TSC1

Summary

TSC1 (TSC complex subunit 1, HGNC:12362) is a protein-coding gene on chromosome 9q34.13, encoding Hamartin (Q92574). Non-catalytic component of the TSC-TBC complex, a multiprotein complex that acts as a negative regulator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolecule biosynthesis to promote cellular bio…. In precision oncology, TSC1 Loss-of-function confers sensitivity to Everolimus in Tuberous Sclerosis (CIViC Level A); 4 further curated variant–drug associations are listed below. It is haploinsufficient (ClinGen: sufficient evidence).

This gene is a tumor suppressor gene that encodes the growth inhibitory protein hamartin. The encoded protein interacts with and stabilizes the GTPase activating protein tuberin. This hamartin-tuberin complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. This protein also functions as a co-chaperone for Hsp90 that inhibits its ATPase activity. This protein functions as a facilitator of Hsp90-mediated folding of kinase and non-kinase clients, including TSC2 and thereby preventing their ubiquitination and proteasomal degradation. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis.

Source: NCBI Gene 7248 — RefSeq curated summary.

At a glance

• Gene–disease (curated): tuberous sclerosis 1 (Definitive, GenCC) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 5,704 total — 628 pathogenic, 100 likely-pathogenic
• Phenotypes (HPO): 119
• Precision-oncology evidence (CIViC): 5 curated variant–drug associations
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 9 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000368

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12362
Approved symbol	TSC1
Name	TSC complex subunit 1
Location	9q34.13
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0243, LAM, hamartin
Ensembl gene	ENSG00000165699
Ensembl biotype	protein_coding
OMIM	605284
Entrez	7248

Gene structure

Transcript identifiers

Ensembl transcripts: 64 — 29 protein_coding, 18 nonsense_mediated_decay, 9 retained_intron, 8 protein_coding_CDS_not_defined

ENST00000298552, ENST00000403810, ENST00000461879, ENST00000475903, ENST00000490179, ENST00000493467, ENST00000642249, ENST00000642261, ENST00000642344, ENST00000642617, ENST00000642627, ENST00000642646, ENST00000642745, ENST00000642811, ENST00000642854, ENST00000643072, ENST00000643275, ENST00000643362, ENST00000643583, ENST00000643625, ENST00000643691, ENST00000643875, ENST00000644097, ENST00000644184, ENST00000644255, ENST00000644319, ENST00000644786, ENST00000644882, ENST00000644997, ENST00000645129, ENST00000645150, ENST00000645346, ENST00000645901, ENST00000645904, ENST00000646391, ENST00000646440, ENST00000646625, ENST00000646788, ENST00000646831, ENST00000647078, ENST00000647262, ENST00000647279, ENST00000647462, ENST00000647506, ENST00000647534, ENST00000714459, ENST00000714460, ENST00000714461, ENST00000714462, ENST00000714463, ENST00000714464, ENST00000714465, ENST00000714466, ENST00000714467, ENST00000714468, ENST00000714491, ENST00000714492, ENST00000714493, ENST00000714494, ENST00000911224, ENST00000911225, ENST00000911226, ENST00000935873, ENST00000935874

RefSeq mRNA: 43 — MANE Select: NM_000368 NM_000368, NM_001162426, NM_001162427, NM_001362177, NM_001406592, NM_001406593, NM_001406594, NM_001406595, NM_001406596, NM_001406597, NM_001406598, NM_001406599, NM_001406600, NM_001406601, NM_001406602, NM_001406603, NM_001406604, NM_001406605, NM_001406606, NM_001406607, NM_001406608, NM_001406609, NM_001406610, NM_001406611, NM_001406612, NM_001406613, NM_001406614, NM_001406615, NM_001406616, NM_001406617, NM_001406618, NM_001406619, NM_001406620, NM_001406621, NM_001406622, NM_001406623, NM_001406624, NM_001406625, NM_001406626, NM_001406627, NM_001406628, NM_001406629, NM_001406630

CCDS: CCDS55350, CCDS6956, CCDS87703

Canonical transcript exons

ENST00000298552 — 23 exons

Exon	Start	End
ENSE00001095630	132904411	132904454
ENSE00003822619	132905581	132906139
ENSE00003829834	132944543	132944616
ENSE00004012966	132935033	132935095
ENSE00004012967	132907301	132907370
ENSE00004012968	132912282	132912457
ENSE00004012969	132923348	132923492
ENSE00004012970	132925587	132925739
ENSE00004012971	132910571	132910692
ENSE00004012972	132927201	132927304
ENSE00004012973	132911002	132911113
ENSE00004012974	132928767	132928952
ENSE00004012975	132906731	132906835
ENSE00004012976	132911453	132911568
ENSE00004012977	132921819	132921973
ENSE00004012979	132921363	132921436
ENSE00004013088	132897423	132897610
ENSE00004013089	132900715	132900837
ENSE00004013091	132901589	132901699
ENSE00004013092	132897184	132897345
ENSE00004013094	132891349	132896754
ENSE00004013095	132902605	132902787
ENSE00004013096	132903651	132903817

Expression profiles

Bgee: expression breadth ubiquitous, 297 present calls, max score 96.00.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.2398 / max 131.3090, expressed in 1804 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
102916	17.7770	1801
102915	0.4569	225
102917	0.0059	3

Top tissues by expression

299 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
substantia nigra pars compacta	UBERON:0001965	96.00	gold quality
gluteal muscle	UBERON:0002000	95.83	gold quality
lateral globus pallidus	UBERON:0002476	95.73	gold quality
CA1 field of hippocampus	UBERON:0003881	95.59	gold quality
substantia nigra pars reticulata	UBERON:0001966	95.48	gold quality
lateral nuclear group of thalamus	UBERON:0002736	94.58	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	94.55	gold quality
inferior olivary complex	UBERON:0002127	94.50	gold quality
superior vestibular nucleus	UBERON:0007227	93.97	gold quality
medulla oblongata	UBERON:0001896	93.72	gold quality
middle temporal gyrus	UBERON:0002771	93.67	gold quality
sural nerve	UBERON:0015488	93.63	gold quality
corpus callosum	UBERON:0002336	93.49	gold quality
parietal lobe	UBERON:0001872	93.38	gold quality
biceps brachii	UBERON:0001507	93.29	gold quality
pons	UBERON:0000988	93.23	gold quality
orbitofrontal cortex	UBERON:0004167	93.22	gold quality
ventral tegmental area	UBERON:0002691	93.18	gold quality
subthalamic nucleus	UBERON:0001906	93.15	gold quality
postcentral gyrus	UBERON:0002581	93.10	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	92.99	gold quality
Brodmann (1909) area 23	UBERON:0013554	92.92	gold quality
Brodmann (1909) area 46	UBERON:0006483	92.88	gold quality
triceps brachii	UBERON:0001509	92.85	gold quality
trigeminal ganglion	UBERON:0001675	92.85	gold quality
cerebellar hemisphere	UBERON:0002245	92.79	gold quality
cerebellar cortex	UBERON:0002129	92.78	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.77	gold quality
renal medulla	UBERON:0000362	92.73	gold quality
left testis	UBERON:0004533	92.64	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.11
E-ENAD-17	no	493.05

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, APEX1, AR, ATF3, CTNNBL1, CUX1, DMTF1, DNMT1, E2F1, E2F3, EGR1, ELF1, EPAS1, ETS1, ETV4, EZH2, FOXI1, FOXO3, GLI1, HAND1, HIF1A, HOXC8, IRF8, JUN, MAZ, MBD2, MSX1, MTA1, MXD1, MYC, PAX2, PAX8, PRDM2, RARA, RARB, RCOR2, RELA, RUNX1, RUNX3, SALL4

miRNA regulators (miRDB)

273 targeting TSC1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• negative regulators of cell division; control of transition from G0/G1 to S phase (PMID:11686512)
• The 352 insA mutation in TSC1 gene is a new causative mutation and the 347A–>C is a rare single nucleotide polymorphism. (PMID:11774213)
• Novel TSC1 and TSC2 mutations in Japanese patients with tuberous sclerosis complex. (PMID:12015165)
• TSC1 and TSC2 mutations in tuberous sclerosis - used DHPLC analysis to facilitate the detection of a mosaic mutation, in the presence of a coexisting constitutional polymorphism. (PMID:12062115)
• hamartin and tuberin function together to inhibit mammalian target of rapamycin (mTOR)-mediated signaling to eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1) (PMID:12271141)
• We conclude that the hamartin/tuberin complex exerted a direct effect on the morphology and adhesive properties of 293 cells through regulation of the level and/or activity of cellular E-cadherin/beta-catenin (PMID:12766909)
• mutated in suberous sclerosis (REVIEW). (PMID:12773159)
• Mutated in tuberous sclerosis. (PMID:12773162)
• mutated in bladder cancer (REVIEW) (PMID:12773163)
• TSC1 is a GAP for rheb and insulin-mediated rheb activation is PI3K dependent. (PMID:12820960)
• TSC1 mutation possibly has a causative role in the initiation or progression of some bladder tumors and this process is possibly related to the functional loss of p27. (PMID:12853839)
• Human TSC1 triggera mammalian cell size reduction. (PMID:12894220)
• data support a model in which phosphorylation of hamartin regulates the function of the hamartin-tuberin complex during the G2/M phase of the cell cycle (PMID:14551205)
• the TSC1.TSC2 complex is regulated by pam and its ortholog highwire (PMID:14559897)
• Haploinsufficiency for TSC1 can contribute to the development of bladder cancer and, if this is so, the LOH of TSC1 observed in >50% of transitional cell carcinomas is biologically significant. (PMID:14633685)
• Western blot analyses confirmed the deregulation of 14-3-3 proteins upon ectopic overexpression of TSC1 and TSC2. (PMID:14680818)
• TSC1 gene, which is responsible for tuberous sclerosis was identified, and all the exons of TSC1 were analyzed by using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) from peripheral blood of 28 patients . (PMID:14756965)
• people with TSC2 mutations were significantly more likely than those with TSC1 mutations to have autistic disorder, a low IQ, and a history of infantile spasms (PMID:14985384)
• Down regulation or loss of tuberin and/or hamartin expression may be permissive to fibrocyte proliferation or promote collagen production leading to fibroepithelial polyp formation. (PMID:15059224)
• tsc1 gene expression is reduced in the majority of subependymal giant cell astrocytomas in tuberous sclerosis complex (PMID:15072102)
• Cortical tuber giant cells in a case of epileptogenic tuberous sclerosis showed predominantly nuclear hamartin, cytosolic tuberin, and hyperphosphorylation of S6. (PMID:15477556)
• A total of 12 mutations were detected in 24 Indian TSC families in TSC genes. (PMID:15595939)
• Five of 6 subependymal giant cell astrocytomas(SEGAs) also showed evidence of biallelic mutation of TSC1 or TSC2, suggesting that SEGAs develop due to complete loss of a functional tuberin-hamartin complex. (PMID:15624760)
• monitored 14 previously uncharacterized and six known phosphorylation events after phorbol ester stimulation in the ERK/p90 ribosomal S6 kinase-signaling targets, TSC1 and TSC2, and a protein kinase C-dependent pathway to TSC2 phosphorylation (PMID:15647351)
• identified three sites of TSC2 phosphorylation and a novel site of TSC1 phosphorylation, and investigated the roles of these sites in regulating the activity of the TSC1-TSC2 complex (PMID:15963462)
• study provides new insights into cellular roles of TSC proteins and promotes discussion on whether separable functions of these proteins might be associated with clinical differences of TSC1- and TSC2-associated disease (PMID:16211238)
• Tuberous sclerosis tumor suppressors TSC1 and TSC2 form a protein complex that integrates and transmits cellular growth factor and stress signals to negatively regulate checkpoint kinase TOR activity, as described in this review. (PMID:16258273)
• Hamartin, the tuberous sclerosis complex 1 gene product, interacts with polo-like kinase 1 in a phosphorylation-dependent manner. (PMID:16339216)
• Denaturing high performance liquid chromatography and DNA sequencing analysis of TSC1 and TSC2 revealed 13 types of mutations (30%). One novel mutation of TSC1 was identified. (PMID:16554133)
• According to Knudson’s two-hit model of tumorigenesis, second-hit mutation and resulting loss of heterozygosity of a tumor suppressor gene (tsc1 and tsc2) is necessary for tumor formation (PMID:16897363)
• Low TSC1 mRNA plays an important role in pleomorphic xanthoastrocytoma. (PMID:16909113)
• documents the incidence, natural history, and outcome of cardiac tumors in patients with TSC in the largest series yet reported and provides a comparison of these features with TSC1 versus TSC2 mutation (PMID:16940165)
• increase in the steady state level of resident TSC1-TSC2 complex is sufficient to reduce muscle mass and cause atrophy (PMID:16996505)
• mTOR-dependent pathways have roles in IFN signaling and 4E-BP1 and TSC1-TSC2 are key components in the generation of IFN-dependent biological responses (PMID:17114181)
• During conditions of cell stress, GADD34 forms a stable complex with tuberous sclerosis complex (TSC) 1/2, causes TSC2 dephosphorylation, and inhibits signaling by mammalian target of the rapamycin (mTOR). (PMID:17273797)
• We conclude that large deletions in TSC1 and TSC2 account for about 0.5 and 6% of mutations seen in TSC patients, respectively, and MLPA is a highly sensitive and accurate detection method, including for mosaicism. (PMID:17287951)
• hamartin binds to NADE to regulate neuronal cell function and loss of this association is likely to contribute to the brain pathology in tuberous sclerosis complex (PMID:17355907)
• loss of hamartin results in abnormal neurite elongation through Rho inactivation in NGF-treated PC12h cells, which may be associated with the neurological manifestations of Tuberous sclerosis complex. (PMID:17376623)
• The constellation of autopsy findings suggested a diagnosis of TSC, for which there are gene defects that can be identified in surviving family members. (PMID:17378684)
• In mice engineered for cortical neuron loss of Tsc1, the brain model implicates an important function of Tsc1/Tsc2 in neuronal development. (PMID:17522300)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tsc1a	ENSDARG00000026048
danio_rerio	tsc1b	ENSDARG00000057918
mus_musculus	Tsc1	ENSMUSG00000026812
rattus_norvegicus	Tsc1	ENSRNOG00000011470
drosophila_melanogaster	Tsc1	FBGN0026317

