Human Gene Module / Chromosome 9 / TSC1

TSC1tuberous sclerosis 1

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
16 / 39
Rare Variants / Common Variants
53 / 0
EAGLE Score
17.1
Strong Learn More
Aliases
TSC1, LAM,  TSC,  KIAA0243,  MGC86987
Associated Syndromes
-
Chromosome Band
9q34.13
Associated Disorders
ASD
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
Relevance 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.

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

1

High Confidence

See all Category 1 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."

1/1/2020
1
icon
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
icon
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
icon
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
icon
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
icon
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
icon
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
icon
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.
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
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