GNAO1
protein-codingG protein subunit alpha o1, the group of G protein subunits alpha, group i|MicroRNA protein coding host genes
Gene summary
The protein encoded by this gene represents the alpha subunit of the Go heterotrimeric G-protein signal-transducing complex. Defects in this gene are a cause of early-onset epileptic encephalopathy. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2015]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~167.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0005395
Submitter: Illumina
Inheritance Pattern: AD
Disease ID:MONDO:0014199
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0005395
Submitter: ClinGen
GNAO1 was first reported in relation to autosomal dominant (AD) rare genetic movement disorder in 2016 [Saitsu et al., PMID:25966631]. At least 10 unique variants have been reported in humans. These are all missense variants except for one variant that is predicted to result in loss of a splice donor. Evidence supporting this gene-disease relationship includes case-level data. All probands had hypotonia, developmental and motor delay, movement disorder, intellectual disability, and no to very limited speech. Some probands (6/20, 30%) had seizures, usually focal and well-controlled on anti-epileptic drugs. Many patients ( 8/20, 40%) had abnormal MRI or brain atrophy. There are many recurrent variants at two major residues: p.Arg209 and p.Glu246. This is because both of these sites are CpG sites that are prone to mutation. Variants identified include p.Arg209His, p.Arg209Gly, p.Arg209Cys, p.Arg209Leu, p.Glu246Lys and p.Glu246Gly. Seven probands improved with placement of deep brain stimulators into the bilateral internal globus pallidus (29758257). Variants in this gene have been reported in at least 20 probands in 7 publications. The maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease may be heterozygous gain-of-function (28747448), but more experimental evidence is needed. Of note, this gene has also been implicated in early-infantile epileptic encephalopathy. This has been assessed separately. In summary, GNAO1 is definitively associated with AD rare genetic movement 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 Epilepsy Gene Curation Expert Panel on 2/19/2019 (SOP Version 6).
Inheritance Pattern: AD
Disease ID:MONDO:0014199
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0100062
Submitter: ClinGen
GNAO1 was first reported in relation to autosomal dominant (AD) early infantile epileptic encephalopathy in 2013 [Nakamura et al. PMID: 23993195]. At least 13 unique variants have been reported in humans. These are all missense variants except for one variant that results in a deletion. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 16 probands in 11 publications. The maximum score for genetic evidence (12 pts) has been reached. Experiments performed on non-patient (HEK-293T) cells transfected with human GNAO1 cDNA demonstrated that several variants had reduced expression and loss-of-function in a cAMP inhibition assay. Notably, variant p.Gly203Arg demonstrated gain-of-function effects, but these probands have more prominent movement disorders compared to probands with other variants. The mechanism for disease may be heterozygous loss-of-function [Feng et al. PMID: 28747448], however more experimental evidence is needed to delineate contributions of loss versus gain of function mechanisms. Of note, this gene has also been implicated in autosomal dominant rare genetic movement disorder. This has been assessed separately. In summary, GNAO1 is definitively associated with autosomal dominant early infantile epileptic encephalopathy. 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 Epilepsy GCEP on 12/18/2018.
Inheritance Pattern: AD
Disease ID:MONDO:0014199
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0060491
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0100062
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0060491
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0014199
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Neurologic
Intervention: Neurologic
Rationale: In Neurodevelopmental disorder with involuntary movements (NEDIM), specific medications (eg, topiramate) have been reported in some individuals as beneficial for treatment of the movement disorder
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GNAO1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_020988.3. 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 | 2 | 119 | 2 | 123 | ||
| missense | 34 | 60 | 142 | 28 | 1 | 265 |
| nonsense | 1 | 1 | 1 | 3 | ||
| start loss | 0 | |||||
| frameshift | 3 | 2 | 1 | 6 | ||
| splice donor/acceptor (+/-2bp) | 3 | 4 | 6 | 13 | ||
| Total | 41 | 67 | 152 | 147 | 3 | 410 |
Highest pathogenic variant AF is 0.000006569094
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_066268.1 | 8 | MANE Select | |
| Ensembl | ENSP00000262493.6 | 8 | MANE Select | |
| RefSeq | NP_620073.2 | 8 | Standard | |
| Ensembl | ENSP00000262494.7 | 8 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Relaxin signaling pathway - Homo sapiens (human)
- Oxytocin signaling pathway - Homo sapiens (human)
- Retrograde endocannabinoid signaling - Homo sapiens (human)
- GABAergic synapse - Homo sapiens (human)
- Serotonergic synapse - Homo sapiens (human)
Biological Process
- protein folding
- muscle contraction
- adenylate cyclase-modulating G protein-coupled receptor signaling pathway
- dopamine receptor signaling pathway
- Wnt signaling pathway, calcium modulating pathway
Molecular Function
- G protein-coupled receptor binding
- GTPase activity
- GTP binding
- G-protein beta/gamma-subunit complex binding
- G protein-coupled serotonin receptor binding
Cellular Component
- heterotrimeric G-protein complex
- plasma membrane
- dendrite
- myelin sheath
- cell body
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000262494
- Coding exons
- 8
- Length
- 166055
- Individuals with no LoFs
- 125744
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 3
- Defined
- 125747
- p
- 0.0000119
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.19 | 93 | 229 | 0.406 | 0.0000142 | 2343 |
| Missense (PolyPhen) | 33 | 95.675 | 0.34492 | 988 | ||
| Synonymous | 0.771 | 86 | 95.6 | 0.900 | 0.00000683 | 648 |
| Loss of Function | 3.73 | 1 | 18.1 | 0.0551 | 9.38e-7 | 209 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000018 | 0.000018 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(o) protein function is not clear. Stimulated by RGS14.;
- Disease
- DISEASE: Epileptic encephalopathy, early infantile, 17 (EIEE17) [MIM:615473]: A severe neurologic disorder characterized by onset of intractable seizures in the first weeks or months of life and usually associated with EEG abnormalities. Affected infants have very poor psychomotor development and may have brain abnormalities, such as cerebral atrophy or thin corpus callosum. Some patients may show involuntary movements. {ECO:0000269|PubMed:23993195, ECO:0000269|PubMed:25966631, ECO:0000269|PubMed:26485252, ECO:0000269|PubMed:27476654, ECO:0000269|PubMed:27864847}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Neurodevelopmental disorder with involuntary movements (NEDIM) [MIM:617493]: A neurodevelopmental disorder manifesting with a wide range of clinical symptoms. Clinical features range from severe motor and cognitive impairment with marked choreoathetosis, self-injurious behavior and epileptic encephalopathy, to a milder phenotype featuring moderate developmental delay associated with complex stereotypies, mainly facial dyskinesia, and mild epilepsy. Hyperkinetic movements are often exacerbated by specific triggers, such as illness, emotion and high ambient temperature. Some patients have brain abnormalities, such as cerebral atrophy or thin corpus callosum. {ECO:0000269|PubMed:25966631, ECO:0000269|PubMed:26060304, ECO:0000269|PubMed:27068059, ECO:0000269|PubMed:27625011, ECO:0000269|PubMed:28357411}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.179
Intolerance Scores
- RVIS EVS
- -0.74
- RVIS percentile EVS
- 13.94
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.848
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |