Human Gene Module / Chromosome 3 / SLC6A1

SLC6A1Solute carrier family 6 (neurotransmitter transporter), member 1

Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
11 / 18
Rare Variants / Common Variants
48 / 3
Aliases
SLC6A1, GABATHG,  GABATR,  GAT1
Associated Syndromes
Tourette syndrome
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association
Chromosome Band
3p25.3
Associated Disorders
ID, ASD
Relevance to Autism

A de novo missense variant in the SLC6A1 gene was identified in an ASD proband from the Simons Simplex Collection (Sanders et al., 2012). This same variant was recently found in two patients (a mother and her female offspring) presenting with myoclonic atonic epilepsy (Carvill et al., 2015). Additional de novo variants in SLC6A1 were identified in patients with myoclonic atonic epilepsy in this report, many of whom also presented with autistic features. This gene was identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (Sanders et al., 2015).

Molecular Function

The SLC6A1 gene encodes a gamma-aminobutyric acid (GABA) transporter, which removes GABA from the synaptic cleft.

Reports related to SLC6A1 (18 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Sanders SJ , et al. (2012) Yes -
2 Support Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
3 Support The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
4 Recent Recommendation Mutations in the GABA Transporter SLC6A1 Cause Epilepsy with Myoclonic-Atonic Seizures. Carvill GL , et al. (2015) No ID, autistic features
5 Support Excess of rare, inherited truncating mutations in autism. Krumm N , et al. (2015) Yes -
6 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
7 Recent Recommendation Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci. Sanders SJ , et al. (2015) Yes -
8 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Lelieveld SH , et al. (2016) No -
9 Support Genome-wide characteristics of de novo mutations in autism. Yuen RK , et al. (2016) Yes -
10 Support Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Stessman HA , et al. (2017) Yes -
11 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. C Yuen RK , et al. (2017) Yes -
12 Positive Association SLC6A1 gene involvement in susceptibility to attention-deficit/hyperactivity disorder: A case-control study and gene-environment interaction. Yuan FF , et al. (2017) No -
13 Positive Association De Novo Coding Variants Are Strongly Associated with Tourette Disorder. Willsey AJ , et al. (2017) No -
14 Support Genomic diagnosis for children with intellectual disability and/or developmental delay. Bowling KM , et al. (2017) Yes -
15 Support Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients. Chrot E , et al. (2017) No -
16 Recent Recommendation Defining the phenotypic spectrum of SLC6A1 mutations. Johannesen KM , et al. (2018) No ASD or autistic features
17 Support Phenotypic consequences of gene disruption by a balanced de novo translocation involving SLC6A1 and NAA15. Pesz K , et al. (2018) No -
18 Support Language Regression in an Atypical SLC6A1 Mutation. Islam MP , et al. (2018) Yes Language delay, regression
Rare Variants   (48)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.863C>T p.Ala288Val missense_variant De novo - Simplex 22495306 Sanders SJ , et al. (2012)
c.1078G>A p.Gly360Ser missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
A>G p.Tyr420Cys missense_variant Familial Paternal - 25363760 De Rubeis S , et al. (2014)
c.723C>A p.Tyr241Ter stop_gained Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
G>T p.Asp165Tyr missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
C>T p.Arg172Cys missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.896G>T p.Gly299Val missense_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.131G>A p.Arg44Gln missense_variant De novo - Simplex 25865495 Carvill GL , et al. (2015)
c.889G>A p.Gly297Arg missense_variant De novo - - 25865495 Carvill GL , et al. (2015)
c.1000G>C p.Ala334Pro missense_variant Familial Maternal - 25865495 Carvill GL , et al. (2015)
