CASR

Chr 3ADAR

calcium sensing receptor

Also known as: CAR, EIG8, FHH, FIH, GPRC2A, HHC, HHC1, HYPOC1

NCBI Gene: 846 ENSG00000036828 UniProt: P41180 OMIM: 601199

This G protein-coupled receptor senses extracellular calcium concentrations and regulates calcium homeostasis by modifying parathyroid hormone secretion and renal calcium handling. Mutations cause familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia, with neonatal severe hyperparathyroidism presenting in the newborn period. The gene is highly constrained against loss-of-function variants (LOEUF 0.451), reflecting its essential role in calcium regulation.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a plasma membrane G protein-coupled receptor that senses small changes in circulating calcium concentration. The encoded protein couples this information to intracellular signaling pathways that modify parathyroid hormone secretion or renal cation handling, and thus this protein plays an essential role in maintaining mineral ion homeostasis. Mutations in this gene are a cause of familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. [provided by RefSeq, Aug 2017]

OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.455 OMIM phenotypes

Clinical Summary— CASR

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Gene-Disease Validity (ClinGen)

neonatal severe primary hyperparathyroidism · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

4 total gene-disease associations curated

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.27) despite low pLI — interpret in context.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

0.45LOEUF

pLI 0.047

Z-score 4.17

OE 0.27 (0.16–0.45)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

3.12Z-score

OE missense 0.65 (0.59–0.70)

399 obs / 617.4 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.27 (0.16–0.45)

0≤0.351.4

Missense OE?0.65 (0.59–0.70)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 10 / 37.6Missense obs/exp: 399 / 617.4Syn Z: 0.12

This gene — mechanism propensity

0.74top 25%

GOF

0.83top 10%

LOF

0.2678th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function, dominant-negative and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

DNprediction above median · 1 literature citation

LOF1 literature citation · LOEUF 0.45

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNThus this de novo, heterozygous CaR mutation may exert a dominant negative action on the normal CaR, producing NHPT and more severe hypercalcemia than typically seen with FBHH.1

GOFExcessive signal transduction of gain-of-function variants of the calcium-sensing receptor (CaSR) are associated with increased ER to cytosol calcium gradient2

LOFWe hereby report the identification of a novel heterozygous loss-of-function mutation of the CASR gene in a Greek family from Nisyros island.3

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References