TSC1tuberous sclerosis 1
Autism Reports / Total Reports
16 / 39Rare Variants / Common Variants
53 / 0Aliases
TSC1, LAM, TSC, KIAA0243, MGC86987Associated Syndromes
-Chromosome Band
9q34.13Associated Disorders
ASDGenetic Category
Rare Single Gene Mutation, Syndromic, FunctionalRelevance to Autism
This gene has been associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, genetic association exists between autism and tuberous sclerosis (and hence the TSC1 and TSC2 genes as well).
Molecular Function
This gene encodes a growth inhibitory protein thought to play a role in the stabilization of tuberin and has been implicated as a tumor supressor.
External Links
SFARI Genomic Platforms
Reports related to TSC1 (39 Reports)
| # | Type | Title | Author, Year | Autism Report | Associated Disorders |
|---|---|---|---|---|---|
| 1 | Highly Cited | Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling | Gao X , et al. (2002) | No | - |
| 2 | Recent Recommendation | Neuroepileptic correlates of autistic symptomatology in tuberous sclerosis | Bolton PF (2004) | No | - |
| 3 | Recent Recommendation | Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2 | Tavazoie SF , et al. (2005) | No | - |
| 4 | Recent Recommendation | Antisense suppression of TSC1 gene product, hamartin, enhances neurite outgrowth in NGF-treated PC12h cells | Floricel F , et al. (2007) | No | - |
| 5 | Recent Recommendation | Cognitive deficits in Tsc1+/- mice in the absence of cerebral lesions and seizures | Goorden SM , et al. (2007) | No | - |
| 6 | Recent Recommendation | Tuberous sclerosis complex proteins control axon formation | Choi YJ , et al. (2008) | No | - |
| 7 | Support | Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders | Schaaf CP , et al. (2011) | Yes | - |
| 8 | Support | High-throughput sequencing of mGluR signaling pathway genes reveals enrichment of rare variants in autism | Kelleher RJ 3rd , et al. (2012) | Yes | - |
| 9 | Negative Association | Lack of association of rare functional variants in TSC1/TSC2 genes with autism spectrum disorder | Bahl S , et al. (2013) | Yes | - |
| 10 | Support | Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations | Toma C , et al. (2013) | Yes | - |
| 11 | Recent Recommendation | Loss of mTOR repressors Tsc1 or Pten has divergent effects on excitatory and inhibitory synaptic transmission in single hippocampal neuron cultures | Weston MC , et al. (2014) | No | - |
| 12 | Support | Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene panel | Brett M , et al. (2014) | Yes | MCA |
| 13 | Recent Recommendation | Identification of regions critical for the integrity of the TSC1-TSC2-TBC1D7 complex | Santiago Lima AJ , et al. (2014) | No | - |
| 14 | Support | Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia | Lim JS , et al. (2017) | No | - |
| 15 | Support | Diagnostic exome sequencing of syndromic epilepsy patients in clinical practice | Tumien B , et al. (2017) | No | - |
| 16 | Recent Recommendation | Regionally specific TSC1 and TSC2 gene expression in tuberous sclerosis complex | Li Y , et al. (2018) | No | - |
| 17 | Support | Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes | Xiong J , et al. (2019) | Yes | Tuberous sclerosis complex |
| 18 | Support | The Clinical and Genetic Features of Co-occurring Epilepsy and Autism Spectrum Disorder in Chinese Children | Long S , et al. (2019) | Yes | - |
| 19 | Recent recommendation | TSC patient-derived isogenic neural progenitor cells reveal altered early neurodevelopmental phenotypes and rapamycin-induced MNK-eIF4E signaling | Martin P , et al. (2020) | No | - |
| 20 | Support | - | Amegandjin CA et al. (2021) | Yes | - |
| 21 | Support | - | Zou D et al. (2021) | No | - |
| 22 | Support | - | Mahjani B et al. (2021) | Yes | - |
| 23 | Support | - | Chen S et al. (2021) | Yes | Epilepsy/seizures |
| 24 | Support | - | Verberne EA et al. (2022) | No | - |
| 25 | Support | - | Chuan Z et al. (2022) | No | - |
| 26 | Support | - | Serra I et al. (2022) | No | - |
| 27 | Support | - | Wu X et al. (2022) | No | Epilepsy/seizures |
| 28 | Support | - | Zhou X et al. (2022) | Yes | - |
| 29 | Support | - | Kashii H et al. (2023) | Yes | - |
| 30 | Support | - | Cirnigliaro M et al. (2023) | Yes | - |
| 31 | Support | - | Sheth F et al. (2023) | Yes | DD, ID |
| 32 | Support | - | Amerh S Alqahtani et al. (2023) | No | - |
| 33 | Support | - | Inci S Aksoylu et al. (2023) | No | ASD |
| 34 | Support | - | Lena H Nguyen et al. (2024) | No | - |
| 35 | Support | - | Alessia Romagnolo et al. (2024) | No | - |
| 36 | Support | - | Marta Viggiano et al. (2024) | Yes | ID |
| 37 | Support | - | Karen Lob et al. () | Yes | DD, epilepsy/seizures |
| 38 | Highly Cited | Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products | van Slegtenhorst M , et al. (1998) | No | - |
| 39 | Primary | Autism and tuberous sclerosis | Smalley SL (1998) | No | ASD |
Rare Variants (53)
| Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Parental Transmission | Family Type | PubMed ID | Author, Year |
|---|---|---|---|---|---|---|---|---|
| - | - | - | - | - | - | 9813776 | Smalley SL (1998) | |
| c.64C>T | p.Arg22Trp | missense_variant | - | - | - | 28215400 | Lim JS , et al. (2017) | |
| c.445C>T | p.Gln149Ter | stop_gained | Unknown | - | - | 34145886 | Zou D et al. (2021) | |
| c.610C>T | p.Arg204Cys | missense_variant | - | - | - | 28215400 | Lim JS , et al. (2017) | |
| c.751G>T | p.Glu251Ter | stop_gained | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.2380C>T | p.Gln794Ter | stop_gained | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.2773G>T | p.Glu925Ter | stop_gained | Unknown | - | - | 34615535 | Mahjani B et al. (2021) | |
| c.1006C>T | p.Arg336Trp | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.2722C>T | p.Arg908Trp | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.1591del | p.Val531Ter | frameshift_variant | Unknown | - | - | 34145886 | Zou D et al. (2021) | |
| c.2144G>A | p.Arg715Gln | missense_variant | Unknown | - | - | 35571021 | Chuan Z et al. (2022) | |
| c.210+18A>G | - | intron_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.2626-3C>T | - | intron_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.982C>T | p.Gln328Ter | stop_gained | Familial | Paternal | - | 39136901 | Karen Lob et al. () | |
| c.2392-13T>C | - | intron_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.16A>G | p.Asn6Asp | missense_variant | Familial | Maternal | - | 24690944 | Brett M , et al. (2014) | |
| c.1797dup | p.Gln600AlafsTer6 | frameshift_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.1816C>T | p.His606Tyr | missense_variant | Unknown | - | Simplex | 37543562 | Sheth F et al. (2023) | |
| c.1079C>A | p.Thr360Asn | missense_variant | Familial | - | Simplex | 23514105 | Bahl S , et al. (2013) | |
| c.658del | p.Val220SerfsTer4 | frameshift_variant | De novo | - | - | 29286531 | Tumien B , et al. (2017) | |
| c.201A>G | p.Pro67= | synonymous_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.1342C>T | p.Pro448Ser | missense_variant | Unknown | - | Simplex | 21624971 | Schaaf CP , et al. (2011) | |
