CASR
calcium sensing receptor, the group of Calcium sensing receptors
Basic information
Region (hg38): 3:122183668-122291629
Previous symbols: [ "HHC", "HHC1" ]
Links
Phenotypes
GenCC
Source:
- autosomal dominant hypocalcemia 1 (Definitive), mode of inheritance: AD
- familial hypocalciuric hypercalcemia 1 (Strong), mode of inheritance: AD
- neonatal severe primary hyperparathyroidism (Supportive), mode of inheritance: AR
- autosomal dominant hypocalcemia (Supportive), mode of inheritance: AD
- familial hypocalciuric hypercalcemia 1 (Supportive), mode of inheritance: AD
- familial hypocalciuric hypercalcemia 1 (Definitive), mode of inheritance: AD
- epilepsy, idiopathic generalized, susceptibility to, 8 (Limited), mode of inheritance: AD
- familial hypocalciuric hypercalcemia 1 (Strong), mode of inheritance: AD
- neonatal severe primary hyperparathyroidism (Strong), mode of inheritance: AD
- autosomal dominant hypocalcemia 1 (Strong), mode of inheritance: AD
- neonatal severe primary hyperparathyroidism (Strong), mode of inheritance: AR
- neonatal severe primary hyperparathyroidism (Definitive), mode of inheritance: AR
- familial hypocalciuric hypercalcemia 1 (Definitive), mode of inheritance: AD
- epilepsy (Disputed Evidence), mode of inheritance: AD
- autosomal dominant hypocalcemia 1 (Definitive), mode of inheritance: AD
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Hyperparathyroidism, neonatal; Hypocalcemia, autosomal dominant 1; Hypocalciuric hypercalcemia, type I; Hyperparathyroidism, neonatal severe primary; Hypoparathyroidism, familial isolated; Hyperparathyroidism, familial primary | AD/AR | Endocrine; Renal | Sequelae, which can be severe in some individuals with hyperparathyrodism, can include seizures, and treatment (eg, with Vitamin D and calcium) can be effective at preventing morbidity; Early diagnosis of NSPHT is critical as the disorder can neurologically devastating or lethal without parathyroidectomy; In some forms of hypoparathyroidism, treatment of hypocalcemia with vitamin D/ vitamin D metabolites can cause hypercalciuria and resultant renal impairment, and PTH injections or diuretic treatment may be effective; In familial hypocalciuric hypercalcemia, accurate diagnosis may be important in order to decrease the use of unhelpful therapies | Endocrine; Musculoskeletal; Neurologic; Renal | 18887540; 14089114; 5013415; 830920; 619857; 7054696; 3966479; 7916660; 7874174; 7673400; 7726161; 8132750; 8675635; 8733126; 8813042; 9109436; 9011580; 9253358; 9642634; 9661634; 11013439; 10770217; 11134112; 11701698; 11293637; 12107202; 12241879; 12915654; 15579740; 15241791; 16608894; 17698911; 17018660; 18328986; 18756473; 21986511; 19250271; 22315359 |
ClinVar
This is a list of variants' phenotypes submitted to
- Familial hypocalciuric hypercalcemia;Autosomal dominant hypocalcemia 1 (68 variants)
- not provided (37 variants)
- Autosomal dominant hypocalcemia 1;Familial hypocalciuric hypercalcemia (27 variants)
- Nephrolithiasis/nephrocalcinosis (13 variants)
- Familial hypocalciuric hypercalcemia (8 variants)
- Familial hypocalciuric hypercalcemia 1 (8 variants)
- Neonatal severe primary hyperparathyroidism (7 variants)
- CASR-related disorder (7 variants)
- Autosomal dominant hypocalcemia 1 (6 variants)
- Autosomal dominant hypocalcemia (3 variants)
- Neonatal severe primary hyperparathyroidism;Familial hypocalciuric hypercalcemia;Autosomal dominant hypocalcemia 1;Bartter syndrome with hypocalcemia (1 variants)
- Inborn genetic diseases (1 variants)
- Epilepsy, idiopathic generalized, susceptibility to, 8;Autosomal dominant hypocalcemia 1;Familial hypocalciuric hypercalcemia 1;Neonatal severe primary hyperparathyroidism (1 variants)
- Neonatal severe primary hyperparathyroidism;Familial hypocalciuric hypercalcemia 1;Autosomal dominant hypocalcemia 1;Epilepsy, idiopathic generalized, susceptibility to, 8 (1 variants)
- Epilepsy, idiopathic generalized, susceptibility to, 8;Neonatal severe primary hyperparathyroidism;Familial hypocalciuric hypercalcemia 1;Autosomal dominant hypocalcemia 1 (1 variants)
- Familial hypocalciuric hypercalcemia 1;Autosomal dominant hypocalcemia 1;Neonatal severe primary hyperparathyroidism;Epilepsy, idiopathic generalized, susceptibility to, 8 (1 variants)
- Hypocalcemia (1 variants)
- Familial hypocalciuric hypercalcemia 1;Neonatal severe primary hyperparathyroidism;Epilepsy, idiopathic generalized, susceptibility to, 8;Autosomal dominant hypocalcemia 1 (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the CASR gene is commonly pathogenic or not.
