GABRA1

protein-coding

gamma-aminobutyric acid type A receptor subunit alpha1, the group of Gamma-aminobutyric acid type A receptor subunits

Gene summary

This gene encodes a gamma-aminobutyric acid (GABA) receptor. 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. GABA-A receptors are pentameric, consisting of proteins from several subunit classes: alpha, beta, gamma, delta and rho. Mutations in this gene cause juvenile myoclonic epilepsy and childhood absence epilepsy type 4. Multiple transcript variants encoding the same protein have been identified for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001127644.2

Inheritance

ClinVar variants

P:114U:280B:171

Top phenotype

Epilepsy, idiopathic, generalized, susceptibility to, 13; Epilepsy, childhood absence, susceptibility to, 4; Developmental and epileptic encephalopathy 19

gnomAD constraint

pLI —, LoF o/e 0.14

Max pathogenic AF

—

Genomic locus

chr5:161,847,063-161,899,981

External References & Databases

Ensembl (ENSG00000022355)

Transcript & Mutation Effects

hg38 • Region Span ~52.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

developmental and epileptic encephalopathy, 19DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014328

Submitter: Ambry Genetics

developmental and epileptic encephalopathy, 19STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014328

Submitter: G2P

epilepsy, idiopathic generalized, susceptibility to, 13STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012627

Submitter: G2P

developmental and epileptic encephalopathy, 19STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014328

Submitter: PanelApp Australia

epilepsyDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0005027

Submitter: ClinGen

*GABRA1* was first reported in relation to autosomal dominant (AD) epilepsy in 2014 (Epi4K Consortium et al. PMID: 23934111). *GABRA1*-related epilepsy is characterized by seizures and highly variable degrees of intellectual disability and movement disorders such as dystonia. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found evidence for two different molecular mechanisms for heterozygous variants: loss of function and gain of function as measured by GABA-evoked current amplitudes. While all individuals present with epilepsy, individuals with gain of function variants have been associated with more severe clinical outcomes, while individuals with loss of function variants are associated with a broader spectrum of clinical outcomes (PMID: 37606373). Due to the considerable overlap in phenotypes, the following disease entities have been lumped into the disease term “epilepsy” (http://purl.obolibrary.org/obo/MONDO_0005027): developmental and epileptic encephalopathy (OMIM:615744) and epilepsy, juvenile myoclonic or absence (OMIM:611136). As with most splitting or lumping determinations, this may change over time as more variants are characterized mechanistically and phenotypically. Thirty-two missense variants that have been reported in 32 probands in 10 publications (PMIDs: 23934111, 24623842, 26918889, 27521439, 28864462, 31618474, 32047208, 34399161, 34673242, 37606373) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is also supported by animal models, expression studies, and in-vitro functional assays (PMIDs: 25954001, 27521439, 37606373). In summary, there is definitive evidence supporting the relationship between *GABRA1* and autosomal dominant (AD) epilepsy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This gene-disease pair was originally evaluated by the Epilepsy GCEP on 05/21/2019 using the disease term developmental and epileptic encephalopathy (DEE). It was reevaluated on 9/3/2024 to reassess the disease term (SOP Version 10). As a result of this reevaluation, the disease term was changed in order to reflect the spectrum of phenotypes observed with heterozygous variants in *GABRA1*, but the classification did not change.

Dravet syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011794

Submitter: Orphanet

juvenile myoclonic epilepsySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009696

Submitter: Orphanet

developmental and epileptic encephalopathy, 19STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014328

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Epilepsy, idiopathic, generalized, susceptibility to, 13; Epilepsy, childhood absence, susceptibility to, 4; Developmental and epileptic encephalopathy 19AD

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: 11992121; 16718694; 20551311; 24623842

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GABRA1 variants in ClinVar

18 Conditions Cataloged

Epilepsy, idiopathic generalized, susceptibility to, 13Total: 479

Epilepsy, childhood absence 4Total: 465

Idiopathic generalized epilepsyTotal: 464

not providedTotal: 218

not specifiedTotal: 72

Inborn genetic diseasesTotal: 64

Developmental and epileptic encephalopathy, 19Total: 63

GABRA1-related disorderTotal: 19

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001127644.2. 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			4 clinvar	137 clinvar	3 clinvar	144
missense	29 clinvar	65 clinvar	260 clinvar	22 clinvar	9 clinvar	385
nonsense	4 clinvar	1 clinvar	7 clinvar			12
start loss						0
frameshift	5 clinvar	2 clinvar	8 clinvar			15
splice donor/acceptor (+/-2bp)	3 clinvar	5 clinvar	1 clinvar			9
Total	41	73	280	159	12	565

Highest pathogenic variant AF is 0.0000065722024

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 34 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001127644.2	RefSeq	NP_001121116.1	9	MANE Select
ENST00000393943.10	Ensembl	ENSP00000377517.4	9	MANE Select
NM_000806.5	RefSeq	NP_000797.2	9	Standard
NM_001127643.2	RefSeq	NP_001121115.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Benzodiazepine Pathway, Pharmacodynamics
Retrograde endocannabinoid signaling - Homo sapiens (human)
GABAergic 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
ion transmembrane transport
regulation of membrane potential

Molecular Function

GABA-A receptor activity
extracellular ligand-gated ion channel activity
inhibitory extracellular ligand-gated ion channel activity
chloride channel activity
drug binding

Cellular Component

plasma membrane
integral component of plasma membrane
cell junction
cytoplasmic vesicle membrane
dendrite membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000428797
Coding exons: 9
Length: 52779
Individuals with no LoFs: 125704
Homozygous LoFs: 0
Heterozygous LoFs: 10
Defined: 125714
p: 0.0000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.15	105	243	0.432	0.0000129	2963
Missense (PolyPhen)		26	104.33	0.24921		1302
Synonymous	-1.91	116	92.6	1.25	0.00000530	901
Loss of Function	3.65	3	21.1	0.142	9.85e-7	271

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000055	0.000054	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.000035	0.000035	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

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 (By similarity). {ECO:0000250}.;
Disease: DISEASE: Epilepsy, childhood absence 4 (ECA4) [MIM:611136]: 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:16718694}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Epilepsy, idiopathic generalized 13 (EIG13) [MIM:611136]: 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. Seizure types include juvenile myoclonic seizures, absence seizures, and generalized tonic-clonic seizures. {ECO:0000269|PubMed:21714819}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Juvenile myoclonic epilepsy 5 (EJM5) [MIM:611136]: 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. {ECO:0000269|PubMed:11992121}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Epileptic encephalopathy, early infantile, 19 (EIEE19) [MIM:615744]: A severe neurologic disorder characterized by onset of seizures in the first months of life and usually associated with EEG abnormalities. Affected infants have convulsive seizures (hemiclonic or generalized) that are often prolonged and triggered by fever. Other seizure types include focal, myoclonic, absence seizures, and drop attacks. Development is normal in the first year of life with later slowing and intellectual disability. {ECO:0000269|PubMed:24623842, ECO:0000269|PubMed:27864847}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.268

Intolerance Scores

LoFtool: 0.0185
RVIS EVS: -0.45
RVIS percentile EVS: 24

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.854

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium