ClinVar Miner

Submissions for variant NM_152296.5(ATP1A3):c.2443G>A (p.Glu815Lys) (rs387907281)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000432504 SCV000521282 pathogenic not provided 2019-12-02 criteria provided, single submitter clinical testing Functional studies indicate E815K significantly reduces enzyme activity compared to the wild-type (Heinzen et al., 2012; Li et al., 2015); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Missense variants in nearby residues reported in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 29396171, 28637637, 24842602, 24631656, 22842232, 23409136, 22850527, 25681536, 30071271, 28138908, 31164858, 29895895, 31959558)
Invitae RCV000469482 SCV000544728 pathogenic Dystonia 12 2020-09-15 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 815 of the ATP1A3 protein (p.Glu815Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant is a common cause of alternating hemiplegia of childhood. It has been shown to arise de novo in many (>20) affected individuals, and is often associated with a severe phenotype variably including epilepsy, motor function deficits, cognitive impairment and respiratory failure (PMID: 22850527, 23409136, 24631656, 22842232). ClinVar contains an entry for this variant (Variation ID: 37108). Experimental studies have shown that this missense change leads to a reduction in ATP1A3 Na+/K+ ATPase activity (PMID: 25681536). For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626997 SCV000747700 pathogenic Global developmental delay; Hemiplegia; Oculogyric crisis 2017-01-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763433 SCV000894199 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
CeGaT Praxis fuer Humangenetik Tuebingen RCV000432504 SCV001247064 pathogenic not provided 2019-01-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192636 SCV001360890 pathogenic not specified 2019-10-01 criteria provided, single submitter clinical testing Variant summary: ATP1A3 c.2443G>A (p.Glu815Lys) results in a conservative amino acid change located in the Cation-transporting P-type ATPase, C-terminal domain (IPR006068) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251402 control chromosomes (gnomAD). c.2443G>A has been reported in the literature in multiple individuals affected with alternating hemiplegia of childhood (AHC) (e.g. Heinzen_2012, Ishii_2013, Rosewich_2012). In most of these individuals, this variant was seen as a de novo mutation and was associated with the severe form of the disease. Heinzen et al and Ishii et al suggest that the recurrence of de novo mutation could be due to its location in hypermutable GC-rich sequences of ATP1A3 (Heinzen_2012, Ishii_2013). These data indicate that the variant is very likely to be associated with disease. In functional studies, the variant was found to have reduced Na+/K+ ATPase activity, loss of forward cycling, proton transport and phosphorylation (Heinzen_2012, Li_2015, and Weigand_2014). Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics RCV001267254 SCV001445435 pathogenic Inborn genetic diseases 2018-12-14 criteria provided, single submitter clinical testing
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000432504 SCV001450209 pathogenic not provided 2017-06-28 criteria provided, single submitter clinical testing
Baylor Genetics RCV000469482 SCV001528620 pathogenic Dystonia 12 2018-04-18 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Johns Hopkins Genomics, Johns Hopkins University RCV000030750 SCV001711936 pathogenic Alternating hemiplegia of childhood 2 2021-05-06 criteria provided, single submitter clinical testing This variant in the ATP1A3 gene is absent from a large population database and has an entry in ClinVar. It has been reported as a de novo variant in multiple unrelated individuals with alternating hemiplegia of childhood. Individuals with this variant demonstrate an earlier age of onset, more severe motor impairment and a higher prevalence of status epilepticus. Three bioinformatic tools queried predict that this substitution would be damaging, and the glutamate residue at this position is strongly conserved across the vertebrate species assessed. Independent functional studies have shown that this missense change leads to a reduction in ATP1A3 Na+/K+ ATPase activity. We consider this variant to be pathogenic.
OMIM RCV000030750 SCV000053411 pathogenic Alternating hemiplegia of childhood 2 2014-01-01 no assertion criteria provided literature only
GeneReviews RCV000030750 SCV000195716 pathogenic Alternating hemiplegia of childhood 2 2014-05-04 no assertion criteria provided literature only
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000030750 SCV001190829 pathogenic Alternating hemiplegia of childhood 2 2020-02-05 no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000432504 SCV001953661 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000432504 SCV001971538 pathogenic not provided no assertion criteria provided clinical testing

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