Submission Details

The CASR gene is located on chromosome 3 at q13.33-q21.1 and encodes the calcium-sensing receptor that determines extracellular calcium concentration and is predominantly expressed in PTH-producing chief cells of the parathyroid gland and the cortical thick ascending limb of the kidney tubule. Multiple disease entities have been reported in association with this gene. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there was evidence of differences in their inheritance pattern and phenotypic spectrum, with implications for clinical management. Therefore, the following disease entities have been split into multiple disease entities and curated separately: autosomal dominant hypocalciuric hypercalcemia, type I (OMIM:145980), autosomal recessive hyperparathyroidism, neonatal (OMIM:239200) and autosomal dominant hypocalcemia (OMIM:601198) lumped with hypocalcemia, autosomal dominant, with Bartter syndrome (OMIM:601198). The preferred disease name suggested for this entity is ‘autosomal dominant hypocalciuric hypercalcemia - CASR’.

CASR was first reported in relation to autosomal dominant hypocalciuric hypercalcemia, type 1 in 1993 (Pollak et al., PMID: 7916660). The mechanism of pathogenicity is predominantly reported to be loss of function. There have been isolated reports of heterozygous variants associated with a more severe phenotype with a dominant negative mechanism of pathogenicity postulated (Ward et al., PMID: 16649980). Autosomal dominant hypocalciuric hypercalcemia, type 1 is characterised by high serum calcium concentration, relative hypocalciuria and inappropriately normal serum parathyroid hormone level. At least 19 variants (13 missense, 2 nonsense, 2 frameshift, 1 canonical splice site, 1 complex insertional variant) have been reported in 19 probands in 7 publications (PMIDs: 7916660, 7726161, 35380381, 7717399, 8675635, 23817301, 22422767) and are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached, considering case-level and segregation data. This gene-disease relationship is also supported by animal models, in vitro assays in non-patient cells and expression studies. Heterozygous Casr+/- mice had higher serum total and ionised calcium levels, elevated parathyroid hormone and significant hypocalciuria, recapitulating the human phenotype and supporting loss-of-function as a disease mechanism (Ho et al., PMID: 7493018). HEK-293 cells cultured and transfected with CASR variants reported in individuals with autosomal dominant hypocalciuric hypercalcemia, type 1 showed an increase in EC50 set-point compared with wild-type cells (Pearce et al., PMID: 8878438). Human CaSR cDNA was able to be isolated from an adenomatous parathyroid gland and healthy parathyroid tissue. The cloned receptor when expressed in Xenopus oocytes responded to extracellular application of physiologically relevant concentrations of calcium and other calcium receptor agonists with the same rank order of potency compared with water-injected control oocytes. This demonstrates both expression of CaSR in parathyroid tissue and its biochemical function (Garrett et al., PMID:7759551). A total of 4/6 pts. for experimental evidence was reached.

In summary, there is definitive evidence supporting the relationship between CASR and autosomal dominant hypocalciuric hypercalcemia, type 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.