GABRB1
protein-codinggamma-aminobutyric acid type A receptor subunit beta1, the group of Gamma-aminobutyric acid type A receptor subunits
Gene summary
The gamma-aminobutyric acid (GABA) A receptor is a multisubunit chloride channel that mediates the fastest inhibitory synaptic transmission in the central nervous system. This gene encodes GABA A receptor, beta 1 subunit. It is mapped to chromosome 4p12 in a cluster comprised of genes encoding alpha 4, alpha 2 and gamma 1 subunits of the GABA A receptor. Alteration of this gene is implicated in the pathogenetics of schizophrenia. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~432.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0014942
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0014942
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0014942
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0100062
Submitter: ClinGen
Gamma-aminobutyric acid (GABA) receptors are a group of related proteins that function in the GABAergic neurotransmission of the mammalian central nervous system. *GABRB1* is a member of this receptor gene family of ligand-gated ion channels through which GABA, the major inhibitory neurotransmitter in the brain acts. General forms of GABA receptors include two essential α subunits (α1-6), two essential β subunits (β1-3) with one ϒ subunit (ϒ1-3) or one δ subunit. A functional receptor is constituted of an obligatory heterodimer of GABRB1 (β1 subunit) and GABRB2 subunits in which GABRB1 is required for ligand binding and GABRB2 is necessary for interactions with G proteins and increasing the affinity of GABRB1 to GABA [Kaupmann 1998, PMID: 9872317]. ---------- *GABRB1* was first reported in relation to autosomal dominant developmental and epileptic encephalopathy in 2013 (Epi4K 2013, PMID: 23934111). A single inframe insertion/deletion and 7 missense variants reported in 10 probands across 8 publications are included in this curation (PMIDs: 23934111, 27273810, 31618474, 33994118, 36553572, 37518907, 38024579 and 38633326). Reported features include developmental delay, seizures, hypsarrhythmia, and hypotonia. Even though multiple individuals have been reported, most of these individuals have missense variants without supportive functional evidence; because of this, there is limited evidence to support the relationship between *GABRB1* and autosomal dominant developmental and epileptic encephalopathy. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. ---------- This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on August 6, 2024 (SOP version 11).
Clinical Genomic Database (CGD)
Manifestation: Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GABRB1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000812.4. 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 | 114 | 4 | 119 | ||
| missense | 1 | 6 | 198 | 4 | 1 | 210 |
| nonsense | 8 | 8 | ||||
| start loss | 0 | |||||
| frameshift | 4 | 4 | ||||
| splice donor/acceptor (+/-2bp) | 3 | 3 | ||||
| Total | 1 | 6 | 214 | 118 | 5 | 344 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000803.2 | 9 | MANE Select | |
| Ensembl | ENSP00000295454.3 | 9 | MANE Select | |
| Ensembl | ENSP00000426766.1 | 3 | Standard | |
| Ensembl | ENSP00000426753.1 | 3 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Retrograde endocannabinoid signaling - Homo sapiens (human)
- GABAergic synapse - Homo sapiens (human)
- Serotonergic synapse - Homo sapiens (human)
- Nicotine addiction - Homo sapiens (human)
- Neuroactive ligand-receptor interaction - Homo sapiens (human)
Biological Process
- ion transport
- signal transduction
- gamma-aminobutyric acid signaling pathway
- chemical synaptic transmission
- response to toxic substance
Molecular Function
- GABA-A receptor activity
- extracellular ligand-gated ion channel activity
- ligand-gated ion channel activity
- GABA-gated chloride ion channel activity
- GABA receptor binding
Cellular Component
- nuclear envelope
- cytoplasm
- plasma membrane
- integral component of plasma membrane
- cell junction
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000295454
- Coding exons
- 9
- Length
- 432722
- Individuals with no LoFs
- 125741
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 6
- Defined
- 125747
- p
- 0.0000239
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.65 | 156 | 281 | 0.555 | 0.0000156 | 3108 |
| Missense (PolyPhen) | 36 | 118.1 | 0.30482 | 1397 | ||
| Synonymous | -0.998 | 121 | 108 | 1.12 | 0.00000636 | 918 |
| Loss of Function | 4.11 | 3 | 25.3 | 0.118 | 0.00000155 | 257 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000087 | 0.000087 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000055 | 0.000054 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine. Functions as receptor for diazepines and various anesthetics, such as pentobarbital; these are bound at a separate allosteric effector binding site. Functions as ligand- gated chloride channel. {ECO:0000269|PubMed:26950270}.;
- Disease
- DISEASE: Epileptic encephalopathy, early infantile, 45 (EIEE45) [MIM:617153]: A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. {ECO:0000269|PubMed:23934111, ECO:0000269|PubMed:26950270, ECO:0000269|PubMed:27273810}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.112
Intolerance Scores
- LoFtool
- 0.0690
- RVIS EVS
- -0.36
- RVIS percentile EVS
- 28.93
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.302
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |