SLC6A1Solute carrier family 6 (neurotransmitter transporter), member 1
Autism Reports / Total Reports
27 / 56Rare Variants / Common Variants
157 / 3Aliases
SLC6A1, GABATHG, GABATR, GAT1Associated Syndromes
Tourette syndromeChromosome Band
3p25.3Associated Disorders
DD/NDD, ADHD, ID, EPS, ASDGenetic Category
Rare Single Gene Mutation, Syndromic, Genetic AssociationRelevance 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). Four de novo missense variants that were predicted to be deleterious (defined as having an MPC score 2) were identified in the SLC6A1 gene in ASD probands from the Autism Sequencing Consortium in Satterstrom et al., 2020; subsequent TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in this report identified SLC6A1 as a candidate gene with a false discovery rate (FDR) 0.01. A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified SLC6A1 as a gene reaching exome-wide significance (P < 2.5E-06). Phenotypic evaluation of 34 individuals (30 novel, 4 previously published) with SLC6A1 mutations in Johannesen et al., 2018 demonstrated that impaired cognitive development (intellectual disability or learning disability) and epilepsy were the most common phenotypes; in addition, behavioral problems were frequently observed in individuals in this study, with eight patients presenting with ASD or autistic features. Mermer et al., 2021 experimentally assessed twenty-two SLC6A1 variants identified in patients with a broad spectrum of phenotypes, including SLC6A1 missense variants identified in ASD probands, and found that partial or complete loss of function (characterized by reduced GABA uptake and surface expression) was a common disease mechanism regardless of disease phenotype.
Molecular Function
The SLC6A1 gene encodes a gamma-aminobutyric acid (GABA) transporter, which removes GABA from the synaptic cleft.
External Links
SFARI Genomic Platforms
Reports related to SLC6A1 (56 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 2 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 |
19 | Support | SLC6A1 variants identified in epilepsy patients reduce ?-aminobutyric acid transport | Mattison KA , et al. (2018) | No | ID, ASD |
20 | Support | Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes | Xiong J , et al. (2019) | Yes | ID, epilepsy/seizures |
21 | Support | The Clinical and Genetic Features of Co-occurring Epilepsy and Autism Spectrum Disorder in Chinese Children | Long S , et al. (2019) | Yes | - |
22 | Support | A missense mutation in SLC6A1 associated with Lennox-Gastaut syndrome impairs GABA transporter 1 protein trafficking and function | Cai K , et al. (2019) | No | - |
23 | Support | Clinical utility of multigene panel testing in adults with epilepsy and intellectual disability | Borlot F , et al. (2019) | No | ADHD, behavioral problems |
24 | Support | Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder | Munnich A , et al. (2019) | Yes | - |
25 | Support | Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism | Satterstrom FK et al. (2020) | Yes | - |
26 | Support | Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability | Chevarin M et al. (2020) | No | Marfanoid habitus |
27 | Support | Endoplasmic reticulum retention and degradation of a mutation in SLC6A1 associated with epilepsy and autism | Wang J et al. (2020) | Yes | DD, ID |
28 | Support | Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures | Tang S et al. (2020) | No | ASD |
29 | Support | SLC6A1 G443D associated with developmental delay and epilepsy | Devries S et al. (2020) | Yes | - |
30 | Support | Clinical and genetic characteristics of patients with Doose syndrome | Hinokuma N et al. (2020) | No | DD, ID |
31 | Support | Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders | Wang T et al. (2020) | Yes | ID |
32 | Support | - | Alonso-Gonzalez A et al. (2021) | Yes | - |
33 | Support | - | Brunet T et al. (2021) | No | - |
34 | Support | - | Poliquin S et al. (2021) | No | - |
35 | Recent Recommendation | - | Kahen A et al. (2021) | No | ASD, ADHD, ID |
36 | Recent Recommendation | - | Mermer F et al. (2021) | Yes | - |
37 | Support | - | Qaiser F et al. (2021) | Yes | - |
38 | Support | - | Aguilera C et al. (2021) | No | Stereotypy |
39 | Support | - | Chen S et al. (2021) | Yes | Epilepsy/seizures |
40 | Support | - | Brea-Fernández AJ et al. (2022) | No | - |
41 | Support | - | Chuan Z et al. (2022) | No | - |
42 | Support | - | Bain JM et al. (2022) | No | ASD, ADHD |
43 | Support | - | Nwosu G et al. (2022) | No | ASD, DD, ID |
44 | Support | - | Zhou X et al. (2022) | Yes | - |
45 | Support | - | Verhoeven W et al. (2022) | Yes | - |
46 | Support | - | Piniella D et al. (2023) | Yes | - |
47 | Support | - | Kasture AS et al. (2023) | No | - |
48 | Support | - | Goodspeed K et al. (2023) | No | ASD |
49 | Support | - | Miyake N et al. (2023) | Yes | - |
50 | Support | - | Caputo D et al. (2023) | No | ID |
51 | Support | - | Kassabian B et al. (2023) | No | ASD or autistic features, ADHD, BPD, stereotypy |
52 | Support | - | Sanchis-Juan A et al. (2023) | No | ID |
53 | Support | - | Johannesen KM et al. (2023) | No | ASD or autistic features, epilepsy/seizures |
54 | Support | - | Marina Trivisano et al. (2023) | No | Stereotypy |
55 | Support | - | Lucie Sedlackova et al. (2024) | No | - |
56 | Recent Recommendation | - | Dina Buitrago Silva et al. (2024) | Yes | - |
Rare Variants (157)
Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Parental Transmission | Family Type | PubMed ID | Author, Year |
---|---|---|---|---|---|---|---|---|
- | - | translocation | De novo | - | - | 29621621 | Pesz K , et al. (2018) | |
c.*221G>A | - | stop_gained | Unknown | - | - | 30132828 | Mattison KA , et al. (2018) | |
- | - | copy_number_loss | De novo | - | Simplex | 25865495 | Carvill GL , et al. (2015) | |
c.714+1G>A | - | splice_site_variant | De novo | - | - | 34800434 | Chen S et al. (2021) | |
c.1696-1G>A | - | splice_site_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
c.714+1G>A | - | splice_site_variant | De novo | - | - | 31031587 | Xiong J , et al. (2019) | |
c.1595G>A | p.Trp532Ter | stop_gained | Unknown | - | - | 34006619 | Kahen A et al. (2021) | |
c.131G>A | p.Arg44Gln | missense_variant | Unknown | - | - | 33004838 | Wang T et al. (2020) | |
c.154G>A | p.Asp52Asn | missense_variant | Unknown | - | - | 33004838 | Wang T et al. (2020) | |
c.223G>C | p.Gly75Arg | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
c.*76A>T | - | stop_gained | De novo | - | Simplex | 29315614 | Johannesen KM , et al. (2018) | |
c.419A>G | p.Tyr140Cys | missense_variant | De novo | - | - | 32469098 | Tang S et al. (2020) | |
c.478C>T | p.Pro160Ser | missense_variant | Unknown | - | - | 33004838 | Wang T et al. (2020) | |
c.607G>A | p.Gly203Arg | missense_variant | Unknown | - | - | 33004838 | Wang T et al. (2020) | |
c.779C>T | p.Thr260Met | missense_variant | Unknown | - | - | 33004838 | Wang T et al. (2020) | |
c.820C>T | p.Pro274Ser | missense_variant | Unknown | - | - | 33004838 | Wang T et al. (2020) | |
c.863C>T | p.Ala288Val | missense_variant | Unknown | - | - | 33004838 | Wang T et al. (2020) | |
c.889G>A | p.Gly297Arg | missense_variant | Unknown | - | - | 33004838 | Wang T et al. (2020) | |
c.913G>A | p.Ala305Thr | missense_variant | Unknown | - | - | 33004838 | Wang T et al. (2020) | |
c.919G>A | p.Gly307Arg | missense_variant | Unknown | - | - | 33004838 | Wang T et al. (2020) | |
c.995T>G | p.Met332Arg | missense_variant | De novo | - | - | 34800434 | Chen S et al. (2021) | |
c.863C>T | p.Ala288Val | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
c.131G>A | p.Arg44Gln | missense_variant | Unknown | - | - | 34006619 | Kahen A et al. (2021) | |
