Human Gene Module / Chromosome 15 / GABRG3

GABRG3gamma-aminobutyric acid type A receptor gamma3 subunit

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
12 / 13
Rare Variants / Common Variants
8 / 6
Aliases
-
Associated Syndromes
-
Chromosome Band
15q12
Associated Disorders
-
Relevance to Autism

Nominal association between the GABRG3 gene and ASD has been observed in a Caucasian cohort (Menold et al., 2001) and, more recently, a Chinese ASD cohort (Wang et al., 2018); however, other studies have failed to show association between this gene and ASD (McCauley et al., 2004; Ma et al., 2005; Tochigi et al., 2007; Kelemenova et al., 2010; Mahdavi et al., 2018). Yang et al., 2017 found association between the GABRG3 SNP rs208129 and symptom-based phenotypes, as evaluated by CARS and ABC, in a cohort of 99 Chinese Han children and adolescents with ASD. Wang et al., identified a rare missense variant that was predicted to be deleterious (p.Val233Met) that was statistically enriched in Han Chinese ASD cases compared to controls (9/512 ASD cases vs. 2/575 controls; p = 0.020).

Molecular Function

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. The protein encoded by this gene is a gamma subunit, which contains the benzodiazepine binding site.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
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SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to GABRG3 (13 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Association analysis of chromosome 15 gabaa receptor subunit genes in autistic disorder Menold MM , et al. (2002) Yes -
2 Negative Association A linkage disequilibrium map of the 1-Mb 15q12 GABA(A) receptor subunit cluster and association to autism McCauley JL , et al. (2004) Yes -
3 Negative Association Identification of significant association and gene-gene interaction of GABA receptor subunit genes in autism Ma DQ , et al. (2005) Yes -
4 Support An analysis paradigm for investigating multi-locus effects in complex disease: examination of three GABA receptor subunit genes on 15q11-q13 as risk factors for autistic disorder Ashley-Koch AE , et al. (2006) No -
5 Negative Association No evidence for significant association between GABA receptor genes in chromosome 15q11-q13 and autism in a Japanese population Tochigi M , et al. (2007) Yes -
6 Negative Association Polymorphisms of candidate genes in Slovak autistic patients Kelemenova S , et al. (2010) Yes -
7 Positive Association GABA A receptor subunit gene polymorphisms predict symptom-based and developmental deficits in Chinese Han children and adolescents with autistic spectrum disorders Yang S , et al. (2017) Yes -
8 Negative Association Meta-Analysis of the Association between GABA Receptor Polymorphisms and Autism Spectrum Disorder (ASD) Mahdavi M , et al. (2018) Yes -
9 Positive Association Association study and mutation sequencing of genes on chromosome 15q11-q13 identified GABRG3 as a susceptibility gene for autism in Chinese Han population Wang L , et al. (2018) Yes -
10 Positive Association - Ali ZA et al. (2022) Yes -
11 Support - Zhou X et al. (2022) Yes -
12 Positive Association - Adak P et al. (2023) Yes -
13 Support - Sheth F et al. (2023) Yes DD, ID, epilepsy/seizures
Rare Variants   (8)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1036C>A p.Pro346Thr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.697G>A p.Val233Met missense_variant De novo - - 30108208 Wang L , et al. (2018)
c.1093C>T p.Pro365Ser missense_variant De novo - - 30108208 Wang L , et al. (2018)
c.757G>A p.Ala253Thr missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1328C>T p.Ser443Leu missense_variant Unknown - Simplex 37543562 Sheth F et al. (2023)
c.697G>A p.Val233Met missense_variant Familial Maternal - 30108208 Wang L , et al. (2018)
c.697G>A p.Val233Met missense_variant Familial Paternal - 30108208 Wang L , et al. (2018)
c.1093C>T p.Pro365Ser missense_variant Familial Paternal - 30108208 Wang L , et al. (2018)
Common Variants   (6)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.270+95603A>G - intron_variant - - - 36943547 Adak P et al. (2023)
c.271-147049A>T - intron_variant - - - 35403940 Ali ZA et al. (2022)
c.203-18722C>A - intron_variant - - - 30108208 Wang L , et al. (2018)
c.574+81T>C - intron_variant - - - 12092907 Menold MM , et al. (2002)
c.271-147049A>T - intron_variant - - - 28607477 Yang S , et al. (2017)
c.507T>C p.(=) synonymous_variant - - - 12092907 Menold MM , et al. (2002)
SFARI Gene score
2

Strong Candidate

Nominal association between the GABRG3 gene and ASD has been observed in a Caucasian cohort (Menold et al., 2001) and, more recently, a Chinese ASD cohort (Wang et al., 2018); however, other studies have failed to show association between this gene and ASD (McCauley et al., 2004; Ma et al., 2005; Tochigi et al., 2007; Kelemenova et al., 2010; Mahdavi et al., 2018). Yang et al., 2017 found association between the GABRG3 SNP rs208129 and symptom-based phenotypes, as evaluated by CARS and ABC, in a cohort of 99 Chinese Han children and adolescents with ASD. Wang et al., identified a rare missense variant that was predicted to be deleterious (p.Val233Met) that was statistically enriched in Han Chinese ASD cases compared to controls (9/512 ASD cases vs. 2/575 controls; p = 0.020).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

Nominal association between the GABRG3 gene and ASD has been observed in a Caucasian cohort (Menold et al., 2001) and, more recently, a Chinese ASD cohort (Wang et al., 2018); however, other studies have failed to show association between this gene and ASD (McCauley et al., 2004; Ma et al., 2005; Tochigi et al., 2007; Kelemenova et al., 2010; Mahdavi et al., 2018). Yang et al., 2017 found association between the GABRG3 SNP rs208129 and symptom-based phenotypes, as evaluated by CARS and ABC, in a cohort of 99 Chinese Han children and adolescents with ASD. Wang et al., identified a rare missense variant that was predicted to be deleterious (p.Val233Met) that was statistically enriched in Han Chinese ASD cases compared to controls (9/512 ASD cases vs. 2/575 controls; p = 0.020).

Reports Added
[New Scoring Scheme]
7/1/2018
icon
3

Increased from to 3

Description

Nominal association between the GABRG3 gene and ASD has been observed in a Caucasian cohort (Menold et al., 2001) and, more recently, a Chinese ASD cohort (Wang et al., 2018); however, other studies have failed to show association between this gene and ASD (McCauley et al., 2004; Ma et al., 2005; Tochigi et al., 2007; Kelemenova et al., 2010; Mahdavi et al., 2018). Yang et al., 2017 found association between the GABRG3 SNP rs208129 and symptom-based phenotypes, as evaluated by CARS and ABC, in a cohort of 99 Chinese Han children and adolescents with ASD. Wang et al., identified a rare missense variant that was predicted to be deleterious (p.Val233Met) that was statistically enriched in Han Chinese ASD cases compared to controls (9/512 ASD cases vs. 2/575 controls; p = 0.020).

Krishnan Probability Score

Score 0.5699058242114

Ranking 990/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.99367984420864

Ranking 1622/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.94182427251601

Ranking 15076/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.28450435899971

Ranking 2963/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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