Human Gene Module / Chromosome 9 / SLC1A1

SLC1A1solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, system Xag), member 1

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
5 / 12
Rare Variants / Common Variants
5 / 8
Aliases
SLC1A1, EAAC1,  EAAT3
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Genetic Association
Chromosome Band
9p24.2
Associated Disorders
BPD
Relevance to Autism

Studies have found genetic association between polymorphisms of the SLC1A1 gene and autism.

Molecular Function

This gene encodes a member of the high-affinity glutamate transporters that play an essential role in transporting glutamate across plasma membranes. This transporter also transports aspartate.

Reports related to SLC1A1 (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Modulation of the neuronal glutamate transporter EAAC1 by the interacting protein GTRAP3-18. Lin CI , et al. (2001) No -
2 Highly Cited Primary structure and functional characterization of a high-affinity glutamate transporter. Kanai Y and Hediger MA (1992) No -
3 Highly Cited Glutamate transporter gene SLC1A1 associated with obsessive-compulsive disorder. Arnold PD , et al. (2006) No -
4 Primary Family-Based Association Testing of OCD-associated SNPs of SLC1A1 in an autism sample. Brune CW , et al. (2009) Yes -
5 Positive Association Glutamate transporter gene (SLC1A1) single nucleotide polymorphism (rs301430) and repetitive behaviors and anxiety in children with autism spectrum... Gadow KD , et al. (2010) Yes -
6 Positive Association Association of SNPs linked to increased expression of SLC1A1 with schizophrenia. Horiuchi Y , et al. (2011) No -
7 Support A discovery resource of rare copy number variations in individuals with autism spectrum disorder. Prasad A , et al. (2013) Yes -
8 Support Deletion at the SLC1A1 glutamate transporter gene co-segregates with schizophrenia and bipolar schizoaffective disorder in a 5-generation family. Myles-Worsley M , et al. (2013) No BPD
9 Support Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder. Girirajan S , et al. (2013) Yes -
10 Support Recessive gene disruptions in autism spectrum disorder. Doan RN , et al. (2019) Yes -
11 Highly Cited Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Rothstein JD , et al. (1996) No -
12 Highly Cited EAAC1, a high-affinity glutamate tranporter, is localized to astrocytes and gabaergic neurons besides pyramidal cells in the rat cerebral cortex. Conti F , et al. (1998) No -
Rare Variants   (5)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss Unknown - Unknown 23275889 Prasad A , et al. (2013)
- - copy_number_gain Familial Maternal Simplex 23375656 Girirajan S , et al. (2013)
- - copy_number_gain Familial Paternal Simplex 23375656 Girirajan S , et al. (2013)
c.142G>T p.Glu48Ter stop_gained Familial Both parents Simplex 31209396 Doan RN , et al. (2019)
- - copy_number_loss Familial Maternal & Paternal Multi-generational 23341099 Myles-Worsley M , et al. (2013)
Common Variants   (8)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.91+14774A>C - intron_variant - - - 22095641 Horiuchi Y , et al. (2011)
c.91+23476A>G - intron_variant - - - 22095641 Horiuchi Y , et al. (2011)
c.1194-195T>C T/C intron_variant - - - 16818866 Arnold PD , et al. (2006)
c.1194-956C>T T/C intron_variant - - - 16818866 Arnold PD , et al. (2006)
c.232+200A>C A/C intron_variant - - - 22095641 Horiuchi Y , et al. (2011)
c.1193+88G>C C to G intron_variant - - - 19360657 Brune CW , et al. (2009)
c.1110T>C p.(=) synonymous_variant - - - 20155310 Gadow KD , et al. (2010)
c.92-16815C>G C/G intron_variant - - - 22095641 Horiuchi Y , et al. (2011)
SFARI Gene score
3

Suggestive Evidence

Association studies with positive association, which does not reach genome-wide significance (Brune et al., 2008; Gadow et al., 2010).

Score Delta: Score remained at 4

3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Association studies with positive association, which does not reach genome-wide significance (Brune et al., 2008; Gadow et al., 2010).

Reports Added
[New Scoring Scheme]
7/1/2019
4
icon
4

Decreased from 4 to 4

Description

Association studies with positive association, which does not reach genome-wide significance (Brune et al., 2008; Gadow et al., 2010).

7/1/2014
No data
icon
4

Increased from No data to 4

Description

Association studies with positive association, which does not reach genome-wide significance (Brune et al., 2008; Gadow et al., 2010).

4/1/2014
No data
icon
4

Increased from No data to 4

Description

Association studies with positive association, which does not reach genome-wide significance (Brune et al., 2008; Gadow et al., 2010).

Krishnan Probability Score

Score 0.60669152418158

Ranking 314/25841 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 0.0012711667210719

Ranking 11610/18225 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
Sanders TADA Score

Score 0.84354955973418

Ranking 3244/18665 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).
Larsen Cumulative Evidence Score

Score 1

Ranking 434/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Zhang D Score

Score 0.15124247460906

Ranking 5150/20870 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.
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
APOOL MICOS complex subunit MIC27 Human Protein Binding 139322 Q6UXV4
CST6 Cystatin-M Human Protein Binding 1474 Q15828
EAAT4 solute carrier family 1 (high affinity aspartate/glutamate transporter), member 6 Rat Protein Binding 84012 O35921
GOLGA7 Golgin subfamily A member 7 Human Protein Binding 51125 Q7Z5G4
PDZK1 PDZ domain containing 1 Mouse Protein Binding 59020 Q9JIL4
RTN2 reticulon 2 Rat Protein Binding 308410 Q6WN19
SBSN Suprabasin Human Protein Binding 374897 E9PBV3
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SFARI Gene Update

We are pleased to announce some changes to the ongoing curation of the data in SFARI Gene. In the context of a continued effort to develop the human gene module and its manually curated list of autism risk genes, we are modifying other aspects of the site to focus on the information that is of greatest interest to the research community. The version of SFARI Gene that has been developed until now will be frozen and will remain available as “SFARI Gene Archive”. Please see the announcement for more details.
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