In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.
Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.
| Variant type | Pathogenic | Likely pathogenic | VUS | Likely benign | Benign | Sum |
|---|---|---|---|---|---|---|
| synonymous | 741 | 749 | ||||
| missense | 33 | 59 | 1373 | 1478 | ||
| nonsense | 28 | 42 | ||||
| start loss | 4 | |||||
| frameshift | 54 | 13 | 75 | |||
| inframe indel | 26 | 28 | ||||
| splice donor/acceptor (+/-2bp) | 11 | 17 | ||||
| splice region | 23 | 16 | 39 | |||
| non coding | 19 | 69 | 16 | 104 | ||
| Total | 123 | 92 | 1441 | 819 | 22 |
Highest pathogenic variant AF is 0.00000657
Variants in CASR
This is a list of pathogenic ClinVar variants found in the CASR region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 3-122183675-AC-A | Neonatal severe primary hyperparathyroidism • Familial hypoparathyroidism • Hypocalcemia • Familial hypocalciuric hypercalcemia | Likely benign (Jun 14, 2016) | ||
| 3-122254036-T-A | Neonatal severe primary hyperparathyroidism • Familial hypocalciuric hypercalcemia 1 • Familial hypoparathyroidism • Autosomal dominant hypocalcemia 1 | Conflicting classifications of pathogenicity (Jan 12, 2018) | ||
| 3-122254053-C-A | Autosomal dominant hypocalcemia 1 • Familial hypoparathyroidism • Neonatal severe primary hyperparathyroidism • Familial hypocalciuric hypercalcemia 1 | Uncertain significance (Jan 13, 2018) | ||
| 3-122254053-C-T | Familial hypoparathyroidism • Autosomal dominant hypocalcemia 1 • Neonatal severe primary hyperparathyroidism • Familial hypocalciuric hypercalcemia 1 | Uncertain significance (Jan 13, 2018) | ||
| 3-122254079-C-A | Autosomal dominant hypocalcemia 1 • Familial hypoparathyroidism • Familial hypocalciuric hypercalcemia 1 • Neonatal severe primary hyperparathyroidism | Conflicting classifications of pathogenicity (Jan 12, 2018) | ||
| 3-122254180-C-T | Neonatal severe primary hyperparathyroidism • Familial hypocalciuric hypercalcemia 1 • Autosomal dominant hypocalcemia 1 • Familial hypoparathyroidism | Conflicting classifications of pathogenicity (Apr 02, 2024) | ||
| 3-122254185-G-A | Nephrolithiasis/nephrocalcinosis | Uncertain significance (Jan 16, 2024) | ||
| 3-122254188-C-T | Nephrolithiasis/nephrocalcinosis | Uncertain significance (Jun 24, 2023) | ||
| 3-122254190-A-C | Nephrolithiasis/nephrocalcinosis | Likely pathogenic (Nov 10, 2020) | ||
| 3-122254190-A-G | Familial hypocalciuric hypercalcemia | Likely pathogenic (Aug 27, 2024) | ||
| 3-122254191-T-C | Familial hypocalciuric hypercalcemia;Autosomal dominant hypocalcemia 1 • Familial hypocalciuric hypercalcemia | Pathogenic/Likely pathogenic (Sep 26, 2023) | ||
| 3-122254191-T-G | Autosomal dominant hypocalcemia 1;Familial hypocalciuric hypercalcemia | Pathogenic (May 26, 2022) | ||
| 3-122254193-G-A | Nephrolithiasis/nephrocalcinosis | Uncertain significance (Jun 19, 2024) | ||
| 3-122254195-A-C | Familial hypocalciuric hypercalcemia 1 • Autosomal dominant hypocalcemia 1 • Neonatal severe primary hyperparathyroidism • Familial hypoparathyroidism • Familial hypocalciuric hypercalcemia;Autosomal dominant hypocalcemia 1 • not specified • Hereditary cancer-predisposing syndrome • Nephrolithiasis/nephrocalcinosis | Conflicting classifications of pathogenicity (Jan 18, 2024) | ||
| 3-122254198-T-G | Autosomal dominant hypocalcemia 1;Familial hypocalciuric hypercalcemia | Uncertain significance (Nov 20, 2019) | ||
| 3-122254199-T-C | Familial hypocalciuric hypercalcemia;Autosomal dominant hypocalcemia 1 • Nephrolithiasis/nephrocalcinosis | Uncertain significance (Jan 09, 2024) | ||