c.1369_1370delGG p.Gly457HisfsTer10 frameshift_variant De novo - Simplex 25865495 Carvill GL , et al. (2015)
c.578G>A p.Trp193Ter stop_gained De novo - Simplex 25865495 Carvill GL , et al. (2015)
c.863C>T p.Ala288Val missense_variant Familial Maternal Multi-generational 25865495 Carvill GL , et al. (2015)
- - copy_number_loss De novo - Simplex 25865495 Carvill GL , et al. (2015)
c.1648G>A p.Gly550Arg missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.1024G>A p.Val342Met missense_variant De novo - - 27479843 Lelieveld SH , et al. (2016)
c.1015T>C p.Phe339Leu missense_variant De novo - Simplex 27525107 Yuen RK , et al. (2016)
c.723C>A p.Tyr241Ter stop_gained De novo - Multiplex (suspected twins) 28191889 Stessman HA , et al. (2017)
c.137C>T p.Thr46Met missense_variant De novo - Simplex 28472652 Willsey AJ , et al. (2017)
c.1352A>G p.Asp451Gly missense_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.223G>A p.Gly75Arg missense_variant De novo - - 28708303 Chrot E , et al. (2017)
c.104dupA p.Lys36GlufsTer171 frameshift_variant De novo - Simplex 29315614 Johannesen KM , et al. (2018)
c.223G>A p.Gly75Arg missense_variant De novo - - 29315614 Johannesen KM , et al. (2018)
c.419A>G p.Tyr140Cys missense_variant De novo - Simplex 29315614 Johannesen KM , et al. (2018)
c.434C>T p.Ser145Phe missense_variant De novo - Simplex 29315614 Johannesen KM , et al. (2018)
c.695G>T p.Gly232Val missense_variant De novo - Simplex 29315614 Johannesen KM , et al. (2018)
c.695G>T p.Gly232Val missense_variant Familial Maternal Multi-generational 29315614 Johannesen KM , et al. (2018)
c.809T>C p.Phe270Ser missense_variant De novo - Simplex 29315614 Johannesen KM , et al. (2018)
c.863C>T p.Ala288Val missense_variant De novo - Simplex 29315614 Johannesen KM , et al. (2018)
c.863C>T p.Ala288Val missense_variant Unknown - Not simplex 29315614 Johannesen KM , et al. (2018)
c.881_883del p.Phe294del inframe_deletion De novo - Simplex 29315614 Johannesen KM , et al. (2018)
c.987C>A p.Cys329Ter stop_gained De novo - Simplex 29315614 Johannesen KM , et al. (2018)
c.1024G>A p.Val342Met missense_variant Familial Paternal Multi-generational 29315614 Johannesen KM , et al. (2018)
c.1024G>A p.Val342Met missense_variant De novo - Simplex 29315614 Johannesen KM , et al. (2018)
c.1024G>A p.Val342Met missense_variant De novo - Simplex 29315614 Johannesen KM , et al. (2018)
c.1024G>A p.Val342Met missense_variant De novo - Not simplex 29315614 Johannesen KM , et al. (2018)
c.1070C>T p.Ala357Val missense_variant De novo - Simplex 29315614 Johannesen KM , et al. (2018)
c.1084G>A p.Gly362Arg missense_variant Unknown - Unknown 29315614 Johannesen KM , et al. (2018)
c.1084G>A p.Gly362Arg missense_variant Familial Maternal Simplex 29315614 Johannesen KM , et al. (2018)
c.1155C>G p.Phe385Leu missense_variant De novo - Simplex 29315614 Johannesen KM , et al. (2018)
c.1342A>T p.Lys448Ter stop_gained De novo - Simplex 29315614 Johannesen KM , et al. (2018)
c.1377C>G p.Ser459Arg missense_variant De novo - Simplex 29315614 Johannesen KM , et al. (2018)
c.1531G>A p.Val511Met missense_variant De novo - Simplex 29315614 Johannesen KM , et al. (2018)
c.1600C>T p.Gln534Ter stop_gained De novo - Simplex 29315614 Johannesen KM , et al. (2018)
c.850-2A>G p.? splice_site_variant De novo - Unknown 29315614 Johannesen KM , et al. (2018)
c.1528-1G>C p.? splice_site_variant De novo - - 29315614 Johannesen KM , et al. (2018)
- - translocation De novo - - 29621621 Pesz K , et al. (2018)
c.302A>G p.Glu101Gly missense_variant De novo - - 29961511 Islam MP , et al. (2018)
Common Variants   (3)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.-215-4116T>C;c.-154-4116T>C - 2_KB_upstream_variant - - - 28442423 Yuan FF , et al. (2017)
c.-215-2020A>G;c.-154-2020A>G - 5_prime_UTR_variant - - - 28442423 Yuan FF , et al. (2017)
c.-216+5824G>T;c.-155+5824G>T - intron_variant - - - 28442423 Yuan FF , et al. (2017)
SFARI Gene score
2S

Strong Candidate, Syndromic

2S

Score Delta: Score remained at 2.1 + S

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.

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

7/1/2017
2
icon
2

Score remained at 2

Description

A de novo missense variant in the SLC6A1 gene was identified in an ASD proband from the Simons Simplex Collection (Sanders et al., 2012). This same variant was recently found in two patients (a mother and her female offspring) presenting with myoclonic atonic epilepsy (Carvill et al., 2015). Additional de novo variants in SLC6A1 were identified in patients with myoclonic atonic epilepsy in this report, many of whom also presented with autistic features. Two additional de novo missense variants in SLC6A1 that were predicted to be damaging were observed in ASD probands in De Rubeis 2014 and Iossifov 2014. This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). This gene was subsequently identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of < 0.1 (Sanders et al., 2015). A de novo nonsense variant in the SLC6A1 gene was identified in a pair of suspected twins from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017.

4/1/2017
2
icon
2

Score remained at 2

Description

A de novo missense variant in the SLC6A1 gene was identified in an ASD proband from the Simons Simplex Collection (Sanders et al., 2012). This same variant was recently found in two patients (a mother and her female offspring) presenting with myoclonic atonic epilepsy (Carvill et al., 2015). Additional de novo variants in SLC6A1 were identified in patients with myoclonic atonic epilepsy in this report, many of whom also presented with autistic features. Two additional de novo missense variants in SLC6A1 that were predicted to be damaging were observed in ASD probands in De Rubeis 2014 and Iossifov 2014. This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). This gene was subsequently identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (Sanders et al., 2015). A de novo nonsense variant in the SLC6A1 gene was identified in a pair of suspected twins from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017.

1/1/2017
2
icon
2

Score remained at 2

Description

A de novo missense variant in the SLC6A1 gene was identified in an ASD proband from the Simons Simplex Collection (Sanders et al., 2012). This same variant was recently found in two patients (a mother and her female offspring) presenting with myoclonic atonic epilepsy (Carvill et al., 2015). Additional de novo variants in SLC6A1 were identified in patients with myoclonic atonic epilepsy in this report, many of whom also presented with autistic features. Two additional de novo missense variants in SLC6A1 that were predicted to be damaging were observed in ASD probands in De Rubeis 2014 and Iossifov 2014. This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). This gene was subsequently identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (Sanders et al., 2015). A de novo nonsense variant in the SLC6A1 gene was identified in a pair of suspected twins from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017.

7/1/2016
2
icon
2

Score remained at 2

Description

A de novo missense variant in the SLC6A1 gene was identified in an ASD proband from the Simons Simplex Collection (Sanders et al., 2012). This same variant was recently found in two patients (a mother and her female offspring) presenting with myoclonic atonic epilepsy (Carvill et al., 2015). Additional de novo variants in SLC6A1 were identified in patients with myoclonic atonic epilepsy in this report, many of whom also presented with autistic features. Two additional de novo missense variants in SLC6A1 that were predicted to be damaging were observed in ASD probands in De Rubeis 2014 and Iossifov 2014. This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). This gene was subsequently identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (Sanders et al., 2015).

1/1/2016
2
icon
2

Score remained at 2

Description

A de novo missense variant in the SLC6A1 gene was identified in an ASD proband from the Simons Simplex Collection (Sanders et al., 2012). This same variant was recently found in two patients (a mother and her female offspring) presenting with myoclonic atonic epilepsy (Carvill et al., 2015). Additional de novo variants in SLC6A1 were identified in patients with myoclonic atonic epilepsy in this report, many of whom also presented with autistic features. Two additional de novo missense variants in SLC6A1 that were predicted to be damaging were observed in ASD probands in De Rubeis 2014 and Iossifov 2014. This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). This gene was subsequently identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (Sanders et al., 2015).

10/1/2015
icon
2

Increased from to 2

Description

A de novo missense variant in the SLC6A1 gene was identified in an ASD proband from the Simons Simplex Collection (Sanders et al., 2012). This same variant was recently found in two patients (a mother and her female offspring) presenting with myoclonic atonic epilepsy (Carvill et al., 2015). Additional de novo variants in SLC6A1 were identified in patients with myoclonic atonic epilepsy in this report, many of whom also presented with autistic features. Two additional de novo missense variants in SLC6A1 that were predicted to be damaging were observed in ASD probands in De Rubeis 2014 and Iossifov 2014. This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). This gene was subsequently identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (Sanders et al., 2015).

Krishnan Probability Score

Score 0.6100404632439

Ranking 238/25841 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.
ExAC Score

Score 0.99930187916582

Ranking 1000/18225 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
Iossifov Probability Score

Score 0.843

Ranking 201/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Sanders TADA Score

Score 0.029094456788286

Ranking 38/18665 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).
Zhang D Score

Score 0.034682481977119

Ranking 7636/20870 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.
CNVs associated with SLC6A1(1 CNVs)
3p25.3 19 Deletion-Duplication 31  /  89
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