Submissions for variant NM_152296.5(ATP1A3):c.2839G>A (p.Gly947Arg) (rs398122887)

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000418823	SCV000515905	pathogenic	not provided	2015-03-19	criteria provided, single submitter	clinical testing	The G947R variant in the ATP1A3 gene has been reported previously in the heterozygous state inmultiple unrelated individuals with alternating hemiplegia of childhood; this variant was found to haveoccurred de novo in all individuals for which parental analysis was available (Heinzen et al., 2012). TheG947R variant was not observed in approximately 6,500 individuals of European and African Americanancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in thesepopulations. The G947R variant is a non-conservative amino acid substitution, which occurs at a positionthat is conserved across species. Functional characterization of G947R indicates that while proteinexpression levels are similar for G947R compared to wild-type ATP1A3, the G947R substitution results in absent phosphorylation capacity, ouabain binding and ATPase activity, consistent with complete loss ofATP1A3 function. We interpret G947R as a pathogenic variant.
Invitae	RCV000476589	SCV000544726	pathogenic	Dystonia 12	2018-06-05	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with arginine at codon 947 of the ATP1A3 protein (p.Gly947Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in many individuals affected with alternating hemiplegia of childhood (AHC); in many cases it was shown to arise de novo (PMID: 22842232, 24100174, 24523486, 24842602, 24996492, 25996915, 26410222, 26993267). It has been reported to be the third most common AHC causative variant in European populations (PMID: 25447930). ClinVar contains an entry for this variant (Variation ID: 37110). 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 (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.
OMIM	RCV000030752	SCV000053413	pathogenic	Alternating hemiplegia of childhood 2	2014-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000030752	SCV000195725	pathogenic	Alternating hemiplegia of childhood 2	2014-05-04	no assertion criteria 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