| 3-122254200-A-G | Familial hypocalciuric hypercalcemia;Autosomal dominant hypocalcemia 1 • Familial hypocalciuric hypercalcemia 1 • Nephrolithiasis/nephrocalcinosis | Uncertain significance (Oct 28, 2023) | ||
| 3-122254201-T-C | Nephrolithiasis/nephrocalcinosis | Likely benign (Jun 27, 2023) | ||
| 3-122254204-C-G | Nephrolithiasis/nephrocalcinosis | Uncertain significance (Jun 06, 2022) | ||
| 3-122254204-CT-GG | Familial hypocalciuric hypercalcemia;Autosomal dominant hypocalcemia 1 | Uncertain significance (Jun 09, 2023) | ||
| 3-122254205-T-G | Nephrolithiasis/nephrocalcinosis • Familial hypocalciuric hypercalcemia;Autosomal dominant hypocalcemia 1 | Uncertain significance (Jun 06, 2022) | ||
| 3-122254206-G-A | Nephrolithiasis/nephrocalcinosis | Uncertain significance (Aug 05, 2024) | ||
| 3-122254209-G-A | Autosomal dominant hypocalcemia 1;Familial hypocalciuric hypercalcemia | Uncertain significance (Aug 17, 2023) | ||
| 3-122254209-G-C | Familial hypocalciuric hypercalcemia;Autosomal dominant hypocalcemia 1 | Uncertain significance (Jul 12, 2022) | ||
| 3-122254209-G-T | Autosomal dominant hypocalcemia 1;Familial hypocalciuric hypercalcemia | Uncertain significance (Sep 01, 2021) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| CASR | protein_coding | protein_coding | ENST00000498619 | 6 | 102813 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 0.0467 | 0.953 | 125726 | 1 | 21 | 125748 | 0.0000875 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 3.12 | 399 | 617 | 0.646 | 0.0000382 | 7179 |
| Missense in Polyphen | 111 | 275.4 | 0.40304 | 3204 | ||
| Synonymous | 0.117 | 264 | 266 | 0.991 | 0.0000180 | 2180 |
| Loss of Function | 4.17 | 10 | 37.6 | 0.266 | 0.00000231 | 410 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.000247 | 0.000246 |
| Ashkenazi Jewish | 0.0000992 | 0.0000992 |
| East Asian | 0.000217 | 0.000217 |
| Finnish | 0.00 | 0.00 |
| European (Non-Finnish) | 0.0000352 | 0.0000352 |
| Middle Eastern | 0.000217 | 0.000217 |
| South Asian | 0.000294 | 0.000261 |
| Other | 0.000163 | 0.000163 |
dbNSFP
Source:
- Function
- FUNCTION: G-protein-coupled receptor that senses changes in the extracellular concentration of calcium ions and plays a key role in maintaining calcium homeostasis (PubMed:7759551, PubMed:8702647, PubMed:8636323, PubMed:8878438, PubMed:17555508, PubMed:19789209, PubMed:21566075, PubMed:22114145, PubMed:23966241, PubMed:25292184, PubMed:25104082, PubMed:26386835, PubMed:25766501, PubMed:22789683). Senses fluctuations in the circulating calcium concentration and modulates the production of parathyroid hormone (PTH) in parathyroid glands (By similarity). The activity of this receptor is mediated by a G-protein that activates a phosphatidylinositol- calcium second messenger system (PubMed:7759551). The G-protein- coupled receptor activity is activated by a co-agonist mechanism: aromatic amino acids, such as Trp or Phe, act concertedly with divalent cations, such as calcium or magnesium, to achieve full receptor activation (PubMed:27434672, PubMed:27386547). {ECO:0000250|UniProtKB:Q9QY96, ECO:0000269|PubMed:17555508, ECO:0000269|PubMed:19789209, ECO:0000269|PubMed:21566075, ECO:0000269|PubMed:22114145, ECO:0000269|PubMed:22789683, ECO:0000269|PubMed:23966241, ECO:0000269|PubMed:25104082, ECO:0000269|PubMed:25292184, ECO:0000269|PubMed:25766501, ECO:0000269|PubMed:26386835, ECO:0000269|PubMed:27386547, ECO:0000269|PubMed:27434672, ECO:0000269|PubMed:7759551, ECO:0000269|PubMed:8636323, ECO:0000269|PubMed:8702647, ECO:0000269|PubMed:8878438}.;
- Disease