| c.2285A>G | p.Asn762Ser | missense_variant | Unknown | - | Simplex | 21624971 | Schaaf CP , et al. (2011) | |
| c.346T>G | p.Leu116Val | missense_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.692C>T | p.Pro231Leu | missense_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.2199A>G | p.Met1067Leu | missense_variant | Unknown | - | Simplex | 21624971 | Schaaf CP , et al. (2011) | |
| c.3103G>A | p.Gly1035Ser | missense_variant | Unknown | - | Simplex | 21624971 | Schaaf CP , et al. (2011) | |
| c.1006C>T | p.Arg336Trp | missense_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.1178C>T | p.Thr393Ile | missense_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.1342C>T | p.Pro448Ser | missense_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.1580A>G | p.Gln527Arg | missense_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.1960C>G | p.Gln654Glu | missense_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.2718A>C | p.Gln906His | missense_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.1888_1891del | p.Lys630GlnfsTer22 | frameshift_variant | Unknown | - | - | 34145886 | Zou D et al. (2021) | |
| c.2559_2563del | p.Leu853PhefsTer49 | frameshift_variant | Unknown | - | - | 34145886 | Zou D et al. (2021) | |
| c.3042C>T | p.His1014= | synonymous_variant | - | - | Multiplex | 22558107 | Kelleher RJ 3rd , et al. (2012) | |
| c.1530_1531del | p.Asp510GlufsTer24 | frameshift_variant | De novo | - | - | 31139143 | Long S , et al. (2019) | |
| c.2506_2509del | p.Ser836ThrfsTer12 | inframe_deletion | De novo | - | - | 29286531 | Tumien B , et al. (2017) | |
| c.2023G>T | p.Asp675Tyr | missense_variant | De novo | - | Simplex | 38519481 | Marta Viggiano et al. (2024) | |
| c.2074C>T | p.Arg692Ter | stop_gained | Unknown | - | Multiplex | 37799141 | Amerh S Alqahtani et al. (2023) | |
| c.2047_2048insTG | p.Pro683LeufsTer42 | frameshift_variant | Unknown | - | - | 34800434 | Chen S et al. (2021) | |
| c.1342C>T | p.Pro448Ser | missense_variant | Familial | Paternal | Simplex | 23514105 | Bahl S , et al. (2013) | |
| c.556G>T | p.Ala186Ser | missense_variant | Familial | Maternal | Multiplex | 23999528 | Toma C , et al. (2013) | |
| c.2047_2048insTG | p.Pro683LeufsTer42 | frameshift_variant | Unknown | - | - | 31031587 | Xiong J , et al. (2019) | |
| c.-80-2A>G | - | splice_site_variant | Familial | Maternal | Multiplex | 37506195 | Cirnigliaro M et al. (2023) | |
| c.2509_2512del | p.Asn837ValfsTer11 | frameshift_variant | Unknown | - | - | 35253369 | Verberne EA et al. (2022) | |
| c.1006C>T | p.Arg336Trp | missense_variant | Familial | Paternal | Simplex | 21624971 | Schaaf CP , et al. (2011) | |
| c.570_583del | p.Leu191ProfsTer22 | frameshift_variant | Familial | Maternal | - | 34800434 | Chen S et al. (2021) | |
| c.570_583del | p.Leu191ProfsTer22 | frameshift_variant | Familial | Maternal | - | 31031587 | Xiong J , et al. (2019) | |
| c.1208C>T | p.Ser403Leu | missense_variant | Familial (1 case); unknown (1 case) | Paternal (1 case) | Simplex | 21624971 | Schaaf CP , et al. (2011) | |
| c.2194C>T | p.His732Tyr | missense_variant | Familial (1 case); unknown (1 case) | Maternal (1 case) | Simplex | 21624971 | Schaaf CP , et al. (2011) | |
| c.1079C>A | p.Thr360Asn | missense_variant | Familial (2 cases); unknown (1 case) | Paternal (2 cases) | Simplex | 21624971 | Schaaf CP , et al. (2011) | |
| c.1760A>G | p.Lys587Arg | missense_variant | Familial (4 cases); unknown (3 cases) | Maternal (3 cases); paternal (1 cases) | Simplex | 21624971 | Schaaf CP , et al. (2011) |
Common Variants
No common variants reported.
