• 1
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
GABRA1 (HGNC:4075) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
gamma-aminobutyric acid type A receptor subunit alpha1
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
No previous names found
Alias symbols
EJM5
%HI
9.56(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0.91(Read more about gnomAD pLI score)
LOEUF
0.37(Read more about gnomAD LOEUF score)
Cytoband
5q34
Genomic Coordinates
GRCh37/hg19: chr5:161274197-161326977 NCBI Ensembl UCSC
GRCh38/hg38: chr5:161847191-161899971 NCBI Ensembl UCSC
MANE Select Transcript
NM_001127644.2 ENST00000393943.10 (Read more about MANE Select)
Function
Ligand-gated chloride channel which is a component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the brain (PubMed:23909897, PubMed:25489750, PubMed:29950725). Plays an important role in the formation of functional inhibitory GABAergic synapses in addition to mediating synaptic inhibition as a GABA-gated ion channel (PubMed:23909897, PubMed:25489750). The gamma2 subunit is necessary but not sufficient for a rapid formation of active synaptic contacts and the... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-15500
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Little Evidence for Haploinsufficiency (1)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
11/09/2021

Haploinsufficiency (HI) Score Details

HI Score:
1
HI Evidence Strength:
Little Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
  • Developmental and epileptic encephalopathy Monarch
HI Evidence:
  • PUBMED: 16718694
    Malijevic et al (2006) sequenced GABRA1 in 98 individuals with epilepsy. A frameshift variant (S326fs328X) was detected in one affected individual with childhood absence epilepsy. The variant was not detected in the parents or unaffected brother and was absent from 292 healthy control individuals. Functional studies showed no detectable GABA-evoked currents for the mutant, truncated receptor, which was not integrated into the surface membrane and was degraded. The authors concluded that this de novo mutation caused childhood epilepsy through loss of function and haploinsufficiency of the GABA(A) receptor alpha(1)-subunit.
  • PUBMED: 21714819
    Lanchance-Touchette et al 2011 sequenced GABRA1 and GABRG2 in 95 individuals with epilepsy. One frameshift variant was detected in GABRA1 (p.K353delins18X). The variant was detected in two additional affected family members and one unaffected carrier. Affected individuals in this family exhibited late-onset, afebrile, general tonic-clonic seizures and photosensitivity. Functional studies also found no GABRA1 p.K353delins18X protein associated with the cell membrane and no detectable GABA-evoked currents.
  • PUBMED: 27613244
    Popp et al (2016) reported a boy with Williams syndrome, due to the recurrent 1.5 Mb microdeletion at 7q11.23, and refractory infantile spasms. As seizures are not a typical feature of Williams syndrome, trio-exome sequencing was performed. A de novo frameshift variant (p.Lys401Serfs*25) was detected in GABRA1. The authors suggest the GABRA1 variant may be the cause of the seizures observed in the patient. However, no functional assays were performed. The variant is located in the last exon and is predicted to escape nonsense-mediated mRNA decay. Therefore, the functional consequence of this variant is unclear.
  • PUBMED: 28554332
    Bowling et al (2017) performed exome or genome sequencing in 371 children with intellectual disability and/or developmental delay. They identified one nonsense variant in GABRA1 (p.Q32X) in an individual with intellectual disability and speech delay. The inheritance of the variant was unknown.
  • PUBMED: 29655203
    Lindy et al (2018) evaluated 70 genes using NGS and exon level array in a cohort of 8565 individuals with epilepsy and neurodevelopmental disorders. They detected 14 variants in GABRA1, one of which was a nonsense variant (p.Q32X). A detailed phenotype for this patient and whether parental studies were performed was not reported.
  • PUBMED: 16123039
    Gallagher et al (2005) investigated the functional impact of the missense variant, p.A322D. This variant had been previously reported by Cossette et al (PMID: 11992121) in eight affected members of a large family with autosomal dominant juvenile myoclonic epilepsy. Mutant protein was found to be retained in the endoplasmic reticulum and degraded prior to formation of GABA(A) receptor complexes. In cells expressing both mutant and wildtype protein, total GABA(A) receptor alpha(1)-subunit levels were reduced and only wildtype subunits were associated with the cell membrane. The authors suggest that the reduction in alpha(1) subunit expression is the predominant disease mechanism of the GABRA1 p.A332D variant.
HI Evidence Comments:
Heterozygous GABRA1 missense variants are associated with autosomal dominant developmental and epileptic encephalopathy; this gene-disease relationship has been classified as "Definitive" by the ClinGen Epilepsy GCEP. Some data suggests loss of function may be a disease mechanism. However, due to the lack of published variants that are expected to reduce protein levels, the haploinsufficiency score is currently 1.

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)

Genomic View

Select assembly: (NC_000005.9) (NC_000005.10)