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Intellectual disability

Gene: ATP1A1

Green List (high evidence)

ATP1A1 (ATPase Na+/K+ transporting subunit alpha 1)
EnsemblGeneIds (GRCh38): ENSG00000163399
EnsemblGeneIds (GRCh37): ENSG00000163399
OMIM: 182310, Gene2Phenotype
ATP1A1 is in 8 panels

2 reviews

Louise Daugherty (Genomics England Curator)

Comment on list classification: New gene added by external expert and reviewed by curation team, enough evidence to support gene-disease association and relevance to this panel to rate this gene Green
Created: 19 Nov 2018, 11:01 a.m.
From Sarah Leigh (Genomics England Curator) review 18 Nov 2018, 10:35 p.m Genetic epilepsy syndromes
Panel version: 0.915
Not associated with phenotype in OMIM or in Gen2Phen. Three heterozygous de novo variants reported in three unrelated cases manifesting with refractory seizures, severe hypomagnesemia and severe intellectual disability. Supportive in vitro studies were also presented.
Created: 19 Nov 2018, 10:57 a.m.

Konstantinos Varvagiannis (Other)

Green List (high evidence)

PMID: 30388404 reports on 3 subjects from 3 families with de novo pathogenic variants in ATP1A1. All 3 presented with similar phenotype consisting of hypomagnesemia, early onset refractory seizures as well as intellectual disability.

Alternative causes of hypomagnesemia with seizures (eg. due to TRPM6 mutations) were excluded while the phenotype of the 3 patients differed from similar disorder in that hypomagnesemia as well as seizures were not responsive to magnesium supplementation.

Three different missense variants are reported (L302R, G303R, M859R) all as de novo occurences and after confirmation of paternity.

Functional studies were suggestive of loss of the ATPase function, abnormal cation permeabilities as well as reduced level of expression (the latter was significant for at least for 2 of the 3 variants).

Mutations in ATP1A1 have also been reported in patients with Charcot-Marie-Tooth type 2 (CMT2DD - MIM: 618036) although the variants reported to date map seem to cluster within the helical linker region (residues 592 to 608). The young age of the patients with epilepsy and intellectual disability did not allow conclusions on eventual peripheral neuropathy in these individuals.

As a result this gene can be considered for inclusion in this panel as green (or amber).
Sources: Expert Review, Literature
Created: 16 Nov 2018, 8:52 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Hypomagnesemia; Seizures; Intellectual disability

Publications

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
Phenotypes
  • Hypomagnesemia
  • Seizures
  • Intellectual disability
OMIM
182310
Clinvar variants
Variants in ATP1A1
Penetrance
unknown
Publications
Panels with this gene

History Filter Activity

19 Nov 2018, Gel status: 3

Entity classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

Gene: atp1a1 has been classified as Green List (High Evidence).

16 Nov 2018, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

gene: ATP1A1 was added gene: ATP1A1 was added to Intellectual disability. Sources: Expert Review,Literature Mode of inheritance for gene: ATP1A1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ATP1A1 were set to 30388404 Phenotypes for gene: ATP1A1 were set to Hypomagnesemia; Seizures; Intellectual disability Penetrance for gene: ATP1A1 were set to unknown Review for gene: ATP1A1 was set to GREEN