TSC1
TSC complex subunit 1, the group of TSC complex|Armadillo like helical domain containing
Basic information
Region (hg38): 9:132891347-132946874
Previous symbols: [ "TSC" ]
Links
Phenotypes
GenCC
Source:
- tuberous sclerosis 1 (Definitive), mode of inheritance: AD
- lung lymphangioleiomyomatosis (Strong), mode of inheritance: AD
- tuberous sclerosis 1 (Strong), mode of inheritance: AD
- tuberous sclerosis 1 (Strong), mode of inheritance: AD
- tuberous sclerosis 1 (Strong), mode of inheritance: AD
- tuberous sclerosis complex (Supportive), mode of inheritance: AD
- tuberous sclerosis 1 (Definitive), mode of inheritance: AD
- lymphangioleiomyomatosis (Definitive), mode of inheritance: AD
- tuberous sclerosis (Definitive), mode of inheritance: AD
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Tuberous sclerosis; Lymphangioleiomyomatosis | AD | Cardiovascular; Neurologic; Oncologic; Pulmonary; Renal | Surveillance for and early treatment of tumors, as well as other manifestations affecting multiple organ systems (eg, renal anomalies, pulmonary manifestations, neurologic manifestations, and cardiac manifestations including arrhythmias) may reduce morbidity and mortality; Treatment with mTOR inhibitors may be beneficial related to neoplastic sequelae as well as related seizures; Lymphangiomyomatosis can occur as an isolated disorder or in association with TSC - the only effective therapy in late stage disease is transplant | Cardiovascular; Dental; Dermatologic; Neurologic; Oncologic; Ophthalmologic; Pulmonary; Renal | 14421523; 2823681; 3210031; 2706800; 8534286; 8592324; 8782048; 9132502; 9242607; 9863590; 9924605; 9579160; 11829138; 12112044; 14985384; 15257730; 15955990; 17003820; 17005952; 17304050; 18722871; 18032745; 19332694; 19419980; 21266383; 20301399; 21813552; 22189265; 22161988; 22490766; 23158522; 23743818; 23796861; 23845174; 23846400; 23851963; 23852707; 23909960 |
ClinVar
This is a list of variants' phenotypes submitted to
- Tuberous sclerosis 1 (3324 variants)
- Hereditary cancer-predisposing syndrome (1537 variants)
- not provided (659 variants)
- Tuberous sclerosis syndrome (613 variants)
- Isolated focal cortical dysplasia type II (360 variants)
- not specified (197 variants)
- Malignant tumor of urinary bladder (38 variants)
- Lymphangiomyomatosis;Tuberous sclerosis 1;Isolated focal cortical dysplasia type II (32 variants)
- Lymphangiomyomatosis;Isolated focal cortical dysplasia type II;Tuberous sclerosis 1 (27 variants)
- TSC1-related condition (23 variants)
- Isolated focal cortical dysplasia type II;Lymphangiomyomatosis;Tuberous sclerosis 1 (12 variants)
- Tuberous sclerosis 1;Lymphangiomyomatosis;Isolated focal cortical dysplasia type II (8 variants)
- Ovarian cancer (8 variants)
- Lymphangiomyomatosis (8 variants)
- Isolated focal cortical dysplasia type II;Tuberous sclerosis 1;Lymphangiomyomatosis (8 variants)
- Inborn genetic diseases (6 variants)
- Tuberous sclerosis 1;Isolated focal cortical dysplasia type II;Lymphangiomyomatosis (6 variants)
- Lymphangiomyomatosis;Tuberous sclerosis syndrome (5 variants)
- Autism spectrum disorder (3 variants)
- See cases (2 variants)
- Malignant tumor of breast (2 variants)
- Seizure (2 variants)
- Craniopharyngioma (2 variants)
- Primitive neuroectodermal tumor (1 variants)
- Seizure;Hamartoma;Cardiac rhabdomyoma (1 variants)
- Neuroblastoma (1 variants)
- Focal cortical dysplasia of Taylor type 2B (1 variants)
- Astrocytoma;Kidney angiomyolipoma;Angiofibromas (1 variants)
- Renal insufficiency;Renal cortical cysts;Cortical dysplasia (1 variants)
- Multiple renal cysts;Cortical tubers;Seizure (1 variants)
- Cortical tubers;Adenoma sebaceum (1 variants)
- Acute myeloid leukemia (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the TSC1 gene is commonly pathogenic or not.
In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.
Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.
| Variant type | Pathogenic | Likely pathogenic | VUS | Likely benign | Benign | Sum |
|---|---|---|---|---|---|---|
| synonymous | 23 | 732 | 757 | |||
| missense | 17 | 1464 | 93 | 1590 | ||
| nonsense | 129 | 14 | 147 | |||
| start loss | 0 | |||||
| frameshift | 273 | 23 | 16 | 312 | ||
| inframe indel | 35 | 42 | ||||
| splice donor/acceptor (+/-2bp) | 31 | 37 | 77 | |||
| splice region ? | 3 | 74 | 96 | 11 | 184 | |
| non coding ? | 151 | 316 | 95 | 567 | ||
| Total | 444 | 97 | 1701 | 1145 | 105 |
Highest pathogenic variant AF is 0.0000209
Variants in TSC1
This is a list of pathogenic ClinVar variants found in the TSC1 region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 9-132891390-C-A | Tuberous sclerosis syndrome • Isolated focal cortical dysplasia type II | Uncertain significance (Jun 14, 2016) | ||
| 9-132891409-T-G | Tuberous sclerosis 1 • Isolated focal cortical dysplasia type II | Uncertain significance (Jan 13, 2018) | ||
| 9-132891447-T-G | Isolated focal cortical dysplasia type II • Tuberous sclerosis 1 | Benign (Jan 13, 2018) | ||
| 9-132891472-A-G | Isolated focal cortical dysplasia type II • Tuberous sclerosis 1 | Benign (Jan 13, 2018) | ||
| 9-132891555-C-A | Tuberous sclerosis 1 • Isolated focal cortical dysplasia type II | Conflicting classifications of pathogenicity (Feb 01, 2023) | ||
| 9-132891603-TA-T | Isolated focal cortical dysplasia type II • Tuberous sclerosis syndrome | Likely benign (Jun 14, 2016) | ||
| 9-132891603-T-TA | Tuberous sclerosis syndrome • Isolated focal cortical dysplasia type II | Uncertain significance (Jun 14, 2016) | ||
| 9-132891613-C-T | Isolated focal cortical dysplasia type II • Tuberous sclerosis syndrome | Uncertain significance (Jun 14, 2016) | ||
| 9-132891644-C-A | Tuberous sclerosis syndrome | not provided (-) | ||
| 9-132891697-T-C | Tuberous sclerosis 1 • Isolated focal cortical dysplasia type II | Uncertain significance (Jan 12, 2018) | ||
| 9-132891713-G-A | Tuberous sclerosis 1 • Isolated focal cortical dysplasia type II | Uncertain significance (Apr 27, 2017) | ||
| 9-132891720-C-T | Tuberous sclerosis 1 • Isolated focal cortical dysplasia type II | Uncertain significance (Jan 13, 2018) | ||
| 9-132891743-A-G | Tuberous sclerosis 1 • Isolated focal cortical dysplasia type II | Uncertain significance (Jan 13, 2018) | ||
| 9-132891788-G-A | Isolated focal cortical dysplasia type II • Tuberous sclerosis 1 | Uncertain significance (Jan 13, 2018) | ||
| 9-132891798-C-T | Tuberous sclerosis 1 • Isolated focal cortical dysplasia type II | Benign (Jan 12, 2018) | ||
| 9-132891850-C-A | Isolated focal cortical dysplasia type II • Tuberous sclerosis 1 | Benign (Jan 12, 2018) | ||
| 9-132891879-G-A | Isolated focal cortical dysplasia type II • Tuberous sclerosis 1 | Uncertain significance (Jan 12, 2018) | ||
| 9-132891981-C-T | Isolated focal cortical dysplasia type II • Tuberous sclerosis 1 | Uncertain significance (Jan 12, 2018) | ||
| 9-132891987-G-A | Tuberous sclerosis syndrome • Isolated focal cortical dysplasia type II | Uncertain significance (Jun 14, 2016) | ||
| 9-132891987-G-T | Isolated focal cortical dysplasia type II • Tuberous sclerosis syndrome | Uncertain significance (Jun 14, 2016) | ||
| 9-132892002-C-A | Tuberous sclerosis syndrome • Isolated focal cortical dysplasia type II | Uncertain significance (Jun 14, 2016) | ||
| 9-132892042-T-G | Isolated focal cortical dysplasia type II • Tuberous sclerosis syndrome | Uncertain significance (Jun 14, 2016) | ||
| 9-132892068-G-T | Tuberous sclerosis syndrome • Isolated focal cortical dysplasia type II | Uncertain significance (Jun 14, 2016) | ||
| 9-132892076-C-A | Isolated focal cortical dysplasia type II • Tuberous sclerosis syndrome | Uncertain significance (Jun 14, 2016) | ||
| 9-132892107-C-T | Tuberous sclerosis 1 • Isolated focal cortical dysplasia type II | Uncertain significance (Jan 12, 2018) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| TSC1 | protein_coding | protein_coding | ENST00000298552 | 21 | 53286 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 1.00 | 1.06e-7 | 125740 | 0 | 8 | 125748 | 0.0000318 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 2.32 | 479 | 645 | 0.743 | 0.0000376 | 7638 |
