ClinVar Genomic variation as it relates to human health

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

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.

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.

PS3, PS4, PP2, PP3, PM1, PM2

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)

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.

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.

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).