Protein

Protein identifiers

Hamartin — Q92574 (reviewed: Q92574)

Alternative names: Tuberous sclerosis 1 protein

All UniProt accessions (30): A0A2R8Y419, A0A2R8Y5F8, A0A2R8Y5J1, A0A2R8Y5M3, A0A2R8Y5N2, A0A2R8Y5Q4, A0A2R8Y5S3, A0A2R8Y5U8, A0A2R8Y6N1, A0A2R8Y6S1, A0A2R8Y6S8, A0A2R8Y6T5, A0A2R8Y6W1, A0A2R8Y756, A0A2R8Y7E9, A0A2R8YD74, A0A2R8YEH9, A0A2R8YFV7, A0A2R8YGX7, A0AAQ5BHZ3, A0AAQ5BHZ5, A0AAQ5BI42, A0AAQ5BI43, A0AAQ5BI60, A0AAQ5BI63, A0AAQ5BI64, Q92574, Q59IT9, Q86WV8, X5D9D2

UniProt curated annotations — full annotation on UniProt →

Function. Non-catalytic component of the TSC-TBC complex, a multiprotein complex that acts as a negative regulator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolecule biosynthesis to promote cellular biomass generation and growth. The TSC-TBC complex acts as a GTPase-activating protein (GAP) for the small GTPase RHEB, a direct activator of the protein kinase activity of mTORC1. In absence of nutrients, the TSC-TBC complex inhibits mTORC1, thereby preventing phosphorylation of ribosomal protein S6 kinase (RPS6KB1 and RPS6KB2) and EIF4EBP1 (4E-BP1) by the mTORC1 signaling. The TSC-TBC complex is inactivated in response to nutrients, relieving inhibition of mTORC1. Within the TSC-TBC complex, TSC1 stabilizes TSC2 and prevents TSC2 self-aggregation. Acts as a tumor suppressor. Involved in microtubule-mediated protein transport via its ability to regulate mTORC1 signaling. Also acts as a co-chaperone for HSP90AA1 facilitating HSP90AA1 chaperoning of protein clients such as kinases, TSC2 and glucocorticoid receptor NR3C1. Increases ATP binding to HSP90AA1 and inhibits HSP90AA1 ATPase activity. Competes with the activating co-chaperone AHSA1 for binding to HSP90AA1, thereby providing a reciprocal regulatory mechanism for chaperoning of client proteins. Recruits TSC2 to HSP90AA1 and stabilizes TSC2 by preventing the interaction between TSC2 and ubiquitin ligase HERC1.

Subunit / interactions. Component of the TSC-TBC complex (also named Rhebulator complex), composed of 2 molecules of TSC1, 2 molecules of TSC2 and 1 molecule of TBC1D7. Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones STIP1/HOP, CDC37, PPP5C, PTGES3/p23, TSC1 and client protein TSC2. Forms a complex composed of chaperones HSP90 and HSP70, co-chaperones CDC37, PPP5C, TSC1 and client protein TSC2, CDK4, AKT, RAF1 and NR3C1; this complex does not contain co-chaperones STIP1/HOP and PTGES3/p23. Forms a complex containing HSP90AA1, TSC1 and TSC2; TSC1 is required to recruit TCS2 to the complex. Interacts (via C-terminus) with the closed form of HSP90AA1 (via the middle domain and TPR repeat-binding motif). Interacts with DOCK7. Interacts with FBXW5. Interacts with WDR45B. Interacts with RPAP3 and URI1.

Subcellular location. Lysosome membrane. Cytoplasm. Cytosol.

Tissue specificity. Highly expressed in skeletal muscle, followed by heart, brain, placenta, pancreas, lung, liver and kidney. Also expressed in embryonic kidney cells.

Post-translational modifications. Phosphorylation at Ser-505 does not affect interaction with TSC2. ‘Lys-63’-linked ubiquitinated at Lys-30 by PELI1; the ubiquitination promotes TSC1/TSC2 complex stability.

Disease relevance. 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. The disease is caused by variants affecting the gene represented in this entry. 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. The disease is caused by variants affecting the gene represented in this entry. 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. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The C-terminal putative coiled-coil domain is necessary for interaction with TSC2.

Isoforms (2)

UniProt ID	Names	Canonical?
Q92574-1	1	yes
Q92574-2	2

RefSeq proteins (43): NP_000359, NP_001155898, NP_001155899, NP_001349106, NP_001393521, NP_001393522, NP_001393523, NP_001393524, NP_001393525, NP_001393526, NP_001393527, NP_001393528, NP_001393529, NP_001393530, NP_001393531, NP_001393532, NP_001393533, NP_001393534, NP_001393535, NP_001393536, NP_001393537, NP_001393538, NP_001393539, NP_001393540, NP_001393541, NP_001393542, NP_001393543, NP_001393544, NP_001393545, NP_001393546, NP_001393547, NP_001393548, NP_001393549, NP_001393550, NP_001393551, NP_001393552, NP_001393553, NP_001393554, NP_001393555, NP_001393556, NP_001393557, NP_001393558, NP_001393559 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007483	Hamartin	Family

Pfam: PF04388

UniProt features (118 total): sequence variant 56, helix 30, mutagenesis site 8, modified residue 6, compositionally biased region 5, region of interest 4, turn 4, chain 1, strand 1, cross-link 1, splice variant 1, coiled-coil region 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
4Z6Y	X-RAY DIFFRACTION	2.81
9CE3	ELECTRON MICROSCOPY	2.9
5EJC	X-RAY DIFFRACTION	3.1
9C9I	X-RAY DIFFRACTION	3.18
7DL2	ELECTRON MICROSCOPY	4.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92574-F1	63.55	0.26

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (7): 487, 505, 511, 521, 598, 1100, 30

Mutagenesis-validated functional residues (8):

Position	Phenotype
30	severe reduction of peli1-induced ubiquitination.
632	moderate reduction of peli1-induced ubiquitination.
941	abolished interaction with tbc1d7; when associated with 965-a–a-969.
954–962	reduced interaction with tbc1d7 without affecting interaction with tsc2.
954	abolished interaction with tbc1d7.
958	abolished interaction with tbc1d7.
962	abolished interaction with tbc1d7.
965–969	slightly reduced interaction with tbc1d7 without affecting interaction with tsc2.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-1632852	Macroautophagy
R-HSA-165181	Inhibition of TSC complex formation by AKT (PKB)
R-HSA-380972	Energy dependent regulation of mTOR by LKB1-AMPK
R-HSA-5628897	TP53 Regulates Metabolic Genes
R-HSA-8854214	TBC/RABGAPs

MSigDB gene sets: 758 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_CARBOHYDRATE_TRANSPORT, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_COGNITION, GOBP_BEHAVIOR, GGGNRMNNYCAT_UNKNOWN, GOCC_VACUOLAR_MEMBRANE, GOBP_T_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_ADULT_BEHAVIOR

GO Biological Process (35): kidney development (GO:0001822), neural tube closure (GO:0001843), regulation of cell-matrix adhesion (GO:0001952), adaptive immune response (GO:0002250), potassium ion transport (GO:0006813), cell-matrix adhesion (GO:0007160), cell population proliferation (GO:0008283), negative regulation of cell population proliferation (GO:0008285), associative learning (GO:0008306), adult locomotory behavior (GO:0008344), cellular response to starvation (GO:0009267), negative regulation of macroautophagy (GO:0016242), hippocampus development (GO:0021766), cerebral cortex development (GO:0021987), cell projection organization (GO:0030030), negative regulation of TOR signaling (GO:0032007), negative regulation of ATP-dependent activity (GO:0032780), response to insulin (GO:0032868), cellular response to decreased oxygen levels (GO:0036294), myelination (GO:0042552), memory T cell differentiation (GO:0043379), negative regulation of cell size (GO:0045792), obsolete D-glucose import (GO:0046323), synapse organization (GO:0050808), protein stabilization (GO:0050821), regulation of stress fiber assembly (GO:0051492), regulation of cell cycle (GO:0051726), positive regulation of focal adhesion assembly (GO:0051894), cardiac muscle cell differentiation (GO:0055007), activation of GTPase activity (GO:0090630), negative regulation of TORC1 signaling (GO:1904262), protein folding (GO:0006457), nervous system development (GO:0007399), TORC1 signaling (GO:0038202), positive regulation of TORC1 signaling (GO:1904263)

GO Molecular Function (6): Hsp70 protein binding (GO:0030544), ATPase inhibitor activity (GO:0042030), protein folding chaperone (GO:0044183), protein-folding chaperone binding (GO:0051087), Hsp90 protein binding (GO:0051879), protein binding (GO:0005515)

GO Cellular Component (18): nucleus (GO:0005634), cytoplasm (GO:0005737), lysosomal membrane (GO:0005765), lipid droplet (GO:0005811), cytosol (GO:0005829), plasma membrane (GO:0005886), cell cortex (GO:0005938), postsynaptic density (GO:0014069), membrane (GO:0016020), lamellipodium (GO:0030027), protein-containing complex (GO:0032991), TSC1-TSC2 complex (GO:0033596), ciliary transition zone (GO:0035869), ciliary basal body (GO:0036064), perinuclear region of cytoplasm (GO:0048471), protein folding chaperone complex (GO:0101031), lysosome (GO:0005764), actin filament (GO:0005884)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
MTOR signalling	2
Autophagy	1
Transcriptional Regulation by TP53	1
Rab regulation of trafficking	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
cytoplasm	3
pallium development	2
anatomical structure development	2
ATP-dependent activity	2
heat shock protein binding	2
cell periphery	2
cilium	2
animal organ development	1
renal system development	1
primary neural tube formation	1
tube closure	1
cell-matrix adhesion	1
regulation of cell-substrate adhesion	1
immune response	1
metal ion transport	1
cell-substrate adhesion	1
cellular process	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
learning	1
locomotory behavior	1
adult behavior	1
cellular response to nutrient levels	1
cellular response to stress	1
response to starvation	1
negative regulation of autophagy	1
macroautophagy	1
regulation of macroautophagy	1
limbic system development	1
cellular component organization	1
TOR signaling	1
regulation of TOR signaling	1
negative regulation of intracellular signal transduction	1
regulation of ATP-dependent activity	1
negative regulation of molecular function	1
response to peptide hormone	1
response to decreased oxygen levels	1
cellular response to oxygen levels	1

Protein interactions and networks

STRING

4851 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TSC1	TSC2	P49815	999
TSC1	TBC1D7	Q9P0N9	997
TSC1	RHEB	Q15382	977
TSC1	USP6	P35125	966
TSC1	MTOR	P42345	915
TSC1	RASA1	P20936	913
TSC1	RPS6KB1	P23443	893
TSC1	RPS6KB2	Q9UBS0	858
TSC1	RPS6	P08227	824
TSC1	RPTOR	Q8N122	817
TSC1	EIF4EBP1	Q13541	799
TSC1	PTEN	P60484	785
TSC1	MLST8	Q9BVC4	777
TSC1	PKD1	P98161	776
TSC1	EIF4E	P06730	741

IntAct

212 interactions, top by confidence:

A	B	Type	Score
TSC2	TSC1	psi-mi:“MI:0915”(physical association)	0.930
TSC1	TSC2	psi-mi:“MI:0915”(physical association)	0.930
TSC1	TSC2	psi-mi:“MI:0403”(colocalization)	0.930
YWHAH	ABLIM1	psi-mi:“MI:0914”(association)	0.800
BECN1	ZWINT	psi-mi:“MI:0914”(association)	0.750
TBC1D7	TSC1	psi-mi:“MI:0915”(physical association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
TSC1	FTH1	psi-mi:“MI:0915”(physical association)	0.630
FTH1	TSC1	psi-mi:“MI:0915”(physical association)	0.630
RNF26	TSC1	psi-mi:“MI:0915”(physical association)	0.620
TSC1	RNF26	psi-mi:“MI:0915”(physical association)	0.620
TSC1	RNF26	psi-mi:“MI:0403”(colocalization)	0.620
RNF26	TSC1	psi-mi:“MI:2364”(proximity)	0.620
IKBKB	TSC1	psi-mi:“MI:0915”(physical association)	0.610
TSC1	IKBKB	psi-mi:“MI:0407”(direct interaction)	0.610
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610

BioGRID (382): TSC2 (Affinity Capture-Western), TSC1 (Affinity Capture-Western), TSC1 (Affinity Capture-RNA), TSC1 (Affinity Capture-RNA), TSC2 (Affinity Capture-Western), DAPK1 (Affinity Capture-Western), TSC1 (Affinity Capture-Western), TSC1 (Affinity Capture-Western), TSC1 (Affinity Capture-MS), TSC1 (Affinity Capture-MS), TSC1 (Two-hybrid), TSC1 (Two-hybrid), TSC1 (Two-hybrid), TSC1 (Two-hybrid), TSC1 (Two-hybrid)

ESM2 similar proteins: A0A7P0TBJ1, A0A804C8T0, A2BE76, A2RRV3, A4IG66, A4IIE8, D4A4K3, O75182, P57095, P97578, Q02225, Q08AY9, Q09YG9, Q09YK4, Q1JPG0, Q28C41, Q2IBF8, Q2QL82, Q2QLF8, Q2QLG9, Q4QQM5, Q503U3, Q5BLE2, Q5M836, Q5XJS0, Q62141, Q62671, Q68EF0, Q6DFB7, Q6GR21, Q6NRB7, Q6P7D5, Q6PCG6, Q7L4E1, Q86YS3, Q8BG30, Q8BHS8, Q8BK03, Q8BQP8, Q8NAN2

Diamond homologs: Q92574, Q9EP53, Q9Z136

SIGNOR signaling

25 interactions.

A	Effect	B	Mechanism
CDK1	unknown	TSC1	phosphorylation
CDK1	down-regulates	TSC1	phosphorylation
PRKAA2	up-regulates	TSC1	phosphorylation
MAPK1	down-regulates	TSC1	phosphorylation
IKBKB	down-regulates	TSC1	phosphorylation
TSC1	“down-regulates activity”	RHEB	binding
AMPK	up-regulates	TSC1	phosphorylation
CyclinB/CDK1	down-regulates	TSC1	phosphorylation
TSC1	“form complex”	TSC	binding
ERK1/2	down-regulates	TSC1	phosphorylation
PLK1	“down-regulates quantity by destabilization”	TSC1	phosphorylation
TSC2	“up-regulates activity”	TSC1	binding
TSC1	“down-regulates activity”	MTOR
FOXO3	“up-regulates quantity”	TSC1	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 170 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of BAD and translocation to mitochondria	7	45.2×	2e-08
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	39.9×	5e-08
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	34.2×	1e-06
Activation of BH3-only proteins	7	29.4×	3e-07
Intrinsic Pathway for Apoptosis	7	17.4×	9e-06
FOXO-mediated transcription	6	17.1×	6e-05
RHO GTPases activate PKNs	6	16.1×	8e-05
Translocation of SLC2A4 (GLUT4) to the plasma membrane	9	11.8×	6e-06

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	6	14.7×	2e-03
positive regulation of gene expression	15	3.9×	3e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 9 cancer types — BLCA, BRCA, COADREAD, HCC, LUAD, RCC, SKCM, STAD, UTUC.

Clinical variants and AI predictions

ClinVar

5704 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	628
Likely pathogenic	100
Uncertain significance	2271
Likely benign	1135
Benign	149