c.1155C>G | p.Phe385Leu | missense_variant | De novo | - | - | 32469098 | Tang S et al. (2020) | |
c.1009G>A | p.Val337Ile | missense_variant | Unknown | - | - | 33004838 | Wang T et al. (2020) | |
c.1070C>T | p.Ala357Val | missense_variant | Unknown | - | - | 33004838 | Wang T et al. (2020) | |
c.1178G>T | p.Gly393Val | missense_variant | Unknown | - | - | 33004838 | Wang T et al. (2020) | |
c.1229A>G | p.Asp410Gly | missense_variant | Unknown | - | - | 33004838 | Wang T et al. (2020) | |
c.1436G>A | p.Arg479Gln | missense_variant | Unknown | - | - | 33004838 | Wang T et al. (2020) | |
c.1436G>C | p.Arg479Pro | missense_variant | Unknown | - | - | 33004838 | Wang T et al. (2020) | |
c.1559C>T | p.Thr520Met | missense_variant | Unknown | - | - | 33004838 | Wang T et al. (2020) | |
c.1256G>A | p.Arg419His | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
c.913G>A | p.Ala305Thr | missense_variant | Unknown | - | - | 34006619 | Kahen A et al. (2021) | |
c.223G>A | p.Gly75Arg | missense_variant | De novo | - | - | 28708303 | Chrot E , et al. (2017) | |
c.1084G>A | p.Gly362Arg | missense_variant | Unknown | - | - | 34006619 | Kahen A et al. (2021) | |
c.995T>G | p.Met332Arg | missense_variant | De novo | - | - | 31031587 | Xiong J , et al. (2019) | |
c.1531G>A | p.Val511Met | missense_variant | Familial | - | - | 34006619 | Kahen A et al. (2021) | |
c.871C>T | p.Gln291Ter | stop_gained | De novo | - | Simplex | 34006619 | Kahen A et al. (2021) | |
c.1695+1G>A | - | splice_site_variant | De novo | - | Simplex | 34006619 | Kahen A et al. (2021) | |
- | p.Gly297Arg | missense_variant | Unknown | - | Multiplex | 34622207 | Qaiser F et al. (2021) | |
c.302A>G | p.Glu101Gly | missense_variant | De novo | - | - | 29961511 | Islam MP , et al. (2018) | |
c.1528-1G>C | - | splice_site_variant | De novo | - | - | 29315614 | Johannesen KM , et al. (2018) | |
NM_001348250.1:c.1848A>G | - | intron_variant | De novo | - | - | 31139143 | Long S , et al. (2019) | |
c.1460T>C | p.Met487Thr | missense_variant | De novo | - | - | 31273778 | Borlot F , et al. (2019) | |
c.1328G>A | p.Gly443Asp | missense_variant | De novo | - | - | 32660967 | Devries S et al. (2020) | |
c.889G>A | p.Gly297Arg | missense_variant | De novo | - | - | 34653234 | Aguilera C et al. (2021) | |
c.881_883del | p.Phe294del | inframe_deletion | Unknown | - | - | 34006619 | Kahen A et al. (2021) | |
c.418_420del | p.Tyr140del | inframe_deletion | Unknown | - | - | 35571021 | Chuan Z et al. (2022) | |
c.889G>A | p.Gly297Arg | missense_variant | De novo | - | - | 25865495 | Carvill GL , et al. (2015) | |
c.281G>A | p.Gly94Glu | missense_variant | Unknown | - | - | 30132828 | Mattison KA , et al. (2018) | |
c.471+20A>C | - | intron_variant | De novo | - | Simplex | 31981491 | Satterstrom FK et al. (2020) | |
c.*111C>G | - | missense_variant | De novo | - | Simplex | 29315614 | Johannesen KM , et al. (2018) | |
c.*265G>A | - | missense_variant | De novo | - | Simplex | 29315614 | Johannesen KM , et al. (2018) | |
c.179A>G | p.Tyr60Cys | missense_variant | De novo | - | Simplex | 35982159 | Zhou X et al. (2022) | |
c.1352A>G | p.Asp451Gly | missense_variant | De novo | - | - | 28554332 | Bowling KM , et al. (2017) | |
c.703T>C | p.Trp235Arg | missense_variant | Unknown | - | - | 30132828 | Mattison KA , et al. (2018) | |
c.317A>G | p.Gln106Arg | missense_variant | De novo | - | Simplex | 35982159 | Zhou X et al. (2022) | |
c.761T>C | p.Leu254Pro | missense_variant | De novo | - | Simplex | 35982159 | Zhou X et al. (2022) | |
c.130C>T | p.Arg44Trp | missense_variant | De novo | - | Simplex | 34006619 | Kahen A et al. (2021) | |
c.578G>A | p.Trp193Ter | stop_gained | De novo | - | Simplex | 25865495 | Carvill GL , et al. (2015) | |
c.1078G>A | p.Gly360Ser | missense_variant | De novo | - | - | 25363760 | De Rubeis S , et al. (2014) | |
c.1024G>A | p.Val342Met | missense_variant | De novo | - | - | 27479843 | Lelieveld SH et al. (2016) | |
c.1334A>G | p.Tyr445Cys | missense_variant | Unknown | - | - | 30132828 | Mattison KA , et al. (2018) | |
c.1648G>A | p.Gly550Arg | missense_variant | Unknown | - | - | 30132828 | Mattison KA , et al. (2018) | |
c.223G>A | p.Gly75Arg | missense_variant | De novo | - | - | 29315614 | Johannesen KM , et al. (2018) | |
c.1349_1350del | p.Phe450Ter | frameshift_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
c.1081C>A | p.Pro361Thr | missense_variant | De novo | - | Simplex | 32398021 | Wang J et al. (2020) | |
c.302A>G | p.Glu101Gly | missense_variant | De novo | - | Simplex | 34006619 | Kahen A et al. (2021) | |
c.331G>A | p.Gly111Arg | missense_variant | De novo | - | Simplex | 34006619 | Kahen A et al. (2021) | |
c.752T>C | p.Leu251Pro | missense_variant | De novo | - | Simplex | 34006619 | Kahen A et al. (2021) | |
c.863C>T | p.Ala288Val | missense_variant | De novo | - | Simplex | 34006619 | Kahen A et al. (2021) | |
c.884C>T | p.Ser295Leu | missense_variant | De novo | - | Simplex | 34006619 | Kahen A et al. (2021) | |
c.889G>A | p.Gly297Arg | missense_variant | De novo | - | Simplex | 34006619 | Kahen A et al. (2021) | |
c.919G>A | p.Gly307Arg | missense_variant | De novo | - | Simplex | 34006619 | Kahen A et al. (2021) | |
c.980A>G | p.Asn327Ser | missense_variant | De novo | - | Simplex | 34006619 | Kahen A et al. (2021) | |
c.991A>G | p.Ser331Gly | missense_variant | De novo | - | Simplex | 34006619 | Kahen A et al. (2021) | |
c.149G>T | p.Arg50Leu | missense_variant | De novo | - | Unknown | 33619735 | Brunet T et al. (2021) | |
c.154G>T | p.Asp52Tyr | missense_variant | De novo | - | Simplex | 36973392 | Miyake N et al. (2023) | |
c.723C>A | p.Tyr241Ter | stop_gained | Unknown | - | Unknown | 25363760 | De Rubeis S , et al. (2014) | |
c.583C>T | p.Arg195Cys | missense_variant | Familial | Paternal | - | 33004838 | Wang T et al. (2020) | |
c.1015T>C | p.Phe339Leu | missense_variant | De novo | - | Simplex | 27525107 | Yuen RK et al. (2016) | |
c.1024G>A | p.Val342Met | missense_variant | De novo | - | Simplex | 34006619 | Kahen A et al. (2021) | |
c.1084G>A | p.Gly362Arg | missense_variant | De novo | - | Simplex | 34006619 | Kahen A et al. (2021) | |
c.850-2A>G | - | splice_site_variant | De novo | - | Unknown | 29315614 | Johannesen KM , et al. (2018) | |
c.863C>T | p.Ala288Val | missense_variant | Familial | Maternal | - | 34006619 | Kahen A et al. (2021) | |
c.1648G>A | p.Gly550Arg | missense_variant | De novo | - | Simplex | 25961944 | Krumm N , et al. (2015) | |
c.1084G>A | p.Gly362Arg | missense_variant | Unknown | - | Simplex | 37457006 | Caputo D et al. (2023) | |
c.1648G>A | p.Gly550Arg | missense_variant | De novo | - | Simplex | 37457006 | Caputo D et al. (2023) | |
c.1702C>T | p.Gln568Ter | stop_gained | Unknown | - | Multiplex | 37502687 | Kassabian B et al. (2023) | |
c.987C>A | p.Cys329Ter | stop_gained | De novo | - | Simplex | 29315614 | Johannesen KM , et al. (2018) | |
c.1222del | p.Leu408TrpfsTer26 | frameshift_variant | Unknown | - | - | 34006619 | Kahen A et al. (2021) | |
c.1255del | p.Arg419AlafsTer15 | frameshift_variant | Unknown | - | - | 34006619 | Kahen A et al. (2021) | |
c.896G>T | p.Gly299Val | missense_variant | De novo | - | Simplex | 25363768 | Iossifov I et al. (2014) | |
c.752T>C | p.Ile251Thr | missense_variant | De novo | - | Simplex | 31406558 | Munnich A , et al. (2019) | |
c.739C>G | p.Pro247Ala | missense_variant | De novo | - | Simplex | 32913952 | Hinokuma N et al. (2020) | |
c.919G>A | p.Gly307Arg | missense_variant | De novo | - | Simplex | 36674476 | Piniella D et al. (2023) | |
c.131G>A | p.Arg44Gln | missense_variant | De novo | - | Simplex | 25865495 | Carvill GL , et al. (2015) | |
c.137C>T | p.Thr46Met | missense_variant | De novo | - | Simplex | 28472652 | Willsey AJ , et al. (2017) | |
