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

Total submissions: 15

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