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1013340	NM_000368.5(TSC1):c.903dup (p.Asn302fs)	Pathogenic
1064009	NC_000009.11:g.(?135777972)(135782777_?)del	Pathogenic
1068682	NM_000368.5(TSC1):c.2547del (p.Asn849fs)	Pathogenic
1068699	NM_000368.5(TSC1):c.398dup (p.Val135fs)	Pathogenic
1069083	NM_000368.5(TSC1):c.2130dup (p.Gln711fs)	Pathogenic
1069326	NM_000368.5(TSC1):c.1201del (p.Cys401fs)	Pathogenic
1069584	NM_000368.5(TSC1):c.561_562dup (p.Phe188fs)	Pathogenic
1069661	NM_000368.5(TSC1):c.1797del (p.Gln600fs)	Pathogenic
1070472	NM_000368.5(TSC1):c.343del (p.Ser115fs)	Pathogenic
1071239	NM_000368.5(TSC1):c.344del (p.Ser115fs)	Pathogenic
1071252	NM_000368.5(TSC1):c.913+1G>T	Pathogenic
1071660	NM_000368.5(TSC1):c.1873_1876dup (p.Glu626fs)	Pathogenic
1071787	NM_000368.5(TSC1):c.526dup (p.Tyr176fs)	Pathogenic
1071872	NM_000368.5(TSC1):c.397_406del (p.Gly132_Val133insTer)	Pathogenic
1072063	NM_000368.5(TSC1):c.393_405del (p.Thr131_Gly132insTer)	Pathogenic
1072658	NM_000368.5(TSC1):c.2599C>T (p.Gln867Ter)	Pathogenic
1072813	NM_000368.5(TSC1):c.17del (p.Asn6fs)	Pathogenic
1073148	NM_000368.5(TSC1):c.2065dup (p.Arg689fs)	Pathogenic
1073268	NM_000368.5(TSC1):c.1898del (p.Gly633fs)	Pathogenic
1073328	NM_000368.5(TSC1):c.2771_2772insTTTTTATTTTTTATTTTTTTTTTTTTTATTTTTTTTTTAAAGGTAACATTCATCAGTAGCGCAGGTTGTTTTTGTATTGGGGGGTAAATCCTCAAGTCAAGCTCGACAGAANNNNNNNNNNTCTCGCTCTCGTGTCCTCGGTAGACGCCGTGTTGGGCCTCCCACAGTGCTGGGATTACTGGCGTGCGCCAGCGCGCCCGGCCGAAAGACCACCTTCTTTT (p.Leu924delinsPhePheTyrPheLeuPhePhePhePheLeuPhePhePheTer)	Pathogenic
1073516	NM_000368.5(TSC1):c.945dup (p.Arg316fs)	Pathogenic
1073564	NM_000368.5(TSC1):c.181dup (p.Leu61fs)	Pathogenic
1074020	NM_000368.5(TSC1):c.1285_1298del (p.Arg429fs)	Pathogenic
1074231	NM_000368.5(TSC1):c.181del (p.Ile60_Leu61insTer)	Pathogenic
1075152	NM_000368.5(TSC1):c.2141del (p.Leu714fs)	Pathogenic
1075215	NC_000009.11:g.(?135771622)(135820530_?)del	Pathogenic
1075216	NC_000009.11:g.(?135782098)(135796843_?)del	Pathogenic
1076275	NM_000368.5(TSC1):c.1027C>T (p.Gln343Ter)	Pathogenic
1076403	NM_000368.5(TSC1):c.1450A>T (p.Arg484Ter)	Pathogenic
1076667	NM_000368.5(TSC1):c.2212_2213dup (p.Asp738fs)	Pathogenic

SpliceAI

3995 predictions. Top by Δscore:

Variant	Effect	Δscore
9:132897441:T:TA	donor_gain	1.0000
9:132897606:ACTTC:A	acceptor_gain	1.0000
9:132897607:CTTC:C	acceptor_gain	1.0000
9:132897607:CTTCC:C	acceptor_gain	1.0000
9:132897608:TTC:T	acceptor_gain	1.0000
9:132897608:TTCCT:T	acceptor_gain	1.0000
9:132897609:TC:T	acceptor_gain	1.0000
9:132897610:CC:C	acceptor_gain	1.0000
9:132897610:CCTG:C	acceptor_gain	1.0000
9:132897610:CCTGA:C	acceptor_loss	1.0000
9:132897611:C:CC	acceptor_gain	1.0000
9:132897611:C:T	acceptor_gain	1.0000
9:132897611:CTGAA:C	acceptor_loss	1.0000
9:132900710:CATA:C	donor_loss	1.0000
9:132900711:ATACC:A	donor_loss	1.0000
9:132900712:TAC:T	donor_loss	1.0000
9:132900713:ACCTT:A	donor_loss	1.0000
9:132900714:C:CT	donor_loss	1.0000
9:132900833:GAGAG:G	acceptor_gain	1.0000
9:132900834:AGAG:A	acceptor_gain	1.0000
9:132900835:GAG:G	acceptor_gain	1.0000
9:132900836:AG:A	acceptor_gain	1.0000
9:132900838:C:CC	acceptor_gain	1.0000
9:132901695:TTCGT:T	acceptor_gain	1.0000
9:132901696:TCGT:T	acceptor_gain	1.0000
9:132901697:CGT:C	acceptor_gain	1.0000
9:132901697:CGTC:C	acceptor_gain	1.0000
9:132901699:TC:T	acceptor_loss	1.0000
9:132901700:C:CC	acceptor_gain	1.0000
9:132901705:C:CT	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000064456 (9:132913848 T>G), RS1000121122 (9:132927452 TTAATAA>T,TTAA), RS1000272966 (9:132939890 G>A), RS1000280320 (9:132934131 TA>T), RS1000311700 (9:132907949 T>C), RS1000362720 (9:132921533 G>A), RS1000395877 (9:132933771 G>A), RS1000466941 (9:132914804 G>A,C), RS1000576420 (9:132913752 GGAGGC>G), RS1000592384 (9:132909888 T>C), RS1000633119 (9:132913563 G>A), RS1000662233 (9:132908143 G>A), RS1000747725 (9:132917038 G>A), RS1000798376 (9:132916707 A>G), RS1000832571 (9:132936188 C>G,T)

Disease associations

OMIM: gene MIM:605284 | disease phenotypes: MIM:191100, MIM:606690, MIM:607341, MIM:109800, MIM:167000, MIM:148300, MIM:601626

GenCC curated gene-disease

Disease	Classification	Inheritance
tuberous sclerosis 1	Definitive	Autosomal dominant
lung lymphangioleiomyomatosis	Strong	Autosomal dominant
tuberous sclerosis complex	Supportive	Autosomal dominant

Mondo (26): tuberous sclerosis 1 (MONDO:0008612), hereditary neoplastic syndrome (MONDO:0015356), tuberous sclerosis (MONDO:0001734), lymphangioleiomyomatosis (MONDO:0011705), isolated focal cortical dysplasia type II (MONDO:0011818), urinary bladder cancer (MONDO:0001187), ovarian cancer (MONDO:0008170), epilepsy (MONDO:0005027), keratoconus (MONDO:0015486), lung lymphangioleiomyomatosis (MONDO:0006277), breast cancer (MONDO:0007254), craniopharyngioma (MONDO:0018907), autism spectrum disorder (MONDO:0005258), primitive neuroectodermal tumor (MONDO:0005462), cleft palate (MONDO:0016064)

Orphanet (15): Inherited cancer-predisposing syndrome (Orphanet:140162), Tuberous sclerosis complex (Orphanet:805), Isolated focal cortical dysplasia type II (Orphanet:268994), Lymphangioleiomyomatosis (Orphanet:538), Rare ovarian cancer (Orphanet:213500), Craniopharyngioma (Orphanet:54595), Cleft palate (Orphanet:2014), Cerebral cortical dysplasia (Orphanet:268950), Neuroblastoma (Orphanet:635), Acute myeloid leukemia (Orphanet:519), NON RARE IN EUROPE: Bladder cancer (Orphanet:157980), OBSOLETE: Keratoconus (Orphanet:156071), NON RARE IN EUROPE: Isolated keratoconus (Orphanet:2335), NON RARE IN EUROPE: Autism (Orphanet:106), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