c.1600C>T | p.Gln534Ter | stop_gained | De novo | - | Simplex | 29315614 | Johannesen KM , et al. (2018) | |
c.1377C>A | p.Ser459Arg | missense_variant | De novo | - | Simplex | 32277047 | Chevarin M et al. (2020) | |
c.863C>T | p.Ala288Val | missense_variant | De novo | - | Simplex | 22495306 | Sanders SJ , et al. (2012) | |
c.640_658del | p.Leu214SerfsTer32 | frameshift_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
c.1163T>G | p.Met388Arg | missense_variant | De novo | - | Simplex | 36582431 | Verhoeven W et al. (2022) | |
c.493G>T | p.Asp165Tyr | missense_variant | Unknown | - | Unknown | 25363760 | De Rubeis S , et al. (2014) | |
c.514C>T | p.Arg172Cys | missense_variant | Unknown | - | Unknown | 25363760 | De Rubeis S , et al. (2014) | |
c.340G>A | p.Gly114Arg | missense_variant | Unknown | - | Multiplex | 37502687 | Kassabian B et al. (2023) | |
c.160C>T | p.Leu54Phe | missense_variant | De novo | - | Simplex | 31981491 | Satterstrom FK et al. (2020) | |
c.167C>T | p.Ser56Phe | missense_variant | Unknown | - | Simplex | 37541188 | Sanchis-Juan A et al. (2023) | |
c.1000G>C | p.Ala334Pro | missense_variant | Familial | Maternal | - | 25865495 | Carvill GL , et al. (2015) | |
c.1531G>A | p.Val511Met | missense_variant | De novo | - | Simplex | 37662110 | Johannesen KM et al. (2023) | |
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.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.593A>C | p.His198Pro | missense_variant | De novo | - | Simplex | 31981491 | Satterstrom FK et al. (2020) | |
c.863C>T | p.Ala288Val | missense_variant | De novo | - | Simplex | 31981491 | Satterstrom FK et al. (2020) | |
c.919G>A | p.Gly307Arg | missense_variant | De novo | - | Simplex | 31981491 | Satterstrom FK et al. (2020) | |
c.1070C>T | p.Ala357Val | missense_variant | De novo | - | - | 35322241 | Brea-Fernández AJ et al. (2022) | |
c.1793A>G | p.Tyr598Cys | missense_variant | Familial | Paternal | - | 25363760 | De Rubeis S , et al. (2014) | |
c.1024G>A | p.Val342Met | missense_variant | De novo | - | Simplex | 29315614 | Johannesen KM , et al. (2018) | |
c.1070C>T | p.Ala357Val | missense_variant | De novo | - | Simplex | 29315614 | Johannesen KM , et al. (2018) | |
c.1155C>G | p.Phe385Leu | missense_variant | De novo | - | Simplex | 29315614 | Johannesen KM , et al. (2018) | |
c.1000G>A | p.Ala334Thr | missense_variant | Unknown | - | Simplex | 37541188 | Sanchis-Juan A et al. (2023) | |
c.1743G>C | p.Glu581Asp | missense_variant | Unknown | - | Simplex | 37541188 | Sanchis-Juan A et al. (2023) | |
c.695G>T | p.Gly232Val | missense_variant | De novo | - | Simplex | 37700749 | Marina Trivisano et al. (2023) | |
c.160C>T | p.Leu54Phe | missense_variant | De novo | - | Simplex | 33431980 | Alonso-Gonzalez A et al. (2021) | |
c.1070C>T | p.Ala357Val | missense_variant | De novo | - | Simplex | 37700749 | Marina Trivisano et al. (2023) | |
c.700G>A | p.Gly234Ser | missense_variant | Unknown | Not paternal | Simplex | 31176687 | Cai K , et al. (2019) | |
c.1702C>T | p.Gln568Ter | stop_gained | Familial | Paternal | Multiplex | 37502687 | Kassabian B et al. (2023) | |
c.881_883del | p.Ser294del | inframe_deletion | 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.286C>G | p.Pro96Ala | missense_variant | Familial | Paternal | Simplex | 37502687 | Kassabian B et al. (2023) | |
c.1024G>A | p.Val342Met | missense_variant | De novo | - | Not simplex | 29315614 | Johannesen KM , et al. (2018) | |
c.1531G>A | p.Val511Met | missense_variant | Familial | Paternal | - | 38008000 | Lucie Sedlackova et al. (2024) | |
c.863C>T | p.Ala288Val | missense_variant | Familial | Maternal | Simplex | 25865495 | Carvill GL , et al. (2015) | |
c.1070C>T | p.Ala357Val | missense_variant | Familial | Paternal | Simplex | 37502687 | Kassabian B et al. (2023) | |
c.889G>A | p.Gly297Arg | missense_variant | Familial | Paternal | Multiplex | 37502687 | Kassabian B et al. (2023) | |
c.1084G>C | p.Gly362Arg | missense_variant | Familial | Maternal | Multiplex | 37502687 | Kassabian B et al. (2023) | |
c.1337del | p.Val446AlafsTer13 | frameshift_variant | De novo | - | Simplex | 37662110 | Johannesen KM et al. (2023) | |
c.638dup | p.Leu214ThrfsTer68 | frameshift_variant | De novo | - | Simplex | 29315614 | Johannesen KM , et al. (2018) | |
c.1349_1351del | p.Phe450_Asp451delinsTyr | inframe_deletion | De novo | - | - | 30132828 | Mattison KA , et al. (2018) | |
c.1084G>A | p.Gly362Arg | missense_variant | Familial | Maternal | Simplex | 29315614 | Johannesen KM , et al. (2018) | |
c.695G>T | p.Gly232Val | missense_variant | Familial | Maternal | Multiplex | 29315614 | Johannesen KM , et al. (2018) | |
c.913G>A | p.Ala305Thr | missense_variant | Familial | Maternal | Simplex | 37700749 | Marina Trivisano et al. (2023) | |
c.959C>T | p.Ser320Phe | missense_variant | Familial | Maternal | Simplex | 37700749 | Marina Trivisano et al. (2023) | |
c.213dup | p.Tyr72LeufsTer135 | frameshift_variant | De novo | - | Simplex | 37700749 | Marina Trivisano et al. (2023) | |
c.1369_1370del | p.Gly457HisfsTer10 | frameshift_variant | De novo | - | Simplex | 25865495 | Carvill GL , et al. (2015) | |
c.194G>A | p.Gly65Asp | missense_variant | Unknown | Not maternal | Multiplex | 37662110 | Johannesen KM et al. (2023) | |
c.723C>A | p.Tyr241Ter | stop_gained | De novo | - | Multiplex (suspected twins) | 28191889 | Stessman HA , et al. (2017) | |
c.801del | p.Ile268SerfsTer36 | frameshift_variant | Familial | Paternal | Simplex | 37502687 | Kassabian B et al. (2023) | |
c.283G>T | p.Val95Phe | missense_variant | Familial | Maternal | Multi-generational | 37502687 | Kassabian B et al. (2023) | |
c.1679dup | p.Ser562LeufsTer24 | frameshift_variant | Familial | Maternal | Unknown | 37662110 | Johannesen KM et al. (2023) | |
c.373G>A | p.Val125Met | missense_variant | De novo (germline mosaicism) | - | Multiplex | 33961861 | Poliquin S et al. (2021) | |
c.1328G>A | p.Gly443Asp | missense_variant | De novo (germline mosaicism) | - | Multiplex | 37502687 | Kassabian B et al. (2023) | |
c.1084G>A | p.Gly362Arg | missense_variant | Familial | Maternal | Extended multiplex | 29315614 | Johannesen KM , et al. (2018) | |
c.1024G>A | p.Val342Met | missense_variant | Familial | Paternal | Multi-generational | 29315614 | Johannesen KM , et al. (2018) |
Common Variants (3)
Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Paternal Transmission | Family Type | PubMed ID | Author, Year |
---|---|---|---|---|---|---|---|---|
c.-216+5824G>T;c.-155+5824G>T | - | intron_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.-215-4116T>C;c.-154-4116T>C | - | 2_KB_upstream_variant | - | - | - | 28442423 | Yuan FF , et al. (2017) |
SFARI Gene score
High Confidence, Syndromic
Score Delta: Score remained at 1S
criteria met
See SFARI Gene'scoring criteriaWe 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."
4/1/2021
Score remained at 1
Description
A de novo missense variant in the SLC6A1 gene (p.Ala288Val) 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). This missense variant was predicted to be damaging, and an amino acid substitution at the same residue (p.Ala288Cys) had previously been shown to reduce GABA transport activity to 5%-7% of wild-type activity (PMID 18381286). 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. Phenotypic evaluation of 34 individuals (30 novel, 4 previously published) with SLC6A1 mutations in Johannesen et al., 2018 demonstrated that impaired cognitive development (intellectual disability or learning disability) and epilepsy were the most common phenotypes; in addition, behavioral problems were frequently observed in individuals in this study, with eight patients presenting with ASD or autistic features.
