ATP1A3
protein-codingATPase Na+/K+ transporting subunit alpha 3, the group of ATPase Na+/K+ transporting subunits
Gene summary
The protein encoded by this gene belongs to the family of P-type cation transport ATPases, and to the subfamily of Na+/K+ -ATPases. Na+/K+ -ATPase is an integral membrane protein responsible for establishing and maintaining the electrochemical gradients of Na and K ions across the plasma membrane. These gradients are essential for osmoregulation, for sodium-coupled transport of a variety of organic and inorganic molecules, and for electrical excitability of nerve and muscle. This enzyme is composed of two subunits, a large catalytic subunit (alpha) and a smaller glycoprotein subunit (beta). The catalytic subunit of Na+/K+ -ATPase is encoded by multiple genes. This gene encodes an alpha 3 subunit. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]
- DYT12
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~30.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0700002
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0030473
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007496
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0013900
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0700002
Submitter: ClinGen
The ATP1A3 gene is located on chromosome 19 at 19q13.2 and encodes the ATPase Na+/K+ Transporting Subunit Alpha 3. ATP1A3 was first reported in relation to autosomal dominant ATP1A3-related neurologic disorders in 2004 (Carvalho Aguiar et al., PMID:15260953). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s), inheritance pattern, and/or phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity, alternating hemiplegia of childhood 2 (OMIM:614820), CAPOS syndrome (OMIM:601338), developmental and epileptic encephalopathy 99 (OMIM:619606), and dystonia 12 (OMIM: 128235). 8 variants (including 7 missense and 1 in-frame indel) have been reported in 9 probands in 3 publications (Heinzen et al., 2012, PMID: 22842232; Marzin et al., 2018, PMID: 29861155; Miyatake et al., 2021, PMID: 33762331) and are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The genotype-phenotype correlation is not fully understood. Differences in ATPase activity, protein trafficking and interaction with beta subunit are thought to contribute to the wide range of pathogenicity of de novo ATP1A3 variants (PMID: 31425744). This gene-disease relationship is also supported by animal models, expression studies, and functional alteration (Arystarkhova et al., 2019, PMID: 31425744; Battle et al., 2017, PMID: 29022597; Sugimoto et al., 2014, PMID: 24983657; Helseth et al., 2018, PMID: 30071271). In summary, ATP1A3 is definitively associated with autosomal dominant ATP1A3-associated neurological disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date 07.16.2021 (SOP Version 8).
Inheritance Pattern: AD
Disease ID:MONDO:0011038
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0030473
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0013900
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0011038
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0013900
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0007496
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0100038
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007496
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0011038
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0013900
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0700002
Submitter: Illumina
Inheritance Pattern: AD
Disease ID:MONDO:0000166
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007496
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0016241
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0011038
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Cardiovascular; Neurologic; Ophthalmologic
Intervention: Cardiovascular; Neurologic
Rationale: In Alternating hemiplegia of childhood 2, medical treatment with calcium channel blockers has been described as beneficial (though not curative) for treatment of the hemiplegic attacks in the majority of individuals patients; Individuals with ATP1A3-related disorders have been described with arrhthymias, and awareness may allow surveillance and management (eg, with ICD or pacemaker placement); In Dystonia 12, reports indicate limited efficacy of levodopa treatment
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ATP1A3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_152296.5. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 18 | 352 | 9 | 380 | |
| missense | 50 | 102 | 416 | 22 | 2 | 592 |
| nonsense | 4 | 5 | 7 | 16 | ||
| start loss | 1 | 1 | ||||
| frameshift | 7 | 3 | 4 | 14 | ||
| splice donor/acceptor (+/-2bp) | 3 | 17 | 8 | 28 | ||
| Total | 64 | 128 | 454 | 374 | 11 | 1031 |
Highest pathogenic variant AF is 0.000006196178
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_689509.1 | 23 | MANE Select | |
| Ensembl | ENSP00000498113.1 | 23 | MANE Select | |
| RefSeq | NP_001243142.1 | 23 | Standard | |
| RefSeq | NP_001243143.1 | 23 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| atp1a3b | Danio rerio | Structure: ventricular system Quality: dilated abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Aldosterone synthesis and secretion - Homo sapiens (human)
- Cardiac muscle contraction - Homo sapiens (human)
- Thyroid hormone synthesis - Homo sapiens (human)
- Protein digestion and absorption - Homo sapiens (human)
- Bile secretion - Homo sapiens (human)
Biological Process
- cellular sodium ion homeostasis
- establishment or maintenance of transmembrane electrochemical gradient
- ATP hydrolysis coupled proton transport
- cellular potassium ion homeostasis
- sodium ion export across plasma membrane
Molecular Function
- amyloid-beta binding
- sodium:potassium-exchanging ATPase activity
- ATP binding
- metal ion binding
- chaperone binding
Cellular Component
- endoplasmic reticulum
- Golgi apparatus
- plasma membrane
- sodium:potassium-exchanging ATPase complex
- membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000545399
- Coding exons
- 23
- Length
- 30916
- Individuals with no LoFs
- 125738
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 2
- Defined
- 125740
- p
- 0.00000795
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 6.33 | 186 | 635 | 0.293 | 0.0000449 | 6745 |
| Missense (PolyPhen) | 73 | 365.49 | 0.19973 | 3855 | ||
| Synonymous | -1.32 | 302 | 274 | 1.10 | 0.0000223 | 2066 |
| Loss of Function | 6.40 | 0 | 47.7 | 0.00 | 0.00000238 | 539 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: This is the catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane. This action creates the electrochemical gradient of sodium and potassium ions, providing the energy for active transport of various nutrients.;
- Disease
- DISEASE: Dystonia 12 (DYT12) [MIM:128235]: An autosomal dominant dystonia-parkinsonism disorder. Dystonia is defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures. DYT12 patients develop dystonia and parkinsonism between 15 and 45 years of age. The disease is characterized by an unusually rapid evolution of signs and symptoms. The sudden onset of symptoms over hours to a few weeks, often associated with physical or emotional stress, suggests a trigger initiating a nervous system insult resulting in permanent neurologic disability. {ECO:0000269|PubMed:15260953, ECO:0000269|PubMed:19351654, ECO:0000269|PubMed:19652145}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Alternating hemiplegia of childhood 2 (AHC2) [MIM:614820]: A rare syndrome of episodic hemi- or quadriplegia lasting minutes to days. Most cases are accompanied by dystonic posturing, choreoathetoid movements, nystagmus, other ocular motor abnormalities, autonomic disturbances, and progressive cognitive impairment. It is typically distinguished from familial hemiplegic migraine by infantile onset and high prevalence of associated neurological deficits that become increasingly obvious with age. {ECO:0000269|PubMed:22842232, ECO:0000269|PubMed:22850527, ECO:0000269|PubMed:23409136, ECO:0000269|PubMed:24631656, ECO:0000269|PubMed:26993267}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) [MIM:601338]: An autosomal dominant neurologic disorder characterized by relapsing and partially remitting, early-onset cerebellar ataxia following a febrile illness. Other features include progressive optic atrophy and sensorineural hearing loss, generalized hypotonia, areflexia and pes cavus without evidence of a peripheral neuropathy on neurophysiological studies. {ECO:0000269|PubMed:24468074}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.184
Intolerance Scores
- LoFtool
- 0.00296
- RVIS EVS
- -1.53
- RVIS percentile EVS
- 3.37
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.295
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |