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

dbSNP: rs387907281

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000432504	SCV000521282	pathogenic	not provided	2022-12-27	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 (gnomAD); 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 (HGMD); This variant is associated with the following publications: (PMID: 29396171, 28637637, 24842602, 35253165, 24631656, 22842232, 23409136, 22850527, 25681536, 30071271, 28138908, 31164858, 29895895, 31959558, 33082768, 33619735, 32653672, 33726816, 33126486, 31175295, 33098801, 33287870, 31069529, 35701389, 34231463)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000469482	SCV000544728	pathogenic	Dystonia 12	2023-04-28	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ATP1A3 function (PMID: 25681536). 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. ClinVar contains an entry for this variant (Variation ID: 37108). This missense change has been observed in individual(s) with epilepsy, motor function deficits, cognitive impairment, and respiratory failure (PMID: 22842232, 22850527, 23409136, 24631656). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 815 of the ATP1A3 protein (p.Glu815Lys).
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 Center for Human Genetics 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 and Genomics, 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.
3billion	RCV001807744	SCV002058644	pathogenic	Developmental and epileptic encephalopathy 99	2022-01-03	criteria provided, single submitter	clinical testing	The variant has been previously reported as de novo in a similarly affected individual (PMID: 24842602, PS2_S). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000037108, PMID:22850527, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.941, 3CNET: 0.982, PP3_P). A missense variant is a common mechanism associated with Developmental and epileptic encephalopathy 99 (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.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000030750	SCV002061762	pathogenic	Alternating hemiplegia of childhood 2	2021-12-10	criteria provided, single submitter	clinical testing	PS3, PS4, PP2, PP3, PM1, PM2
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002243675	SCV002512692	pathogenic	Dystonic disorder; Seizure; Dyskinesia; Neurodevelopmental delay	2021-06-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000432504	SCV003802799	pathogenic	not provided	2022-11-07	criteria provided, single submitter	clinical testing	The ATP1A3 c.2443G>A (p.Glu815Lys) missense variant results in the substitution of glutamic acid at amino acid position 815 with lysine. Across a selection of the available literature, the c.2443G>A variant has been identified in a de novo state in 15-20% of individuals with ATP1A3-related neurologic disorders (PMID:20301294; PMID: 23409136; PMID: 26410222). Individuals with the c.2443G>A variant tend to have an earlier age of onset of the first paroxysmal manifestation and first hemiplegic event, with frequent neonatal cases, frequent but short duration plegic attacks, less frequent dystonic attacks with a relatively short duration, abnormal ocular movements, severe cognitive disability with moderate to severe intellectual disability, moderate or severe language problems, motor disability, movement disorders, epilepsy and status epilepticus (PMID: 26410222). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. The Glu815 residue is located at the intracellular end between the sixth and the seventh transmembrane domains. A knock-in mouse model expressing the E815K variant of the Atp1a3 gene (Atp1a3 E815K+/-, Matoub, Matb+/-), manifests clinical and neurophysiological features of the most severe form of alternating hemiplegia of childhood (AHC), including poor motor initiative, deeply impaired motor performance, and spontaneous and stress induced hemiplegia and dystonia episodes (PMID: 30071271). Based on the available evidence, the c.2443G>A (p.Glu815Lys) variant is classified as pathogenic for ATP1A3-related neurologic disorders.
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV004546416	SCV005043040	pathogenic	Seizure	2024-01-16	criteria provided, single submitter	clinical testing
OMIM	RCV000030750	SCV000053411	pathogenic	Alternating hemiplegia of childhood 2	2014-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000469482	SCV000195716	not provided	Dystonia 12		no assertion 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
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	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
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV001807744	SCV004099325	pathogenic	Developmental and epileptic encephalopathy 99	2023-10-30	no assertion criteria provided	clinical testing