SFARI Gene score
1S
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."
1/1/2020
1
1
Score remained at 1
Description
Mutations in TSC1 cause the autosomal dominant disorder tuberous sclerosis (TSC). About 25% of individuals with TSC have autism and 40%-50% meet diagnostic criteria within the autistic spectrum disorders.
10/1/2019
S
1
Increased from S to 1
New Scoring Scheme
Description
Mutations in TSC1 cause the autosomal dominant disorder tuberous sclerosis (TSC). About 25% of individuals with TSC have autism and 40%-50% meet diagnostic criteria within the autistic spectrum disorders.
Reports Added
[New Scoring Scheme]7/1/2019
S
S
Increased from S to S
Description
Mutations in TSC1 cause the autosomal dominant disorder tuberous sclerosis (TSC). About 25% of individuals with TSC have autism and 40%-50% meet diagnostic criteria within the autistic spectrum disorders.
4/1/2019
S
S
Increased from S to S
Description
Mutations in TSC1 cause the autosomal dominant disorder tuberous sclerosis (TSC). About 25% of individuals with TSC have autism and 40%-50% meet diagnostic criteria within the autistic spectrum disorders.
7/1/2018
S
S
Increased from S to S
Description
Mutations in TSC1 cause the autosomal dominant disorder tuberous sclerosis (TSC). About 25% of individuals with TSC have autism and 40%-50% meet diagnostic criteria within the autistic spectrum disorders.
1/1/2017
S
S
Increased from S to S
Description
Mutations in TSC1 cause the autosomal dominant disorder tuberous sclerosis (TSC). About 25% of individuals with TSC have autism and 40%-50% meet diagnostic criteria within the autistic spectrum disorders.
4/1/2014
No data
S
Increased from No data to S
Description
Mutations in TSC1 cause the autosomal dominant disorder tuberous sclerosis (TSC). About 25% of individuals with TSC have autism and 40%-50% meet diagnostic criteria within the autistic spectrum disorders.
Krishnan Probability Score
Score 0.50948974929021
Ranking 1844/25841 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 0.99997833421239
Ranking 513/18225 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 0.9328815282409
Ranking 12107/18665 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 0.43936652317605
Ranking 1033/20870 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.
Interactome
- Protein Binding
- DNA Binding
- RNA Binding
- Protein Modification
- Direct Regulation
- ASD-Linked Genes
Interaction Table
| Interactor Symbol | Interactor Name | Interactor Organism | Interactor Type | Entrez ID | Uniprot ID |
|---|---|---|---|---|---|
| AKTIP | AKT-interacting protein | Human | Protein Binding | 64400 | Q9H8T0-2 |
| ANKRD24 | ankyrin repeat domain 24 | Human | Protein Binding | 170961 | Q8TF21 |
| CCDC88B | coiled-coil domain containing 88B | Human | Protein Binding | 283234 | A6NC98 |
| CEP110 | Centriolar coiled-coil protein of 110 kDa | Human | Protein Binding | 9738 | O43303 |
| CNTROB | centrobin, centrosomal BRCA2 interacting protein | Human | Protein Binding | 116840 | Q8N137 |
| DACH2 | dachshund homolog 2 (Drosophila) | Human | Protein Binding | 117154 | Q96NX9 |
| KIAA1026 | KIAA1026 protein | Human | Protein Binding | B7ZL87 | |
| LOC347475 | coiled-coil domain containing 160 | Human | Protein Binding | 347475 | A6NGH7 |
| LRSAM1 | leucine rich repeat and sterile alpha motif containing 1 | Human | Protein Binding | 90678 | Q6UWE0 |
| NGFRAP1 | nerve growth factor receptor (TNFRSF16) associated protein 1 | Human | Protein Binding | 27018 | Q00994 |
| SEPW1 | selenoprotein W, 1 | Human | Protein Binding | 6415 | P63302 |