CASR

Inheritance Pattern: AR

Disease ID:MONDO:0009397

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0018543

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0009397

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0005027

Submitter: ClinGen

Variants in the *CASR* gene have been reported in individuals in the literature with disorders of calcium homeostasis, including autosomal dominant hypocalcemia (ADH), autosomal dominant familial (benign) hypocalciuric hypercalcemia (FHH), and autosomal recessive neonatal severe primary hyperparathyroidism (NSHPT). Although individuals with hypocalcemia due to ADH may experience hypocalcemic seizures, the disorders of calcium homeostasis do not cause primary epilepsy. However, in 2008, missense variants in *CASR* were observed in a single family with autosomal dominant epilepsy in the absence of any abnormalities of calcium homeostasis (PMID: 18756473). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a difference in molecular mechanism(s) and phenotypic variability for these disorders. Therefore, epilepsy is curated separately from the disorders of calcium homeostasis, which are not considered in this curation. The Kapoor et al. publication (PMID: 18756473) included a large family reported to have idiopathic generalized epilepsy (IGE). The eight affected family members had juvenile myoclonic epilepsy (JME), nocturnal myoclonic seizures, febrile convulsions, generalized tonic-clonic seizures (GTCS), and/or complex partial seizures. Linkage analysis identified a novel locus at 3q13.3-q21.1, including the *CASR* gene. There were 74 disease-associated genes noted to be within the critical region, but only 13 genes were selected for candidate gene sequencing based on known or suspected expression in the central nervous system. The *CASR* variant c.2693G>A (p.Arg898Gln) was identified in all affected individuals in the family and no unaffected familial individuals, but it is also present in gnomADv4.1 with a minor allele frequency of 0.0132% (12/91056 alleles) in the South Asian population, which is higher than expected given the prevalence of JME. The Kapoor publication also sequenced the *CASR* gene in 96 unrelated individuals reported to have JME, and four additional missense variants were identified in five probands. However, there was limited clinical and family history information for these individuals with no segregation analysis performed. In addition, several of the variants have a minor allele frequency in gnomAD that is higher than expected based on the prevalence of JME in the population, and no other epilepsy genes were tested to evaluate for other possible explanations for the phenotype. Another publication (Rossi 2019, PMID: 31763346) reported a proband with a history of hypocalcemia and seizures who had a missense variant in *CASR* that has been published in other individuals with ADH. However, the proband was also reported to have intractable childhood-onset seizures including eyelid myoclonus with absences, intellectual disability, and behavioral issues that were attributed by the authors to the *CASR* variant. Again, an epilepsy gene panel or exome/genome sequencing was not performed to evaluate for other possible causes of epilepsy, so it is unclear whether the *CASR* variant is the cause of the other neurodevelopmental features observed in this individual. Because other causes of epilepsy in all individuals were not ruled out, none of these cases were scored for this curation. There is currently no functional data that supports a relationship between *CASR* and primary epilepsy. Homozygous and heterozygous knockout mice have features similar to NSHPT or FHH respectively (Ho 1995, PMID: 7493018). A mouse model with a heterozygous missense variant that exhibits a gain-of-function has similar features to ADH (Hough 2004, PMID: 15347804). There is no *CASR* mouse model that exhibits primary epilepsy; thus, these models were not scored for this curation. Without significant supportive genetic evidence, a correlation to primary epilepsy (outside of the setting of hypocalcemia) is not supported. In summary, the evidence supporting the relationship between *CASR* and autosomal dominant epilepsy has been refuted and no valid evidence remains to support the claim. This gene-disease pair was originally evaluated by the Epilepsy GCEP on 03/03/2021. It was re-evaluated on 11/18/2025. As a result of this reevaluation, the classification was changed from disputed to refuted due to the lack of additional supportive evidence. This updated classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on November 18, 2025 (SOP version 11).