Reports Added
[Genetic mosaicism, intrafamilial phenotypic heterogeneity, and molecular defects of a novel missense SLC6A1 mutation associated with epilepsy and ADHD2021] [Neurodevelopmental phenotypes associated with pathogenic variants in SLC6A12021] [Common molecular mechanisms of SLC6A1 variant-mediated neurodevelopmental disorders in astrocytes and neurons2021]1/1/2021
Score remained at 1
Description
A de novo missense variant in the SLC6A1 gene (p.Ala288Val) 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). This missense variant was predicted to be damaging, and an amino acid substitution at the same residue (p.Ala288Cys) had previously been shown to reduce GABA transport activity to 5%-7% of wild-type activity (PMID 18381286). 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. Phenotypic evaluation of 34 individuals (30 novel, 4 previously published) with SLC6A1 mutations in Johannesen et al., 2018 demonstrated that impaired cognitive development (intellectual disability or learning disability) and epilepsy were the most common phenotypes; in addition, behavioral problems were frequently observed in individuals in this study, with eight patients presenting with ASD or autistic features.
10/1/2020
Score remained at 1
Description
A de novo missense variant in the SLC6A1 gene (p.Ala288Val) 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). This missense variant was predicted to be damaging, and an amino acid substitution at the same residue (p.Ala288Cys) had previously been shown to reduce GABA transport activity to 5%-7% of wild-type activity (PMID 18381286). 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. Phenotypic evaluation of 34 individuals (30 novel, 4 previously published) with SLC6A1 mutations in Johannesen et al., 2018 demonstrated that impaired cognitive development (intellectual disability or learning disability) and epilepsy were the most common phenotypes; in addition, behavioral problems were frequently observed in individuals in this study, with eight patients presenting with ASD or autistic features.
7/1/2020
Score remained at 1
Description
A de novo missense variant in the SLC6A1 gene (p.Ala288Val) 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). This missense variant was predicted to be damaging, and an amino acid substitution at the same residue (p.Ala288Cys) had previously been shown to reduce GABA transport activity to 5%-7% of wild-type activity (PMID 18381286). 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. Phenotypic evaluation of 34 individuals (30 novel, 4 previously published) with SLC6A1 mutations in Johannesen et al., 2018 demonstrated that impaired cognitive development (intellectual disability or learning disability) and epilepsy were the most common phenotypes; in addition, behavioral problems were frequently observed in individuals in this study, with eight patients presenting with ASD or autistic features.
4/1/2020
Score remained at 1
Description
A de novo missense variant in the SLC6A1 gene (p.Ala288Val) 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). This missense variant was predicted to be damaging, and an amino acid substitution at the same residue (p.Ala288Cys) had previously been shown to reduce GABA transport activity to 5%-7% of wild-type activity (PMID 18381286). 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. Phenotypic evaluation of 34 individuals (30 novel, 4 previously published) with SLC6A1 mutations in Johannesen et al., 2018 demonstrated that impaired cognitive development (intellectual disability or learning disability) and epilepsy were the most common phenotypes; in addition, behavioral problems were frequently observed in individuals in this study, with eight patients presenting with ASD or autistic features.
Reports Added
[Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability2020] [Endoplasmic reticulum retention and degradation of a mutation in SLC6A1 associated with epilepsy and autism2020] [Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures2020]1/1/2020
Score remained at 1
Description
A de novo missense variant in the SLC6A1 gene (p.Ala288Val) 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). This missense variant was predicted to be damaging, and an amino acid substitution at the same residue (p.Ala288Cys) had previously been shown to reduce GABA transport activity to 5%-7% of wild-type activity (PMID 18381286). 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. Phenotypic evaluation of 34 individuals (30 novel, 4 previously published) with SLC6A1 mutations in Johannesen et al., 2018 demonstrated that impaired cognitive development (intellectual disability or learning disability) and epilepsy were the most common phenotypes; in addition, behavioral problems were frequently observed in individuals in this study, with eight patients presenting with ASD or autistic features.
10/1/2019
Decreased from 2S to 1
New Scoring Scheme
Description
A de novo missense variant in the SLC6A1 gene (p.Ala288Val) 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). This missense variant was predicted to be damaging, and an amino acid substitution at the same residue (p.Ala288Cys) had previously been shown to reduce GABA transport activity to 5%-7% of wild-type activity (PMID 18381286). 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. Phenotypic evaluation of 34 individuals (30 novel, 4 previously published) with SLC6A1 mutations in Johannesen et al., 2018 demonstrated that impaired cognitive development (intellectual disability or learning disability) and epilepsy were the most common phenotypes; in addition, behavioral problems were frequently observed in individuals in this study, with eight patients presenting with ASD or autistic features.
