GeneBe

GABRB3

protein-coding

gamma-aminobutyric acid type A receptor subunit beta3, the group of Gamma-aminobutyric acid type A receptor subunits

Gene summary

This gene encodes a member of the ligand-gated ionic channel family. The encoded protein is one the subunits of a multi-subunit chloride channel that serves as the receptor for gamma-aminobutyric acid, a major inhibitory neurotransmitter of the mammalian nervous system. This gene is located on the long arm of chromosome 15 in a cluster with two other genes encoding related subunits of the family. This gene may be associated with the pathogenesis of several disorders including Angelman syndrome, Prader-Willi syndrome, nonsyndromic orofacial clefts, epilepsy and autism. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2013]

MANE transcript

NM_000814.6

Inheritance

AD

ClinVar variants

P:114U:280B:166

Top phenotype

Epilepsy, childhood absence, susceptibility to, 5; Developmental and epileptic encephalopathy 43

gnomAD constraint

pLI —, LoF o/e 0.13

Max pathogenic AF

—

Genomic locus

chr15:26,543,552-26,939,539

External References & Databases

Ensembl (ENSG00000166206)NCBI Gene (2562)OMIM (137192)HGNC:4083GenCCUniProt (P28472)AlphaFoldClinVar (GABRB3)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~396.0 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

epilepsy, childhood absence, susceptibility to, 5DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012843

Submitter: G2P

epilepsy, childhood absence, susceptibility to, 5LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0012843

Submitter: Labcorp Genetics (formerly Invitae)

developmental and epileptic encephalopathy, 43STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014921

Submitter: Labcorp Genetics (formerly Invitae)

childhood absence epilepsySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0010826

Submitter: Orphanet

developmental and epileptic encephalopathy, 43STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014921

Submitter: PanelApp Australia

developmental and epileptic encephalopathy, 43DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014921

Submitter: Ambry Genetics

Lennox-Gastaut syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016532

Submitter: Orphanet

genetic developmental and epileptic encephalopathyDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100062

Submitter: ClinGen

GABRB3 was first reported in relation to autosomal dominant developmental and epileptic encephalopathy in 2016 (Epi4K Consortium et al., 27476654). Evidence supporting this gene-disease relationship includes case-level and experimental data. Many de novo missense variants have been reported in humans, which reaches the maximum score for genetic evidence (Epi4K Consortium et al. 2016, 27476654; Zhang et al. 2015, 26544041; Le et al. 2017, 28544625; Sterbova et al. 2018, 29444535). This gene-disease association is supported by functional alteration evidence and mouse models (Janve et al. 2016, 26950270; Hernandez et al. 2017, 29162865; Moller et al. 2017, 28053010; DeLorey et al. 2008, 17983671; Ferguson et al. 2007; 17927825). A global knockout and a forebrain selective knockout mouse model were each scored for replicating seizure phenotypes, but were downgraded because the homozygous models do not replicate the heterozygous mechanism observed in humans. Of note, missense variants have been reported to segregate in three families with familial GEFS+. One affected individual of each family is likely a phenocopy, as they do not carry the reported GABRB3 variant (Moller et al. 2017, 28053010). These families were not curated as part of the GABRB3-autosomal dominant developmental epileptic encephalopathy. In summary, GABRB3 is definitively associated with autosomal dominant developmental 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 ClinGen Epilepsy Gene Curation Expert Panel on 2/5/2019.

Clinical Genomic Database (CGD)

Epilepsy, childhood absence, susceptibility to, 5; Developmental and epileptic encephalopathy 43AD

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

Comments: As with other conditions involving seizures, optimal seizure control is beneficial, and awareness of genetic causes may help with medication selection

Refs: 12189488; 11920158; 11810291; 16835263; 17957331; 18514161; 22303015; 23934111; 27476654Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GABRB3 variants in ClinVar

20 Conditions Cataloged
Epilepsy, childhood absence, susceptibility to, 5Total: 532
Epilepsy, childhood absence, susceptibility to, 1Total: 525
not providedTotal: 202
Developmental and epileptic encephalopathy, 43Total: 75
not specifiedTotal: 58
Inborn genetic diseasesTotal: 57
GABRB3-related disorderTotal: 31
Intellectual disabilityTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000814.6. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
134
clinvar
2
clinvar
 137
missense
18
clinvar
71
clinvar
261
clinvar
26
clinvar
4
clinvar
 380
nonsense
8
clinvar
2
clinvar
7
clinvar
 17
start loss
0
frameshift
7
clinvar
8
clinvar
 15
splice donor/acceptor (+/-2bp)
2
clinvar
6
clinvar
3
clinvar
 11
Total35792801606560

Highest pathogenic variant AF is 0.000010559688

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 24 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000814.6RefSeqNP_000805.19MANE Select
ENST00000311550.10EnsemblENSP00000308725.59MANE Select
NM_001191320.2RefSeqNP_001178249.16Standard
NM_001191321.3RefSeqNP_001178250.17Standard

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

  • signal transduction
  • gamma-aminobutyric acid signaling pathway
  • chemical synaptic transmission
  • sensory perception of sound
  • ion transmembrane transport

Molecular Function

  • GABA-A receptor activity
  • extracellular ligand-gated ion channel activity
  • GABA-gated chloride ion channel activity
  • identical protein binding
  • transmitter-gated ion channel activity involved in regulation of postsynaptic membrane potential

Cellular Component

  • plasma membrane
  • integral component of plasma membrane
  • cell junction
  • cytoplasmic vesicle membrane
  • chloride channel complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000311550
Coding exons
9
Length
395994
Individuals with no LoFs
125741
Homozygous LoFs
0
Heterozygous LoFs
5
Defined
125746
p
0.0000199
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense3.391072610.4100.00001493083
Missense (PolyPhen)27134.250.201121590
Synonymous-0.7241131041.090.00000635929
Loss of Function3.83322.70.1320.00000134252

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000290.000029rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish0.0000460.000046rare
European (Non-Finnish)0.0000260.000026rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

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:18281286, ECO:0000269|PubMed:18514161, ECO:0000269|PubMed:22243422, ECO:0000269|PubMed:22303015, ECO:0000269|PubMed:24909990, ECO:0000269|PubMed:26950270}.;
Disease
DISEASE: Epilepsy, childhood absence 5 (ECA5) [MIM:612269]: A subtype of idiopathic generalized epilepsy characterized by an onset at age 6-7 years, frequent absence seizures (several per day) and bilateral, synchronous, symmetric 3-Hz spike waves on EEG. Tonic-clonic seizures often develop in adolescence. Absence seizures may either remit or persist into adulthood. {ECO:0000269|PubMed:18514161, ECO:0000269|PubMed:22303015}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Epileptic encephalopathy, early infantile, 43 (EIEE43) [MIM:617113]: 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. EIEE43 inheritance is autosomal dominant. {ECO:0000269|PubMed:23934111, ECO:0000269|PubMed:25356899, ECO:0000269|PubMed:26950270, ECO:0000269|PubMed:26993267, ECO:0000269|PubMed:27476654, ECO:0000269|PubMed:27864847}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.291

Intolerance Scores

LoFtool
0.124
RVIS EVS
-0.49
RVIS percentile EVS
22.36

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.740

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
Feedback | API | MCP | Annotate VCF | Sitemap | About | Privacy & Terms
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.