Tuberous sclerosis: genes and variants

Genes linked to Tuberous sclerosis

• TSC2: Tuberin

  Together with TSC1, it inactivates RHEB and restrains mTORC1 when growth conditions are unfavorable. Loss-of-function variants cause tuberous sclerosis complex with hamartomas and tumors affecting the brain, kidneys, skin, heart, lungs, and other organs.

  57 disease-causing and 1,975 uncertain variants in TSC2 are linked to Tuberous sclerosis.

• TSC1: Hamartin

  Together with TSC2, it restrains RHEB and mTORC1 signaling, preventing inappropriate cell growth when nutrients or growth signals are limited. Loss-of-function variants cause tuberous sclerosis complex with hamartomas and tumors in the brain, kidney, skin, heart, lungs, and other organs.

  18 disease-causing and 1,773 uncertain variants in TSC1 are linked to Tuberous sclerosis.

• SERPINC1: Antithrombin-III

  It neutralizes thrombin and several activated coagulation proteases and is greatly accelerated by heparin-like molecules. Heterozygous deficiency causes a strong inherited predisposition to venous thrombosis and can reduce responsiveness to heparin.

  0 disease-causing and 0 uncertain variants in SERPINC1 are linked to Tuberous sclerosis.

Weakly linked (only a few uncertain records): NTHL1.

Where Tuberous sclerosis variants cluster

• TSC2 Rap-GAP (positions 1531–1758): 22 of 57 disease-causing changes, 3.1× more than its size predicts.

Known disease-causing variants in Tuberous sclerosis

Showing 60 of 75.

Uncertain variants in Tuberous sclerosis that look disease-causing

Which prediction tools work for Tuberous sclerosis

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• EVE: 89 out of 100
• AlphaMissense: 88 out of 100
• CATVariant: 87 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 83 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 83 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 77 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 76 out of 100
• REVEL: 72 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 69 out of 100
• phyloP: 67 out of 100

Same protein, different disease

• Ovarian cancer is also caused by TSC2 variants; they fall mostly in different places as the Tuberous sclerosis variants (4 disease-causing).

Diseases related to Tuberous sclerosis

• Ovarian cancer, also linked to TSC1 and TSC2
• Isolated focal cortical dysplasia type II, also linked to TSC1 and TSC2
• Tuberous sclerosis syndrome, also linked to TSC1 and TSC2
• Lymphangiomyomatosis, also linked to TSC1 and TSC2
• Hereditary antithrombin deficiency, also linked to SERPINC1
• Familial adenomatous polyposis, also linked to TSC2
• Malignant tumor of urinary bladder, also linked to TSC1
• Hepatocellular carcinoma, also linked to TSC2
• Myocardial infarction, also linked to SERPINC1

Frequently asked questions

Which genes are linked to Tuberous sclerosis?

In CATVariant, Tuberous sclerosis is linked to 3 analyzed proteins: TSC2 (Tuberin), TSC1 (Hamartin) and SERPINC1 (Antithrombin-III).

How many genetic variants are linked to Tuberous sclerosis?

4,108 variants: 75 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 3,749 are of uncertain significance or have conflicting reports.

Which uncertain variants in Tuberous sclerosis look disease-causing?

9 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example TSC1 R190H, TSC2 V709A, TSC2 M1029V, TSC2 M1029L and TSC2 I912L. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Tuberous sclerosis?

Among tools not trained on clinical labels, EVE separates this disease's known disease-causing variants from harmless ones best (AUROC 0.89, based on 29 disease-causing and 46 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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