 gene. Inheritance is unknown, as is paternal family history. She is non-dysmorphic, normocephalic, and does not have any congenital anomalies. At the date of report, the patient was not presenting with signs of migraines or hemiplegia. The variant is absent from population databases. It is a non-conservative substitution that occurs at a position that is conserved across species. In silico analysis predicts that the variant is probably damaging to protein structure/function.
Fulgent Genetics, Fulgent Genetics	RCV000678349	SCV000896172	uncertain significance	Alternating hemiplegia of childhood 1; Migraine, familial hemiplegic, 2	2018-10-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003419835	SCV004114326	pathogenic	ATP1A2-related condition	2023-06-19	criteria provided, single submitter	clinical testing	The ATP1A2 c.889G>A variant is predicted to result in the amino acid substitution p.Ala297Thr. This variant was reported in an individual with dystonia (Table 1: Graziola et al 2019. PubMed ID: 31737037) and found in individuals with hemiplegia/alternating migraine of childhood (Cobb-Pitstick K et al 2020. PubMed ID: 32345385; reported as de novo in Huang D et al 2021. PubMed ID: 33794876; reported as de novo in Table S1: Duan J et al 2022. PubMed ID: 35231114). At PreventionGenetics, we have seen this variant occur de novo in an individual with hemiplegic events undergoing epilepsy testing (internal data). This variant is reported in a single individual of African descent (1/16,256 alleles; 0.0062%) in gnomAD (http://gnomad.broadinstitute.org/variant/1-160097482-G-A). This variant is interpreted as pathogenic.