| Missense in Polyphen | 106 | 189.86 | 0.55829 | 2409 | ||
| Synonymous | 0.585 | 240 | 252 | 0.953 | 0.0000155 | 2288 |
| Loss of Function | 6.51 | 2 | 53.3 | 0.0375 | 0.00000281 | 660 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.0000289 | 0.0000289 |
| Ashkenazi Jewish | 0.000199 | 0.000198 |
| East Asian | 0.0000544 | 0.0000544 |
| Finnish | 0.0000462 | 0.0000462 |
| European (Non-Finnish) | 0.0000176 | 0.0000176 |
| Middle Eastern | 0.0000544 | 0.0000544 |
| South Asian | 0.0000327 | 0.0000327 |
| Other | 0.00 | 0.00 |
dbNSFP
Source:
- Function
- FUNCTION: In complex with TSC2, inhibits the nutrient-mediated or growth factor-stimulated phosphorylation of S6K1 and EIF4EBP1 by negatively regulating mTORC1 signaling (PubMed:12271141, PubMed:28215400). Seems not to be required for TSC2 GAP activity towards RHEB (PubMed:15340059). Implicated as a tumor suppressor. Involved in microtubule-mediated protein transport, but this seems to be due to unregulated mTOR signaling (By similarity). Acts as a co-chaperone for HSP90AA1 facilitating HSP90AA1 chaperoning of protein clients such as kinases, TSC2 and glucocorticoid receptor NR3C1 (PubMed:29127155). Increases ATP binding to HSP90AA1 and inhibits HSP90AA1 ATPase activity (PubMed:29127155). Competes with the activating co-chaperone AHSA1 for binding to HSP90AA1, thereby providing a reciprocal regulatory mechanism for chaperoning of client proteins (PubMed:29127155). Recruits TSC2 to HSP90AA1 and stabilizes TSC2 by preventing the interaction between TSC2 and ubiquitin ligase HERC1 (PubMed:16464865, PubMed:29127155). {ECO:0000250|UniProtKB:Q9Z136, ECO:0000269|PubMed:12271141, ECO:0000269|PubMed:15340059, ECO:0000269|PubMed:16464865, ECO:0000269|PubMed:28215400, ECO:0000269|PubMed:29127155}.;
- Disease
- DISEASE: Tuberous sclerosis 1 (TSC1) [MIM:191100]: An autosomal dominant multi-system disorder that affects especially the brain, kidneys, heart, and skin. It is characterized by hamartomas (benign overgrowths predominantly of a cell or tissue type that occurs normally in the organ) and hamartias (developmental abnormalities of tissue combination). Clinical manifestations include epilepsy, learning difficulties, behavioral problems, and skin lesions. Seizures can be intractable and premature death can occur from a variety of disease-associated causes. {ECO:0000269|PubMed:10227394, ECO:0000269|PubMed:10533069, ECO:0000269|PubMed:10570911, ECO:0000269|PubMed:10874311, ECO:0000269|PubMed:11829138, ECO:0000269|PubMed:18830229, ECO:0000269|PubMed:22161988, ECO:0000269|PubMed:9328481}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Lymphangioleiomyomatosis (LAM) [MIM:606690]: Progressive and often fatal lung disease characterized by a diffuse proliferation of abnormal smooth muscle cells in the lungs. It affects almost exclusively young women and can occur as an isolated disorder or in association with tuberous sclerosis complex. {ECO:0000269|PubMed:11829138}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Focal cortical dysplasia 2 (FCORD2) [MIM:607341]: A form of focal cortical dysplasia, a malformation of cortical development that results in medically refractory epilepsy in the pediatric population and in adults. FCORD2 is a severe form, with onset usually in childhood, characterized by disrupted cortical lamination and specific cytological abnormalities. It is classified in 2 subtypes: type IIA characterized by dysmorphic neurons and lack of balloon cells; type IIB with dysmorphic neurons and balloon cells. {ECO:0000269|PubMed:28215400}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
- Pathway