Inheritance Pattern: AD

Disease ID:MONDO:0007791

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0011013

Submitter: Illumina

Inheritance Pattern: AD

Disease ID:MONDO:0007791

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0007791

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0007791

Submitter: Illumina

Inheritance Pattern: AD

Disease ID:MONDO:0013032

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0011013

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0011013

Submitter: ClinGen

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 no evidence of differences in the molecular mechanisms, inheritance pattern and phenotypic spectrum for Hypocalcemia, autosomal dominant (OMIM:601198) and Hypocalcemia, autosomal dominant, with Bartter syndrome (OMIM:601198). Therefore, these disease entities have been lumped into one disease entity, with the preferred disease name suggested for this disorder being ‘autosomal dominant hypocalcemia - *CASR*’. Autosomal recessive neonatal hyperparathyroidism (OMIM:239200) and autosomal dominant hypocalciuric hypercalcemia, type 1 (OMIM:145980) have been curated separately. The *CASR* gene was first reported in relation to autosomal dominant hypocalcemia in 1996 (Baron et al., PMID: 8733126). The mechanism of pathogenicity is shown to be gain of function. This condition is characterised by hypoparathyroidism, hypocalcemia, hyperphosphatemia due to inadequate secretion of parathyroid hormone and increased urinary calcium excretion. At least 35 missense variants have been reported in 35 probands in 13 publications [PMIDs: 8813042, 22422767, 12191970, 9253358, 35818129, 35402765, 29743878, 25766501, 19915295, 12107202, 14677060, 8733126, 33506158] 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. PMID:15347804 showed that 'Nuf' founder mouse models with the heterozygous gain of function *CASR* Leu723Gln variant recapitulated the human phenotype, with transient expression of wild-type and mutant CaSRs in HEK-293 transfected cells showing significantly lower EC50. A total of 2/6 pts. for experimental evidence was reached. In summary, there is definitive evidence supporting the relationship between CASR and autosomal dominant hypocalcemia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

Inheritance Pattern: AR

Disease ID:MONDO:0009397

Submitter: ClinGen

The CASR gene is located on chromosome 3 at q13.33-q21.1and 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 recessive hyperparathyroidism, neonatal (OMIM:239200), autosomal dominant hypocalciuric hypercalcemia, type I (OMIM:145980), 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 recessive neonatal hyperparathyroidism - *CASR*’. CASR was first reported in relation to autosomal recessive neonatal hyperparathyroidism 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 monoallelic variants associated with neonatal hyperparathyroidism with a dominant negative mechanism of disease postulated (Pearce et al., PMID: 8675635). However, these are isolated case reports, a dominant-negative disease mechanism has not been proven, and a second causative variant in trans cannot be excluded. Therefore, our curation focuses exclusively on autosomal recessive neonatal hyperparathyroidism. Autosomal recessive neonatal hyperparathyroidism is characterised by severe neonatal hypercalcemia, elevated parathyroid hormone levels, enlargement of the parathyroid glands, failure to thrive and hyperparathyroid bone disease leading to multiple fractures, ribcage deformities and respiratory distress. This condition is usually fatal without parathyroidectomy early in life. At least 11 variants (3 missense, 2 nonsense, 3 frameshift, 2 canonical splice site, 1 complex insertional variant) have been reported in 10 probands in 10 publications (PMIDs: 7916660, 37246686, 7717399, 35380381, 34887979, 34111698, 30376845, 29354167, 24735972, 23817301) 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. Homozygous Casr-/- mice had marked reduction in growth from day 2 of life, progressive lethargy and death at day 3 to 30 of life with elevated serum calcium, parathyroid hormone levels 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 neonatal hyperparathyroidism 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 3/6 pts. for experimental evidence was reached. In summary, there is definitive evidence supporting the relationship between CASR and autosomal recessive neonatal hyperparathyroidism. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

Inheritance Pattern: AR

Disease ID:MONDO:0009397

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0007791

Submitter: ClinGen

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.