GABRD
protein-codinggamma-aminobutyric acid type A receptor subunit delta, the group of Gamma-aminobutyric acid type A receptor subunits
Gene summary
Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA-A receptors, which are ligand-gated chloride channels. Chloride conductance of these channels can be modulated by agents such as benzodiazepines that bind to the GABA-A receptor. The GABA-A receptor is generally pentameric and there are five types of subunits: alpha, beta, gamma, delta, and rho. This gene encodes the delta subunit. Mutations in this gene have been associated with susceptibility to generalized epilepsy with febrile seizures, type 5. Alternatively spliced transcript variants have been described for this gene, but their biological validity has not been determined. [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 ~11.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0100038
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0100038
Submitter: ClinGen
Variants in *GABRD* were first reported in individuals with seizures in 2004 (PMID: 15115768). In 2022, variants in *GABRD* were also reported in individuals with phenotypes other than seizures, including developmental delays, autism spectrum disorder, and intellectual disability (PMID:34633442). Of note, some of these individuals had seizures, while others did not. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a difference in phenotypic variability between these cases and therefore have chosen to split this evidence into multiple disease entities: epilepsy (MONDO:0005027) (for those individuals presenting solely with seizures) and complex neurodevelopmental disorder (MONDO:0100038) (for those individuals with neurodevelopmental phenotypes alone, or with neurodevelopmental disorders in addition to epilepsy). The split curation for epilepsy has been evaluated separately. Eight variants (missense, in-frame indel) reported in eight probands in two publications are included in this curation (PMIDs: 34633442, 25156961). Of note, each of these variants is de novo. There are other individuals published in the literature with variants in this gene, but with phenotypes that are either not at the individual level or not specific/detailed enough to determine whether they should be included in this curation or in the separate epilepsy curation (PMIDs: 28600779, 31785789). This gene-disease relationship is also supported by case-level functional evidence from electrophysiological studies in *Xenopus laevis* oocytes (PMIDs: 25156961, 34633442). In summary, there is moderate evidence to support the gene-disease relationship between *GABRD* and complex neurodevelopmental disorder (MONDO:0100038). While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Epilepsy GCEP on the meeting date July 18, 2023 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0005027
Submitter: ClinGen
Variants in *GABRD* were first reported in individuals with seizures in 2004 (PMID: 15115768). In 2022, variants in *GABRD* were also reported in individuals with phenotypes other than seizures, including developmental delays, autism spectrum disorder, and intellectual disability (PMID:34633442). Of note, some of these individuals had seizures, while others did not. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a difference in phenotypic variability between these cases and therefore have chosen to split this evidence into multiple disease entities: epilepsy (MONDO:0005027) (for those individuals presenting solely with seizures) and complex neurodevelopmental disorder (MONDO:0100038) (for those individuals with neurodevelopmental phenotypes alone, or with neurodevelopmental disorders in addition to epilepsy). The split curation for complex neurodevelopmental disorder has been evaluated separately. Three missense variants reported in three probands in three publications are included in this curation (PMIDs: 29924869, 33391346, 15115768). To date, many individuals with epilepsy have been reported with the p.Arg220His variant: at least 16 in case-control studies (PMIDs: 29785705, 16023832) and at least two case reports (PMIDs: 16023832, 29785705). Individuals with the p.Arg220His variant were not awarded points as a part of this curation, as there is currently conflicting evidence of pathogenicity according in small case-control studies (PMIDs: 29785705, 16023832), and there is a high allele frequency of 1.74x10-2 in gnomAD v2.1.1 with 55 homozygotes. It is possible that this variant is a risk allele and therefore does not support a relationship with Mendelian disease. Additionally, the p.Thr401Met variant reported in Lee et al. (2018, PMID:29924869) was not scored due to high allele frequency in gnomAD v.2.1.1, with 554 homozygotes. In summary, there is limited evidence to support the gene-disease relationship between *GABRD* and epilepsy (MONDO:0005027). Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Epilepsy GCEP on the meeting date July 18, 2023 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0100038
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0013103
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0013103
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0013103
Submitter: Ambry Genetics
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GABRD variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000815.5. 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 | 6 | 127 | 7 | 140 | ||
| missense | 1 | 3 | 200 | 16 | 220 | |
| nonsense | 2 | 2 | ||||
| start loss | 0 | |||||
| frameshift | 10 | 10 | ||||
| splice donor/acceptor (+/-2bp) | 2 | 2 | ||||
| Total | 1 | 3 | 220 | 143 | 7 | 374 |
Highest pathogenic variant AF is 0.0000014170187
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000806.2 | 9 | MANE Select | |
| Ensembl | ENSP00000367848.4 | 9 | MANE Select | |
| Ensembl | ENSP00000491632.1 | 9 | Standard | |
| Ensembl | ENSP00000492352.1 | 4 | 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)
- Nicotine addiction - Homo sapiens (human)
- Neuroactive ligand-receptor interaction - Homo sapiens (human)
- Morphine addiction - Homo sapiens (human)
Biological Process
- signal transduction
- chemical synaptic transmission
- ion transmembrane transport
- regulation of membrane potential
- nervous system process
Molecular Function
- GABA-A receptor activity
- extracellular ligand-gated ion channel activity
- chloride channel activity
- protein binding
- transmitter-gated ion channel activity involved in regulation of postsynaptic membrane potential
Cellular Component
- integral component of plasma membrane
- cell junction
- chloride channel complex
- neuron projection
- synapse
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000378585
- Coding exons
- 9
- Length
- 11413
- Individuals with no LoFs
- 125155
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 6
- Defined
- 125161
- p
- 0.0000240
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.17 | 189 | 293 | 0.644 | 0.0000208 | 2901 |
| Missense (PolyPhen) | 94 | 163.27 | 0.57573 | 1613 | ||
| Synonymous | -2.23 | 172 | 139 | 1.24 | 0.0000115 | 928 |
| Loss of Function | 3.87 | 1 | 19.4 | 0.0516 | 9.16e-7 | 215 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000063 | 0.000062 | rare |
| 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) | 0.000028 | 0.000027 | rare |
| South Asian | 0.000038 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel.;
- Disease
- DISEASE: Generalized epilepsy with febrile seizures plus 5 (GEFS+5) [MIM:613060]: A rare autosomal dominant, familial condition with incomplete penetrance and large intrafamilial variability. Patients display febrile seizures persisting sometimes beyond the age of 6 years and/or a variety of afebrile seizure types. This disease combines febrile seizures, generalized seizures often precipitated by fever at age 6 years or more, and partial seizures, with a variable degree of severity. {ECO:0000269|PubMed:15115768}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Epilepsy, idiopathic generalized 10 (EIG10) [MIM:613060]: A disorder characterized by recurring generalized seizures in the absence of detectable brain lesions and/or metabolic abnormalities. Generalized seizures arise diffusely and simultaneously from both hemispheres of the brain. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Juvenile myoclonic epilepsy 7 (EJM7) [MIM:613060]: A subtype of idiopathic generalized epilepsy. Patients have afebrile seizures only, with onset in adolescence (rather than in childhood) and myoclonic jerks which usually occur after awakening and are triggered by sleep deprivation and fatigue. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.170
Intolerance Scores
- LoFtool
- 0.0118
- RVIS EVS
- -0.51
- RVIS percentile EVS
- 21.65
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.896
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |