ClinVar Miner

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

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Total submissions: 8
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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

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