Submissions for variant NM_152296.5(ATP1A3):c.2839G>A (p.Gly947Arg)

dbSNP: rs398122887

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000418823	SCV000515905	pathogenic	not provided	2024-02-26	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect compared to wild-type ATP1A3, the G947R substitution results in absent phosphorylation capacity, ouabain binding and ATPase activity, consistent with complete loss of ATP1A3 function (PMID: 25681536, 32653672); 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: 26993267, 28214164, 31164858, 30657467, 30891744, 31061839, 32627437, 33996181, 31069529, 24631656, 25681536, 29567111, 25996915, 24996492, 36484864, 26410222, 32653672, 36192182, 24523486, 24100174, 22842232)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000476589	SCV000544726	pathogenic	Dystonia 12	2023-10-05	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 947 of the ATP1A3 protein (p.Gly947Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with alternating hemiplegia of childhood (AHC) (PMID: 22842232, 24100174, 24523486, 24842602, 24996492, 25447930, 25996915, 26410222, 26993267). In at least one individual the variant was observed to be de novo. It is commonly reported in individuals of European ancestry (PMID: 25447930). ClinVar contains an entry for this variant (Variation ID: 37110). 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 ATP1A3 protein function. Experimental studies have shown that this missense change affects ATP1A3 function (PMID: 24631656, 25681536). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763431	SCV000894197	pathogenic	Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome; Dystonia 12; Alternating hemiplegia of childhood 2	2018-10-31	criteria provided, single submitter	clinical testing
Genetics Laboratory, Instituto de Ciencias en Reproduccion Humana	RCV000030752	SCV000965683	pathogenic	Alternating hemiplegia of childhood 2	2018-08-18	criteria provided, single submitter	clinical testing	This variant c.2839G>A (p.Gly947Arg) has been reported in patients with alternating hemiplegia of childhood: Heizen et al., Nat Genet. 2012;44(9):1030-4. Rosewich H et al. Neurology. 2014;82(11):945-55 and others. The classification according to ACMG 2015 criteria is pathogenic supported by PS1, PM1, PM2, PM6.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000476589	SCV001370376	pathogenic	Dystonia 12	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic.
3billion	RCV000030752	SCV002059147	pathogenic	Alternating hemiplegia of childhood 2	2022-01-03	criteria provided, single submitter	clinical testing	The variant has been observed in multiple (>3) similarly affected unrelated individuals and one of them was confirmed as de novo (PMID: 24842602, PS2_S, PS4_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000280178,VCV000689735, PMID:30283815, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.969, 3CNET: 0.921, PP3_P). A missense variant is a common mechanism associated with Alternating hemiplegia of childhood 2 (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Centogene AG - the Rare Disease Company	RCV000030752	SCV002059397	pathogenic	Alternating hemiplegia of childhood 2	2020-02-04	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000030752	SCV004047695	pathogenic	Alternating hemiplegia of childhood 2		criteria provided, single submitter	clinical testing	The missense variant c.2839G>A (p.Gly947Arg)in ATP1A3 gene has been reported in heterozygous state in many individuals affected with alternating hemiplegia of childhood (AHC); in many cases it was shown to arise de novo (Trump, Natalie et al., 2016). Experimental studies have shown that this missense change leads to a reduction in the ATPase activity of the Na+, K+-ATPase α3 subunit encoded by the ATP1A3 gene (Weigand KM et al., 2014). The p.Gly947Arg variant is novel (not in any individuals) in gnomAD exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. The amino acid Gly at position 947 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Gly947Arg in ATP1A3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000030752	SCV000053413	pathogenic	Alternating hemiplegia of childhood 2	2014-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000476589	SCV000195725	not provided	Dystonia 12		no assertion provided	literature only
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415180	SCV000492559	pathogenic	Epilepsy; Hemiplegia	2016-06-14	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004549395	SCV004800048	pathogenic	ATP1A3-related disorder	2023-11-10	no assertion criteria provided	clinical testing	The ATP1A3 c.2878G>A variant is predicted to result in the amino acid substitution p.Gly960Arg. This variant, also known as c.2839G>A (p.Gly947Arg) in the literature, has been reported with de novo occurrence in many individuals with alternating hemiplegia of childhood (Heinzen et al. 2012. PubMed ID: 22842232; Delorme et al. 2017. PubMed ID: 28214164; Galaz-Montoya et al. 2019. PubMed ID: 30657467; Demos et al. 2019. PubMed ID: 31164858). This variant is absent from a large population database (https://gnomad.broadinstitute.org/), indicating it is rare. This variant is interpreted as pathogenic.