Familial hypocalciuric hypercalcemia: genes and variants

Genes linked to Familial hypocalciuric hypercalcemia

• CASR: Extracellular calcium-sensing receptor

  It senses extracellular calcium in the parathyroid gland and kidney and adjusts parathyroid-hormone secretion and renal calcium handling accordingly. Loss-of-function variants cause familial hypocalciuric hypercalcemia or neonatal severe hyperparathyroidism, whereas activating variants cause autosomal dominant hypocalcemia.

  81 disease-causing and 1,174 uncertain variants in CASR are linked to Familial hypocalciuric hypercalcemia.

• GNA11: Guanine nucleotide-binding protein subunit alpha-11

  It transmits signals from Gq-coupled receptors to phospholipase C and downstream calcium and protein-kinase-C pathways. Germline activating variants can cause autosomal dominant hypocalcemia, while somatic activating variants drive uveal melanoma and some vascular lesions.

  4 disease-causing and 14 uncertain variants in GNA11 are linked to Familial hypocalciuric hypercalcemia.

Where Familial hypocalciuric hypercalcemia variants cluster

• CASR Ligand-binding 1 (LB1) (positions 22–188): 24 of 81 disease-causing changes, 1.9× more than its size predicts.
• CASR Cysteine-rich (CR) (positions 542–612): 13 of 81 disease-causing changes, 2.4× more than its size predicts.
• CASR Transmembrane (positions 806–828): 4 of 81 disease-causing changes, 2.3× more than its size predicts.
• CASR Intracellular loop 3 (ICL3) (positions 790–805): 3 of 81 disease-causing changes, 2.5× more than its size predicts.
• CASR Interaction with RNF19A (positions 880–900): 3 of 81 disease-causing changes, 1.9× more than its size predicts.

Known disease-causing variants in Familial hypocalciuric hypercalcemia

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Uncertain variants in Familial hypocalciuric hypercalcemia that look disease-causing

Which prediction tools work for Familial hypocalciuric hypercalcemia

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

• CADD: 98 out of 100
• PolyPhen-2: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 93 out of 100
• SIFT: 85 out of 100

Same protein, different disease

• Autosomal dominant hypocalcemia is also caused by CASR variants; they fall in the same places as the Familial hypocalciuric hypercalcemia variants (69 disease-causing).
• Nephrolithiasis/nephrocalcinosis is also caused by CASR variants; they fall in the same places as the Familial hypocalciuric hypercalcemia variants (14 disease-causing).
• Neonatal severe primary hyperparathyroidism is also caused by CASR variants; they fall in the same places as the Familial hypocalciuric hypercalcemia variants (11 disease-causing).
• Familial hyperparathyroidism or Hypocalciuric hypercalcaemia is also caused by CASR variants; they fall partly in the same places as the Familial hypocalciuric hypercalcemia variants (5 disease-causing).
• Autosomal dominant hypocalcemia is also caused by GNA11 variants; they fall mostly in different places as the Familial hypocalciuric hypercalcemia variants (6 disease-causing).

Diseases related to Familial hypocalciuric hypercalcemia

• Autosomal dominant hypocalcemia, also linked to CASR and GNA11
• Familial hypoparathyroidism, also linked to CASR and GNA11
• Hypertrophic cardiomyopathy, also linked to CASR
• Epilepsy, idiopathic generalized, susceptibility to, 13, also linked to CASR
• Idiopathic generalized epilepsy, also linked to CASR
• Nephrolithiasis/nephrocalcinosis, also linked to CASR
• Vascular malformation, also linked to GNA11
• Neonatal severe primary hyperparathyroidism, also linked to CASR
• Familial hyperparathyroidism or Hypocalciuric hypercalcaemia, also linked to CASR
• Familial multiple nevi flammei, also linked to GNA11
• Chronic kidney disease, also linked to CASR

Frequently asked questions

Which genes are linked to Familial hypocalciuric hypercalcemia?

In CATVariant, Familial hypocalciuric hypercalcemia is linked to 2 analyzed proteins: CASR (Extracellular calcium-sensing receptor) and GNA11 (Guanine nucleotide-binding protein subunit alpha-11).

How many genetic variants are linked to Familial hypocalciuric hypercalcemia?

1,297 variants: 85 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 1,188 are of uncertain significance or have conflicting reports.

Which uncertain variants in Familial hypocalciuric hypercalcemia look disease-causing?

18 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example CASR R185L, CASR Y218H, CASR C582R, CASR C562Y and CASR G549E. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Familial hypocalciuric hypercalcemia?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.98, based on 37 disease-causing and 11 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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