Hypothyroidism due to TSH receptor mutations: genes and variants

Genes linked to Hypothyroidism due to TSH receptor mutations

• 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.

  24 disease-causing and 30 uncertain variants in TSHR are linked to Hypothyroidism due to TSH receptor mutations.

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

Where Hypothyroidism due to TSH receptor mutations variants cluster

• TSHR Cytoplasmic (positions 518–537): 5 of 24 disease-causing changes, 8.0× more than its size predicts.
• TSHR LRR 3 (positions 152–174): 3 of 24 disease-causing changes, 4.2× more than its size predicts.

Known disease-causing variants in Hypothyroidism due to TSH receptor mutations

Which prediction tools work for Hypothyroidism due to TSH receptor mutations

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

• CATVariant: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 95 out of 100
• phyloP: 89 out of 100
• SIFT: 88 out of 100
• PolyPhen-2: 85 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Familial hyperthyroidism due to mutations in TSH receptor is also caused by TSHR variants; they fall mostly in different places as the Hypothyroidism due to TSH receptor mutations variants (18 disease-causing).
• Familial gestational hyperthyroidism is also caused by TSHR variants; they fall mostly in different places as the Hypothyroidism due to TSH receptor mutations variants (13 disease-causing).
• Thyroid adenoma, hyperfunctioning, somatic is also caused by TSHR variants; they fall mostly in different places as the Hypothyroidism due to TSH receptor mutations variants (5 disease-causing).
• Ovarian cancer is also caused by TSHR variants; they fall partly in the same places as the Hypothyroidism due to TSH receptor mutations variants (4 disease-causing).

Diseases related to Hypothyroidism due to TSH receptor mutations

• Ovarian cancer, also linked to TSHR
• Familial hyperthyroidism due to mutations in TSH receptor, also linked to TSHR
• Familial gestational hyperthyroidism, also linked to TSHR
• Hyperthyroidism, also linked to TSHR
• Hypothyroidism, also linked to TSHR
• Thyroid adenoma, hyperfunctioning, somatic, also linked to TSHR

Frequently asked questions

Which genes are linked to Hypothyroidism due to TSH receptor mutations?

In CATVariant, Hypothyroidism due to TSH receptor mutations is linked to 1 analyzed protein: TSHR (Thyrotropin receptor).

How many genetic variants are linked to Hypothyroidism due to TSH receptor mutations?

71 variants: 24 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 31 are of uncertain significance or have conflicting reports.

Which uncertain variants in Hypothyroidism due to TSH receptor mutations 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 Hypothyroidism due to TSH receptor mutations?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.95, based on 18 disease-causing and 8 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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