Human Gene Module / Chromosome 9 / TSC1

TSC1tuberous sclerosis 1

Score
S
Syndromic Syndromic
Autism Reports / Total Reports
6 / 19
Rare Variants / Common Variants
33 / 0
Aliases
TSC1, LAM,  TSC,  KIAA0243,  MGC86987
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
9q34.13
Associated Disorders
ASD
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.

Reports related to TSC1 (19 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 ... 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 Highly Cited Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. van Slegtenhorst M , et al. (1998) No -
19 Primary Autism and tuberous sclerosis. Smalley SL (1998) No ASD
Rare Variants   (33)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
N/A N/A - - - - 9813776 Smalley SL (1998)
c.64C>T p.Arg22Trp missense_variant - - - 28215400 Lim JS , et al. (2017)
c.610C>T p.Arg204Cys missense_variant - - - 28215400 Lim JS , et al. (2017)
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.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.658delG p.Val220Serfs frameshift_variant De novo - - 29286531 Tumien B , et al. (2017)
c.201A>G p.(=) synonymous_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.3042C>T p.(=) synonymous_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.2506_2509del p.836_837del inframe_deletion De novo - - 29286531 Tumien B , et al. (2017)
c.2047_2048insTG p.Ala683fs frameshift_variant Unknown - - 31031587 Xiong J , et al. (2019)
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.570_583del p.Glu190fs frameshift_variant Familial Maternal - 31031587 Xiong J , et al. (2019)
c.1342C>T p.Pro448Ser missense_variant Familial Paternal Simplex 23514105 Bahl S , et al. (2013)
c.556G>T p.Ala186Thr missense_variant Familial Maternal Multiplex 23999528 Toma C , et al. (2013)
c.1006C>T p.Arg336Trp missense_variant Familial Paternal Simplex 21624971 Schaaf CP , et al. (2011)
c.1079C>A p.Thr360Asn missense_variant Familial Both parents Simplex 23514105 Bahl S , et al. (2013)
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
S

Syndromic

S

Score Delta: Score remained at S

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."

4/1/2018
1/1/2017
S
icon
S

Score remained at 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

Score remained at 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.
CNVs associated with TSC1(1 CNVs)
9q34.13 9 Deletion-Duplication 18  /  29
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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