Reports Added
[New Scoring Scheme]7/1/2019
Decreased from 2S to 2S
Description
A de novo missense variant in the SLC6A1 gene (p.Ala288Val) 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). This missense variant was predicted to be damaging, and an amino acid substitution at the same residue (p.Ala288Cys) had previously been shown to reduce GABA transport activity to 5%-7% of wild-type activity (PMID 18381286). 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. Phenotypic evaluation of 34 individuals (30 novel, 4 previously published) with SLC6A1 mutations in Johannesen et al., 2018 demonstrated that impaired cognitive development (intellectual disability or learning disability) and epilepsy were the most common phenotypes; in addition, behavioral problems were frequently observed in individuals in this study, with eight patients presenting with ASD or autistic features.
Reports Added
[The Clinical and Genetic Features of Co-occurring Epilepsy and Autism Spectrum Disorder in Chinese Children.2019] [A missense mutation in SLC6A1 associated with Lennox-Gastaut syndrome impairs GABA transporter 1 protein trafficking and function.2019] [Clinical utility of multigene panel testing in adults with epilepsy and intellectual disability.2019] [Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder.2019]4/1/2019
Decreased from 2S to 2S
Description
A de novo missense variant in the SLC6A1 gene (p.Ala288Val) 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). This missense variant was predicted to be damaging, and an amino acid substitution at the same residue (p.Ala288Cys) had previously been shown to reduce GABA transport activity to 5%-7% of wild-type activity (PMID 18381286). 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. Phenotypic evaluation of 34 individuals (30 novel, 4 previously published) with SLC6A1 mutations in Johannesen et al., 2018 demonstrated that impaired cognitive development (intellectual disability or learning disability) and epilepsy were the most common phenotypes; in addition, behavioral problems were frequently observed in individuals in this study, with eight patients presenting with ASD or autistic features.
10/1/2018
Decreased from 2S to 2S
Description
A de novo missense variant in the SLC6A1 gene (p.Ala288Val) 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). This missense variant was predicted to be damaging, and an amino acid substitution at the same residue (p.Ala288Cys) had previously been shown to reduce GABA transport activity to 5%-7% of wild-type activity (PMID 18381286). 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. Phenotypic evaluation of 34 individuals (30 novel, 4 previously published) with SLC6A1 mutations in Johannesen et al., 2018 demonstrated that impaired cognitive development (intellectual disability or learning disability) and epilepsy were the most common phenotypes; in addition, behavioral problems were frequently observed in individuals in this study, with eight patients presenting with ASD or autistic features.
7/1/2018
Decreased from 2 to 2S
Description
A de novo missense variant in the SLC6A1 gene (p.Ala288Val) 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). This missense variant was predicted to be damaging, and an amino acid substitution at the same residue (p.Ala288Cys) had previously been shown to reduce GABA transport activity to 5%-7% of wild-type activity (PMID 18381286). 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. Phenotypic evaluation of 34 individuals (30 novel, 4 previously published) with SLC6A1 mutations in Johannesen et al., 2018 demonstrated that impaired cognitive development (intellectual disability or learning disability) and epilepsy were the most common phenotypes; in addition, behavioral problems were frequently observed in individuals in this study, with eight patients presenting with ASD or autistic features.
7/1/2017
Decreased from 2 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). 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
Decreased from 2 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). 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.
Reports Added
[De novo mutations revealed by whole-exome sequencing are strongly associated with autism.2012] [Mutations in the GABA Transporter SLC6A1 Cause Epilepsy with Myoclonic-Atonic Seizures.2015] [Excess of rare, inherited truncating mutations in autism.2015] [Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci.2015] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016] [Genome-wide characteristics of de novo mutations in autism2016] [Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder2017] [SLC6A1 gene involvement in susceptibility to attention-deficit/hyperactivity disorder: A case-control study and gene-environment interaction.2017] [De Novo Coding Variants Are Strongly Associated with Tourette Disorder.2017] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017]1/1/2017
Decreased from 2 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). 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
Decreased from 2 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).
1/1/2016
Decreased from 2 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).
Reports Added
[De novo mutations revealed by whole-exome sequencing are strongly associated with autism.2012] [Mutations in the GABA Transporter SLC6A1 Cause Epilepsy with Myoclonic-Atonic Seizures.2015] [Excess of rare, inherited truncating mutations in autism.2015] [Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci.2015] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Low load for disruptive mutations in autism genes and their biased transmission.2015]10/1/2015
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
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ExAC Score
Score 0.99930187916582
Ranking 1000/18225 scored genes
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Iossifov Probability Score
Score 0.843
Ranking 201/239 scored genes
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Sanders TADA Score
Score 0.029094456788286
Ranking 38/18665 scored genes
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Zhang D Score
Score 0.034682481977119
Ranking 7636/20870 scored genes
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