119 total (30 of 119 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000008	Abnormal morphology of female internal genitalia
HP:0000077	Abnormality of the kidney
HP:0000083	Renal insufficiency
HP:0000107	Renal cyst
HP:0000113	Polycystic kidney dysplasia
HP:0000169	Gingival fibromatosis
HP:0000238	Hydrocephalus
HP:0000648	Optic atrophy
HP:0000708	Atypical behavior
HP:0000716	Depression
HP:0000717	Autism
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior
HP:0000739	Anxiety
HP:0000752	Hyperactivity
HP:0000790	Hematuria
HP:0000821	Hypothyroidism
HP:0000822	Hypertension
HP:0000826	Precocious puberty
HP:0000957	Cafe-au-lait spot
HP:0001000	Abnormality of skin pigmentation
HP:0001004	Lymphedema
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001269	Hemiparesis
HP:0001328	Specific learning disability
HP:0001407	Hepatic cysts
HP:0001442	Typified by somatic mosaicism
HP:0001482	Subcutaneous nodule

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST000322_7	Psoriasis	6.000000e-06
GCST002078_30	Migraine without aura	3.000000e-10

MeSH disease descriptors (19)

Descriptor	Name	Tree numbers
D001254	Astrocytoma	C04.557.465.625.600.380.080; C04.557.470.670.380.080; C04.557.580.625.600.380.080
D002972	Cleft Palate	C05.500.460.185; C05.660.207.540.460.185; C07.320.440.185; C07.465.525.185; C07.650.500.460.185; C07.650.525.185; C16.131.621.207.540.460.185; C16.131.850.500.460.185; C16.131.850.525.185
D003397	Craniopharyngioma	C04.557.465.625.200; C04.557.580.625.200
D004827	Epilepsy	C10.228.140.490
D006222	Hamartoma	C04.445
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D007640	Keratoconus	C11.204.627
D015470	Leukemia, Myeloid, Acute	C04.557.337.539.275; C15.378.508.539.275
D018192	Lymphangioleiomyomatosis	C04.557.375.460.465; C04.557.450.692.500; C15.604.515.562.465; C20.683.515.710.465
D054220	Malformations of Cortical Development	C10.500.507; C16.131.666.507
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
D009447	Neuroblastoma	C04.557.465.625.600.590.650.550; C04.557.470.670.590.650.550; C04.557.580.625.600.590.650.550
D017599	Neuroectodermal Tumors	C04.557.465.625; C04.557.580.625
D010051	Ovarian Neoplasms	C04.588.322.455; C12.050.351.500.056.630.705; C12.050.351.937.418.685; C12.100.250.056.630.705; C12.900.418.685; C19.344.410; C19.391.630.705
D051437	Renal Insufficiency	C12.050.351.968.419.780; C12.200.777.419.780; C12.950.419.780
D014402	Tuberous Sclerosis	C04.445.810; C04.651.800; C04.700.700; C10.500.507.400.750; C10.562.850; C10.574.500.865; C16.131.666.507.400.750; C16.320.400.880; C16.320.700.700
C537067	Focal cortical dysplasia of Taylor (supp.)
C565346	Tuberous Sclerosis 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

Clinical evidence (CIViC)

Drug × variant × indication: 5 predictive associations from 6 curated evidence items; also 2 predisposing.

Variant	Therapy	Indication	Effect	Level	CIViC
TSC1 Loss-of-function	Everolimus	Tuberous Sclerosis	Sensitivity/Response	CIViC A	EID7280
TSC1 Loss-of-function	MTOR Inhibitor	Renal Cell Carcinoma	Sensitivity/Response	CIViC B	EID5837 +1
TSC1 Frameshift Truncation	Everolimus	Invasive Bladder Transitional Cell Carcinoma	Sensitivity/Response	CIViC B	EID320
TSC1 Loss-of-function	Everolimus	Bladder Carcinoma	Sensitivity/Response	CIViC B	EID155
TSC1 Frameshift Truncation	Sirolimus	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC D	EID154

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs7862221	Toxicity	3	aspirin	Aspirin-induced asthma;Asthma

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs7862221	TSC1	3	3.00	1	aspirin

CTD chemical–gene interactions

48 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression, affects cotreatment	3
sodium arsenite	increases abundance, increases expression, affects cotreatment	2
Cisplatin	affects expression, decreases expression	2
GSK-J4	increases expression	1
FR900359	decreases phosphorylation	1
moringin	affects cotreatment, increases expression	1
TAK-243	decreases sumoylation	1
naringenin	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment	1
trichostatin A	decreases reaction, affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	increases expression	1
butyraldehyde	decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
16-hydroxycleroda-3,13(14)-dien-15,16-olide	increases expression	1
CGP 52608	affects binding, increases reaction	1
calcium fructoborate	affects expression	1
STA 9090	decreases expression	1
antroquinonol	increases reaction, affects binding	1
Temozolomide	decreases expression	1
Decitabine	affects expression	1
Glyphosate	increases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Arbutin	increases expression	1
Arsenic	increases expression, affects cotreatment, increases abundance	1
Atrazine	decreases expression	1
Azacitidine	affects expression, affects methylation	1

Cellosaurus cell lines

32 cell lines: 17 cancer cell line, 9 transformed cell line, 3 embryonic stem cell, 2 induced pluripotent stem cell, 1 finite cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_0036	RT-4	Cancer cell line	Male
CVCL_2715	RT4/31	Cancer cell line	Male
CVCL_5L56	GM06146	Transformed cell line	Male
CVCL_5L58	GM06149	Finite cell line	Male
CVCL_5L63	GM07417	Transformed cell line	Female
CVCL_5L64	GM07418	Transformed cell line	Female
CVCL_5L65	GM07419	Transformed cell line	Male
CVCL_5L66	GM07420	Transformed cell line	Male
CVCL_5L67	GM07421	Transformed cell line	Female
CVCL_8228	HCV-29	Cancer cell line	Male

Clinical trials (associated diseases)

