The calcium-sensing receptor (CaSR) is a 1,078 amino acid G protein-coupled receptor. It is predominantly expressed in the parathyroid glands and kidney and is responsible for regulating calcium homeostasis (1). Inactivating mutations in the calcium-sensing receptor (CASR) gene cause familial hypocalciuric hypercalcemia (FHH) type I and neonatal severe hyperparathyroidism, while activating mutations of the CASR result in autosomal dominant hypocalcemia (ADH) type I and Bartter syndrome type V (1).  Genetic testing of CASR is crucial for confirming diagnoses of these conditions. As the McGill’s CASRdb (2) is no longer available, there is currently a lack of a comprehensive database of variants of the CASR gene and their disease associations.

We created this website with the aim to present a publicly accessible comprehensive database with interactive visualization of the disease-causing variants of the CASR gene based on available literature and genomic databases. We hope that this CASRdb will be a comprehensive resource aiding clinicians in interpreting CASR variants and assisting researchers in variant curation and structure-function analyses.

References

1. Hannan FM, Kallay E, Chang W, Brandi ML, Thakker RV. The calcium-sensing receptor in physiology and in calcitropic and noncalcitropic diseases. Nat Rev Endocrinol. 2018;15(1):33-51.
2. Pidasheva S, D’Souza-Li L, Canaff L, Cole DE, Hendy GN. CASRdb: calcium-sensing receptor locus-specific database for mutations causing familial (benign) hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. Hum Mutat. 2004;24(2):107-11.

We employed a systematic review in the Embase and Pubmed databases from inception to March 2023, using search strategy associated with “Calcium-sensing receptor”. Additionally, we identified supporting references for pathogenic or likely pathogenic variants reported in the ClinVar and LOVD databases. Benign or likely benign variants, or variants of uncertain significance were not included unless they were reported in the literature to be associated with disorders of CaSR. We compiled a comprehensive library of CASR variants associated with specific phenotypes. This library has been made available on a website equipped with a search engine and links to the respective references.

A total of 574 unique CASR variants were identified. Notably, 286 variants (49.8%) reported in the literature to be associated with diseases were not documented in ClinVar. Among the 288 variants reported in ClinVar, 165 (57.3%) were classified as pathogenic/likely pathogenic, 93 (32.3%) as VUS, 10 (3.5%) as benign/likely benign, and 20 (6.9%) had conflicting interpretations of pathogenicity. Among the entire 574 variants, 130 were activating and 392 were inactivating; 52 variants reported in ClinVar/LOVD databases as pathogenic/likely pathogenic, but not reported in the literature, had unknown effects on CaSR function. The majority of these variants are missense variants (427 variants), followed by frameshift (78 variants), nonsense (36 variants), splice site (15 variants) and others (18 variants).