GABRA1

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

Basic information

Region (hg38): 5:161847062-161899981

Links

ENSG00000022355 ∙ NCBI:2554 ∙ OMIM:137160 ∙ HGNC:4075 ∙ Uniprot:P14867 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• epilepsy, idiopathic generalized, susceptibility to, 13 (Strong), mode of inheritance: AD
• developmental and epileptic encephalopathy, 19 (Definitive), mode of inheritance: AD
• juvenile myoclonic epilepsy (Supportive), mode of inheritance: AD
• Dravet syndrome (Supportive), mode of inheritance: AD
• developmental and epileptic encephalopathy, 19 (Strong), mode of inheritance: AD
• developmental and epileptic encephalopathy (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Epilepsy, idiopathic, generalized, susceptibility to, 13; Epilepsy, childhood absence, susceptibility to, 4; Developmental and epileptic encephalopathy 19	AD	General	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	Neurologic	11992121; 16718694; 20551311; 24623842
As with other conditions involving seizures, optimal seizure control is beneficial, and awareness of genetic causes may help with medication selection

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GABRA1 gene.

• not provided (178 variants)
• Epilepsy, idiopathic generalized, susceptibility to, 13 (102 variants)
• Idiopathic generalized epilepsy;Epilepsy, idiopathic generalized, susceptibility to, 13;Epilepsy, childhood absence 4 (97 variants)
• not specified (60 variants)
• Epilepsy, idiopathic generalized, susceptibility to, 13;Epilepsy, childhood absence 4;Idiopathic generalized epilepsy (55 variants)
• Idiopathic generalized epilepsy;Epilepsy, childhood absence 4;Epilepsy, idiopathic generalized, susceptibility to, 13 (46 variants)
• Inborn genetic diseases (46 variants)
• Epilepsy, idiopathic generalized, susceptibility to, 13;Idiopathic generalized epilepsy;Epilepsy, childhood absence 4 (45 variants)
• Epilepsy, childhood absence 4;Idiopathic generalized epilepsy;Epilepsy, idiopathic generalized, susceptibility to, 13 (39 variants)
• Developmental and epileptic encephalopathy, 19 (37 variants)
• Epilepsy, childhood absence 4;Epilepsy, idiopathic generalized, susceptibility to, 13;Idiopathic generalized epilepsy (23 variants)
• Juvenile myoclonic epilepsy (8 variants)
• Epilepsy, idiopathic generalized, susceptibility to, 13;Developmental and epileptic encephalopathy, 19 (4 variants)
• Intellectual disability (2 variants)
• GABRA1-related condition (2 variants)
• Epileptic encephalopathy (1 variants)
• Intractable seizure (1 variants)
• Marfanoid habitus and intellectual disability (1 variants)
• Developmental and epileptic encephalopathy, 19;Epilepsy, idiopathic generalized, susceptibility to, 13 (1 variants)
• Seizure (1 variants)
• Intellectual disability;Sensorineural hearing loss disorder;Seizure (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GABRA1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			4	82	3	89
missense	11	31	142	7	8	199
nonsense		1	6			7
start loss						0
frameshift	4	1	3			8
inframe indel			3			3
splice donor/acceptor (+/-2bp)		3	1			4
splice region			14	15	1	30
non coding			60	61	33	154
Total	15	36	219	150	44