157 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00989742	PHASE4	COMPLETED	Doxycycline In Lymphangioleiomyomatosis (LAM)
NCT05044819	PHASE4	ACTIVE_NOT_RECRUITING	Assessment of Potential for Chronic Liver Injury in Participants Treated With Epidiolex (Cannabidiol) Oral Solution
NCT00414648	PHASE3	COMPLETED	Efficacy and Safety of Sirolimus in LAM
NCT00790400	PHASE3	COMPLETED	Efficacy and Safety of RAD001 in Patients Aged 18 and Over With Angiomyolipoma Associated With Either Tuberous Sclerosis Complex (TSC) or Sporadic Lymphangioleiomyomatosis (LAM)
NCT03150914	PHASE3	ACTIVE_NOT_RECRUITING	Multicenter Interventional Lymphangioleiomyomatosis (LAM) Early Disease Trial
NCT00789828	PHASE3	COMPLETED	Efficacy and Safety of Everolimus (RAD001) in Patients of All Ages With Subependymal Giant Cell Astrocytoma Associated With Tuberous Sclerosis Complex (TSC)(EXIST-1)
NCT02544750	PHASE3	COMPLETED	An Open-label Extension Trial of Cannabidiol (GWP42003-P, CBD) for Seizures in Tuberous Sclerosis Complex (GWPCARE6)
NCT02544763	PHASE3	COMPLETED	A Randomized Controlled Trial of Cannabidiol (GWP42003-P, CBD) for Seizures in Tuberous Sclerosis Complex (GWPCARE6)
NCT02634931	PHASE3	COMPLETED	Long-term Trial of Topical Sirolimus to Angiofibroma in Patient With Tuberous Sclerosis Complex
NCT02635789	PHASE3	COMPLETED	Phase III Trial of Topical Formulation of Sirolimus to Skin Lesions in Patients With Tuberous Sclerosis Complex (TSC)
NCT02962414	PHASE3	ACTIVE_NOT_RECRUITING	Roll-over Study to Collect and Assess Long-term Safety of Everolimus in Patients With TSC and Refractory Seizures Who Have Completed the EXIST-3 Study [CRAD001M2304] and Who Are Benefitting From Continued Treatment
NCT05323734	PHASE3	COMPLETED	Adjunctive GNX Treatment Compared With Placebo in Children and Adults With TSC-related Epilepsy
NCT05495425	PHASE3	COMPLETED	Clinical Study of NPC-12Y Gel in Patients With Skin Lesions Associated With TSC
NCT05534672	PHASE3	RECRUITING	Placebo Controlled Study to Assess the Efficacy and Safety of Rapamycin in Drug Resistant Epilepsy Associated With Tuberous Sclerosis Complex
NCT05604170	PHASE3	TERMINATED	Open-label Study of Adjunctive GNX Treatment in Children and Adults With TSC-related Epilepsy
NCT07403266	PHASE3	RECRUITING	Treatment With Full-spectrum Cannabis Extract of Refractory Epilepsy Associated With Tuberous Sclerosis Complex (TSC)
NCT02201212	PHASE2	COMPLETED	Everolimus for Cancer With TSC1 or TSC2 Mutation
NCT05103358	PHASE2	ACTIVE_NOT_RECRUITING	Phase 2 Basket Trial of Nab-sirolimus in Patients With Malignant Solid Tumors With Pathogenic Alterations in TSC1/TSC2 Genes (PRECISION 1)
NCT00005906	PHASE2	COMPLETED	Treatment With Octreotide in Patients With Lymphangioleiomyomatosis
NCT00457808	PHASE2	COMPLETED	Rapamycin Therapy for Patients With Tuberous Sclerosis Complex and Sporadic LAM
NCT00490789	PHASE2	UNKNOWN	Trial of Efficacy and Safety of Sirolimus in Tuberous Sclerosis and LAM
NCT01059318	PHASE2	COMPLETED	A Study to Determine the Safety and Effectiveness of RAD001 (Everolimus) in Patients With Lymphangioleiomyomatosis
NCT01353209	PHASE2	COMPLETED	Letrozole for Lymphangioleiomyomatosis
NCT02484664	PHASE2	COMPLETED	COLA: A Pilot Clinical Trial of COX-2 Inhibition in LAM and TSC
NCT03062943	PHASE2	COMPLETED	A Study of Nintedanib for LymphAngioleioMyomatosis (LAM)
NCT03253913	PHASE2	COMPLETED	Resveratrol and Sirolimus in Lymphangioleiomyomatosis Trial
NCT03304678	PHASE2	COMPLETED	Discovery of Sirolimus Sensitive Biomarkers in Blood
NCT05190627	PHASE2	UNKNOWN	Effect of Loratadine in Lymphangioleiomyomatosis
NCT00126672	PHASE2	COMPLETED	RAPAMYCIN FOR KIDNEY ANGIOMYOLIPOMAS
NCT01289912	PHASE2	COMPLETED	Trial of RAD001 and Neurocognition in Tuberous Sclerosis Complex (TSC)
NCT01526356	PHASE2	COMPLETED	Topical Rapamycin to Erase Angiofibromas in TSC
NCT01929642	PHASE2	COMPLETED	Rapalogues for Autism Phenotype in TSC: A Feasibility Study
NCT01954693	PHASE2	UNKNOWN	A Study of Everolimus in the Treatment of Neurocognitive Problems in Tuberous Sclerosis
NCT02104011	PHASE2	COMPLETED	Treatment of Renal Angiomyolipomas in Tuberous Sclerosis by Beta-blockers
NCT02451696	PHASE2	COMPLETED	A Pilot Study To Evaluate The Effects of Everolimus on Brain mTOR Activity and Cortical Hyperexcitability in TSC and FCD
NCT02849457	PHASE2	COMPLETED	Preventing Epilepsy Using Vigabatrin In Infants With Tuberous Sclerosis Complex
NCT03356769	PHASE2	UNKNOWN	Aspirin as an add-on Treatment of Refractory Epilepsy in Tuberous Sclerosis Complex
NCT03363763	PHASE2	TERMINATED	Topical Sirolimus Ointment for Cutaneous Angiofibromas in Subjects With Tuberous Sclerosis Complex
NCT04285346	PHASE2	COMPLETED	Adjunctive Ganaxolone Treatment (Part A) in TSC Followed by Long-term Treatment (Part B)
NCT05059327	PHASE2	COMPLETED	Basimglurant (NOE-101) in Children, Adolescents, and Young Adults With TSC