- PI3K-Akt signaling pathway - Homo sapiens (human);mTOR signaling pathway - Homo sapiens (human);Choline metabolism in cancer - Homo sapiens (human);Autophagy - animal - Homo sapiens (human);AMPK signaling pathway - Homo sapiens (human);Thermogenesis - Homo sapiens (human);Longevity regulating pathway - Homo sapiens (human);Phospholipase D signaling pathway - Homo sapiens (human);Cellular senescence - Homo sapiens (human);Insulin signaling pathway - Homo sapiens (human);Human papillomavirus infection - Homo sapiens (human);Leucine Stimulation on Insulin Signaling;AMP-activated Protein Kinase (AMPK) Signaling;Target Of Rapamycin (TOR) Signaling;Integrated Breast Cancer Pathway;Signaling Pathways in Glioblastoma;Nanoparticle triggered autophagic cell death;Polycystic Kidney Disease Pathway;Wnt Signaling Pathway;BDNF-TrkB Signaling;4-hydroxytamoxifen, Dexamethasone, and Retinoic Acids Regulation of p27 Expression;Angiopoietin Like Protein 8 Regulatory Pathway;Focal Adhesion-PI3K-Akt-mTOR-signaling pathway;Pathways in clear cell renal cell carcinoma;PI3K-AKT-mTOR - VitD3 Signalling;PI3K-Akt Signaling Pathway;Insulin Signaling;Signal Transduction;Gene expression (Transcription);mtor signaling pathway;Vesicle-mediated transport;TBC/RABGAPs;Membrane Trafficking;Generic Transcription Pathway;RNA Polymerase II Transcription;Inhibition of TSC complex formation by PKB;Energy dependent regulation of mTOR by LKB1-AMPK;mTOR signalling;insulin Mam;TP53 Regulates Metabolic Genes;Macroautophagy;Cellular responses to external stimuli;Rab regulation of trafficking;Transcriptional Regulation by TP53;mTOR signaling pathway;LKB1 signaling events;insulin
(Consensus)
Recessive Scores
- pRec
- 0.422
Intolerance Scores
- loftool
- 0.00544
- rvis_EVS
- -1.04
- rvis_percentile_EVS
- 7.83
Haploinsufficiency Scores
- pHI
- 0.777
- hipred
- Y
- hipred_score
- 0.794
- ghis
- 0.588
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.801
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Tsc1
- Phenotype
- homeostasis/metabolism phenotype; cellular phenotype; muscle phenotype; endocrine/exocrine gland phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); embryo phenotype; skeleton phenotype; renal/urinary system phenotype; vision/eye phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); neoplasm; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); reproductive system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); respiratory system phenotype; liver/biliary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan);
Zebrafish Information Network
- Gene name
- tsc1a
- Affected structure
- pronephric tubule
- Phenotype tag
- abnormal
- Phenotype quality
- cystic
Gene ontology
- Biological process
- kidney development;neural tube closure;regulation of cell-matrix adhesion;adaptive immune response;rRNA export from nucleus;regulation of translation;potassium ion transport;cell-matrix adhesion;negative regulation of cell population proliferation;adult locomotory behavior;negative regulation of neuron projection development;positive regulation of macroautophagy;negative regulation of macroautophagy;negative regulation of translation;hippocampus development;cerebral cortex development;cell projection organization;negative regulation of TOR signaling;negative regulation of ATPase activity;response to insulin;negative regulation of GTPase activity;myelination;memory T cell differentiation;regulation of phosphoprotein phosphatase activity;negative regulation of cell size;regulation of protein kinase activity;glucose import;negative regulation of insulin receptor signaling pathway;synapse organization;protein stabilization;protein heterooligomerization;regulation of stress fiber assembly;positive regulation of stress fiber assembly;regulation of cell cycle;positive regulation of focal adhesion assembly;cardiac muscle cell differentiation;activation of GTPase activity;cellular response to oxygen-glucose deprivation;regulation of neuron death;negative regulation of oxidative stress-induced neuron death
- Cellular component
- nucleus;cytoplasm;lipid droplet;cytosol;actin filament;plasma membrane;cell cortex;postsynaptic density;membrane;lamellipodium;growth cone;protein-containing complex;TSC1-TSC2 complex;perinuclear region of cytoplasm;chaperone complex
- Molecular function
- protein binding;Hsp70 protein binding;GTPase activating protein binding;ATPase inhibitor activity;protein N-terminus binding;chaperone binding;Hsp90 protein binding