TSC1

Chr 9AD

TSC complex subunit 1

Also known as: LAM, TSC

The protein hamartin forms a complex with tuberin to negatively regulate mTORC1 signaling, which controls cell growth, and also functions as a co-chaperone for Hsp90 to prevent protein degradation. Loss-of-function mutations cause tuberous sclerosis complex type 1, focal cortical dysplasia type II, and lymphangioleiomyomatosis through autosomal dominant inheritance. The pathogenic mechanism involves loss of growth regulation leading to formation of hamartomas and other developmental abnormalities.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
LOFmechanismADLOEUF 0.124 OMIM phenotypes
Clinical SummaryTSC1
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Gene-Disease Validity (ClinGen)
tuberous sclerosis · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
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ClinVar Variants
85 unique Pathogenic / Likely Pathogenic· 278 VUS of 700 total submissions
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Clinical Trials
11 active or recruiting trials — potential therapeutic options may be available
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GeneReview available — TSC1
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

LoF intolerant — likely haploinsufficient
LoF Constraint
0.12LOEUF
pLI 1.000
Z-score 6.51
OE 0.04 (0.010.12)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint
2.32Z-score
OE missense 0.74 (0.690.80)
479 obs / 644.9 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.04 (0.010.12)
00.351.4
Missense OE0.74 (0.690.80)
00.61.4
Synonymous OE0.95
01.21.6
LoF obs/exp: 2 / 53.3Missense obs/exp: 479 / 644.9Syn Z: 0.59
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveTSC1-related tuberous sclerosisLOFAD
DN
0.3296th %ile
GOF
0.3887th %ile
LOF
0.74top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · 92% of P/LP variants are LoF · LOEUF 0.12

Literature Evidence

LOFGenetic disorders frequently accompany autism spectrum disorder, such as tuberous sclerosis complex caused by haploinsufficiency of the TSC1 and TSC2 genes.PMID:23250422

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

700 submitted variants in ClinVar

Classification Summary

Pathogenic68
Likely Pathogenic17
VUS278
Likely Benign172
Benign6
Conflicting158
68
Pathogenic
17
Likely Pathogenic
278
VUS
172
Likely Benign
6
Benign
158
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
63
0
5
0
68
Likely Pathogenic
15
0
2
0
17
VUS
3
217
55
3
278
Likely Benign
0
9
22
141
172
Benign
0
0
6
0
6
Conflicting
158
Total8122690144699

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

TSC1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

Lymphoma, Non-HodgkinMultiple MyelomaAdvanced Solid Tumors

Canadian Profiling and Targeted Agent Utilization Trial (CAPTUR)

RECRUITING
NCT03297606Phase PHASE2Canadian Cancer Trials GroupStarted 2018-03-23
OlaparibDasatinibNivolumab plus Ipilimumab
Polycythemia VeraEssential ThrombocythaemiaMyelofibrosis

Prevalence Of Germline Gene Mutations In Patients With Myeloproliferative Neoplasms With Family History

NOT YET RECRUITING
NCT06923670Phase NAFondazione Policlinico Universitario Agostino Gemelli IRCCSStarted 2025-05-21
NGS testingNGS analysis for mutations in genes involved in familial predisposition to hematological malignancies
Epilepsy

Precision Medicine in the Treatment of Epilepsy

RECRUITING
NCT05450822Gitte Moos KnudsenStarted 2022-02-18
LevetiracetamLevetiracetam TabletsLamotrigine tablet
Fallopian Tube Endometrioid AdenocarcinomaFallopian Tube High Grade Serous AdenocarcinomaOvarian Endometrioid Adenocarcinoma

Testing the Addition of Ipatasertib to the Usual Chemotherapy Treatment (Paclitaxel and Carboplatin) for Stage III or IV Epithelial Ovarian Cancer

ACTIVE NOT RECRUITING
NCT05276973Phase PHASE1National Cancer Institute (NCI)Started 2022-09-08
BiopsyCarboplatinIpatasertib
Malignant Solid Neoplasms

Adapting Treatment to the Tumor Molecular Alterations for Patients With Advanced Solid Tumors: MyOwnSpecificTreatment

RECRUITING
NCT02029001Phase PHASE2Centre Leon BerardStarted 2014-03
Nilotinib (400 mg BID)Everolimus (10 mg QD)Sorafenib (400 mg BID)
Advanced LymphomaAdvanced Malignant Solid NeoplasmBladder Carcinoma

Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma (The MATCH Screening Trial)

ACTIVE NOT RECRUITING
NCT02465060Phase PHASE2National Cancer Institute (NCI)Started 2015-08-17
AdavosertibAfatinibAfatinib Dimaleate
Advanced Malignant Solid NeoplasmAnn Arbor Stage III Non-Hodgkin LymphomaAnn Arbor Stage IV Non-Hodgkin Lymphoma

Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial)

ACTIVE NOT RECRUITING
NCT03155620Phase PHASE2National Cancer Institute (NCI)Started 2017-07-31
Biopsy ProcedureBiospecimen CollectionBone Marrow Aspiration and Biopsy
Advanced Hepatocellular CarcinomaMetastatic Hepatocellular CarcinomaStage III Hepatocellular Carcinoma AJCC v8

Testing the Addition of an Anti-cancer Drug, Sapanisertib, to the Usual Chemotherapy Treatment (Cabozantinib) in Metastatic Liver Cell Cancer With a Change in Genes for the Protein β-Catenin, The SAPHIRE Trial

RECRUITING
NCT06811116Phase PHASE1, PHASE2National Cancer Institute (NCI)Started 2025-11-17
Biospecimen CollectionCabozantinib S-malateImaging Procedure
Lymphoma, Non-HodgkinMultiple MyelomaAdvanced Solid Tumors

TAPUR: Testing the Use of Food and Drug Administration (FDA) Approved Drugs That Target a Specific Abnormality in a Tumor Gene in People With Advanced Stage Cancer

RECRUITING
NCT02693535Phase PHASE2American Society of Clinical OncologyStarted 2016-03-14
PalbociclibSunitinibTemsirolimus
Chronic Obstructive Pulmonary Disease Exacerbation

The CATALINA Study

RECRUITING
NCT05008081Wim JanssensStarted 2022-10-25
TumorTumor, SolidMetastasis

Phase 2 Basket Trial of Nab-sirolimus in Patients With Malignant Solid Tumors With Pathogenic Alterations in TSC1/TSC2 Genes (PRECISION 1)

ACTIVE NOT RECRUITING
NCT05103358Phase PHASE2Aadi Bioscience, Inc.Started 2022-02-15
nab-sirolimus
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Role of TSC1 in physiology and diseases.
Mallela K et al.·Mol Cell Biochem
2021
Drosophila yakuba - Tsc1
Lose B et al.·MicroPubl Biol
2021
Drosophila yakuba - Tsc1
Lose B et al.·MicroPubl Biol
2021
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