Variants in GABRA1

This is a list of pathogenic ClinVar variants found in the GABRA1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
5-161847204-G-A		Epilepsy, idiopathic generalized, susceptibility to, 13	Uncertain significance (Jan 12, 2018)
5-161847209-A-AG		Juvenile myoclonic epilepsy	Conflicting classifications of pathogenicity (Mar 01, 2023)
5-161847210-G-C		Epilepsy, idiopathic generalized, susceptibility to, 13	Conflicting classifications of pathogenicity (May 01, 2023)
5-161847211-G-A		Epilepsy, idiopathic generalized, susceptibility to, 13	Uncertain significance (Jan 12, 2018)
5-161847211-G-C		Epilepsy, idiopathic generalized, susceptibility to, 13	Uncertain significance (Jan 13, 2018)
5-161847212-G-C		Epilepsy, idiopathic generalized, susceptibility to, 13	Conflicting classifications of pathogenicity (May 01, 2022)
5-161847212-G-T		Epilepsy, idiopathic generalized, susceptibility to, 13	Uncertain significance (Apr 27, 2017)
5-161847213-G-C		Epilepsy, idiopathic generalized, susceptibility to, 13	Likely benign (Jan 12, 2018)
5-161847217-GA-G		Juvenile myoclonic epilepsy	Conflicting classifications of pathogenicity (May 01, 2022)
5-161847218-A-G		Epilepsy, idiopathic generalized, susceptibility to, 13	Benign (Jun 26, 2018)
5-161847220-A-G		Epilepsy, idiopathic generalized, susceptibility to, 13	Uncertain significance (Jan 12, 2018)
5-161847254-T-C		Epilepsy, idiopathic generalized, susceptibility to, 13	Uncertain significance (Jan 13, 2018)
5-161847260-C-T		Epilepsy, idiopathic generalized, susceptibility to, 13	Uncertain significance (Mar 23, 2018)
5-161847416-C-T		Epilepsy, idiopathic generalized, susceptibility to, 13	Uncertain significance (Jan 13, 2018)
5-161847419-C-A		Epilepsy, idiopathic generalized, susceptibility to, 13	Uncertain significance (Jan 12, 2018)
5-161847421-C-T		not specified	Likely benign (Jan 19, 2017)
5-161847787-G-T		Developmental and epileptic encephalopathy, 19	Uncertain significance (Jun 18, 2019)
5-161848172-G-T			Benign (Mar 26, 2015)
5-161848175-A-G		not specified	Likely benign (Nov 07, 2017)
5-161848178-T-C			Uncertain significance (Aug 08, 2019)
5-161848180-T-C		not specified • Developmental and epileptic encephalopathy, 19	Conflicting classifications of pathogenicity (Jan 21, 2021)
5-161848181-T-C		not specified	Benign (Feb 01, 2013)
5-161848186-T-C		Epilepsy, idiopathic generalized, susceptibility to, 13	Conflicting classifications of pathogenicity (Jan 13, 2018)
5-161848191-C-T		not specified	Likely benign (May 23, 2016)
5-161848195-A-G		not specified	Likely benign (Mar 24, 2017)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GABRA1	protein_coding	protein_coding	ENST00000428797	9	52779

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.915	0.0851	125704	0	10	125714	0.0000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.15	105	243	0.432	0.0000129	2963
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000124	0.000123
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000546	0.0000544
Finnish	0.000139	0.000139
European (Non-Finnish)	0.0000353	0.0000352
Middle Eastern	0.0000546	0.0000544
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

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.
• Pathway: 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);Taste transduction - Homo sapiens (human);Morphine addiction - Homo sapiens (human);Serotonin and anxiety;GABA receptor Signaling;Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways;cardiac protection against ros;gamma-aminobutyric acid receptor life cycle pathway;GABA A receptor activation;Neuronal System;GABA receptor activation;Neurotransmitter receptors and postsynaptic signal transmission;Transmission across Chemical Synapses (Consensus)

Recessive Scores

• pRec: 0.268

Intolerance Scores

• loftool: 0.0185
• rvis_EVS: -0.45
• rvis_percentile_EVS: 24

Haploinsufficiency Scores

• pHI: 0.566
• hipred: Y
• hipred_score: 0.800
• ghis: 0.647

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.854

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Gabra1
• Phenotype: nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); normal phenotype; reproductive system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); homeostasis/metabolism phenotype; muscle phenotype; growth/size/body region phenotype

Gene ontology

• Biological process: signal transduction;gamma-aminobutyric acid signaling pathway;chemical synaptic transmission;ion transmembrane transport;regulation of membrane potential;nervous system process;synaptic transmission, GABAergic;regulation of postsynaptic membrane potential;cellular response to histamine;chloride transmembrane transport
• Cellular component: plasma membrane;integral component of plasma membrane;cell junction;cytoplasmic vesicle membrane;dendrite membrane;chloride channel complex;neuron projection;synapse;postsynapse;GABA-ergic synapse;integral component of postsynaptic specialization membrane;GABA receptor complex;GABA-A receptor complex
• Molecular function: GABA-A receptor activity;extracellular ligand-gated ion channel activity;inhibitory extracellular ligand-gated ion channel activity;chloride channel activity;drug binding;benzodiazepine receptor activity;GABA receptor activity;GABA-gated chloride ion channel activity;transmitter-gated ion channel activity involved in regulation of postsynaptic membrane potential