Hyperthyroidism: genes and variants

Genes linked to Hyperthyroidism

• THRB: Thyroid hormone receptor beta

  10 disease-causing and 2 uncertain variants in THRB are linked to Hyperthyroidism.

• TSHR: Thyrotropin receptor

  TSH signaling through this pathway drives thyroid-hormone synthesis, iodine handling, and thyroid growth. Activating variants can cause autonomous hyperthyroidism, whereas loss-of-function variants can cause TSH resistance and congenital hypothyroidism.

  1 disease-causing and 1 uncertain variants in TSHR are linked to Hyperthyroidism.

• CTLA4: Cytotoxic T-lymphocyte protein 4

  It restrains T-cell activation by competing with CD28 for CD80 and CD86 and by delivering inhibitory signals after immune activation. Haploinsufficiency causes immune dysregulation with autoimmunity and lymphoproliferation, while therapeutic blockade enhances antitumor immunity.

  0 disease-causing and 0 uncertain variants in CTLA4 are linked to Hyperthyroidism.

• TPO: Thyroid peroxidase

  It oxidizes iodide and catalyzes iodination and coupling reactions on thyroglobulin that generate thyroid hormones. Biallelic loss-of-function variants cause thyroid dyshormonogenesis and congenital hypothyroidism, usually with goiter if untreated.

  0 disease-causing and 0 uncertain variants in TPO are linked to Hyperthyroidism.

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

Where Hyperthyroidism variants cluster

• THRB NR LBD (positions 217–461): 10 of 10 disease-causing changes, 1.9× more than its size predicts.

Known disease-causing variants in Hyperthyroidism

Which prediction tools work for Hyperthyroidism

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

• CATVariant: 100 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 99 out of 100
• MetaLR: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 89 out of 100
• MutPred2: 83 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Thyroid hormone resistance, generalized, autosomal dominant is also caused by THRB variants; they fall mostly in different places as the Hyperthyroidism variants (35 disease-causing).
• Selective pituitary resistance to thyroid hormone is also caused by THRB variants; they fall partly in the same places as the Hyperthyroidism variants (5 disease-causing).
• Generalized resistance to thyroid hormone is also caused by THRB variants; they fall partly in the same places as the Hyperthyroidism variants (4 disease-causing).
• Hypothyroidism due to TSH receptor mutations is also caused by TSHR variants; they fall mostly in different places as the Hyperthyroidism variants (24 disease-causing).
• Familial hyperthyroidism due to mutations in TSH receptor is also caused by TSHR variants; they fall mostly in different places as the Hyperthyroidism variants (18 disease-causing).
• Familial gestational hyperthyroidism is also caused by TSHR variants; they fall mostly in different places as the Hyperthyroidism variants (13 disease-causing).
• Thyroid adenoma, hyperfunctioning, somatic is also caused by TSHR variants; they fall mostly in different places as the Hyperthyroidism variants (5 disease-causing).
• Ovarian cancer is also caused by TSHR variants; they fall mostly in different places as the Hyperthyroidism variants (4 disease-causing).

Diseases related to Hyperthyroidism

• Hypothyroidism, also linked to CTLA4, THRB, TPO and TSHR
• Ovarian cancer, also linked to TSHR
• Thyroid hormone resistance, generalized, autosomal dominant, also linked to THRB
• Hypothyroidism due to TSH receptor mutations, also linked to TSHR
• Deficiency of iodide peroxidase, also linked to TPO
• Familial hyperthyroidism due to mutations in TSH receptor, also linked to TSHR
• Non-small cell lung carcinoma, also linked to CTLA4
• Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency, also linked to CTLA4
• Inherited Immunodeficiency Diseases, also linked to CTLA4
• Familial gestational hyperthyroidism, also linked to TSHR
• Type 1 diabetes mellitus, also linked to CTLA4
• Hepatocellular carcinoma, also linked to CTLA4

Frequently asked questions

Which genes are linked to Hyperthyroidism?

In CATVariant, Hyperthyroidism is linked to 4 analyzed proteins: THRB (Thyroid hormone receptor beta), TSHR (Thyrotropin receptor), CTLA4 (Cytotoxic T-lymphocyte protein 4) and TPO (Thyroid peroxidase).

How many genetic variants are linked to Hyperthyroidism?

18 variants: 11 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 3 are of uncertain significance or have conflicting reports.

Which uncertain variants in Hyperthyroidism look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Hyperthyroidism?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.99, based on 8 disease-causing and 21 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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