- DISEASE: Hypocalciuric hypercalcemia, familial 1 (HHC1) [MIM:145980]: A form of hypocalciuric hypercalcemia, a disorder of mineral homeostasis that is transmitted as an autosomal dominant trait with a high degree of penetrance. It is characterized biochemically by lifelong elevation of serum calcium concentrations and is associated with inappropriately low urinary calcium excretion and a normal or mildly elevated circulating parathyroid hormone level. Hypermagnesemia is typically present. Affected individuals are usually asymptomatic and the disorder is considered benign. However, chondrocalcinosis and pancreatitis occur in some adults. {ECO:0000269|PubMed:11762699, ECO:0000269|PubMed:15572418, ECO:0000269|PubMed:15579740, ECO:0000269|PubMed:15879434, ECO:0000269|PubMed:16598859, ECO:0000269|PubMed:16740594, ECO:0000269|PubMed:17473068, ECO:0000269|PubMed:17698911, ECO:0000269|PubMed:19179454, ECO:0000269|PubMed:19789209, ECO:0000269|PubMed:21566075, ECO:0000269|PubMed:21643651, ECO:0000269|PubMed:22114145, ECO:0000269|PubMed:23169696, ECO:0000269|PubMed:23966241, ECO:0000269|PubMed:25104082, ECO:0000269|PubMed:25292184, ECO:0000269|PubMed:26386835, ECO:0000269|PubMed:27434672, ECO:0000269|PubMed:7673400, ECO:0000269|PubMed:7726161, ECO:0000269|PubMed:7916660, ECO:0000269|PubMed:8636323, ECO:0000269|PubMed:8702647, ECO:0000269|PubMed:8878438, ECO:0000269|PubMed:9298824}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Hyperparathyroidism, neonatal severe (NSHPT) [MIM:239200]: A disorder characterized by severe hypercalcemia, bone demineralization, and failure to thrive usually manifesting in the first 6 months of life. If untreated, NSHPT can be a devastating neurodevelopmental disorder, which in some cases is lethal without parathyroidectomy. {ECO:0000269|PubMed:14985373, ECO:0000269|PubMed:15572418, ECO:0000269|PubMed:17555508, ECO:0000269|PubMed:27434672, ECO:0000269|PubMed:8675635, ECO:0000269|PubMed:8878438, ECO:0000269|PubMed:9253359}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Hypocalcemia, autosomal dominant 1 (HYPOC1) [MIM:601198]: A disorder of mineral homeostasis characterized by blood calcium levels below normal, and low or normal serum parathyroid hormone concentrations. Disease manifestations include mild or asymptomatic hypocalcemia, paresthesias, carpopedal spasm, seizures, hypercalciuria with nephrocalcinosis or kidney stones, and ectopic and basal ganglia calcifications. Few patients manifest hypocalcemia and features of Bartter syndrome, including hypomagnesemia, hypokalemia, metabolic alkalosis, hyperreninemia, and hyperaldosteronemia. {ECO:0000269|PubMed:10487661, ECO:0000269|PubMed:12050233, ECO:0000269|PubMed:12107202, ECO:0000269|PubMed:12241879, ECO:0000269|PubMed:12574188, ECO:0000269|PubMed:12915654, ECO:0000269|PubMed:15551332, ECO:0000269|PubMed:16608894, ECO:0000269|PubMed:19179454, ECO:0000269|PubMed:22789683, ECO:0000269|PubMed:23169696, ECO:0000269|PubMed:23966241, ECO:0000269|PubMed:25766501, ECO:0000269|PubMed:7874174, ECO:0000269|PubMed:8702647, ECO:0000269|PubMed:8733126, ECO:0000269|PubMed:8813042, ECO:0000269|PubMed:8878438, ECO:0000269|PubMed:9253358, ECO:0000269|PubMed:9661634, ECO:0000269|PubMed:9920108}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Epilepsy, idiopathic generalized 8 (EIG8) [MIM:612899]: A disorder characterized by recurring generalized seizures in the absence of detectable brain lesions and/or metabolic abnormalities. Seizure types are variable, but include myoclonic seizures, absence seizures, febrile seizures, complex partial seizures, and generalized tonic-clonic seizures. {ECO:0000269|PubMed:18756473}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;
- Pathway
- NOD-like receptor signaling pathway - Homo sapiens (human);Proton Pump Inhibitor Pathway, Pharmacodynamics;GPCRs, Class C Metabotropic glutamate, pheromone;Signaling by GPCR;Signal Transduction;Class C/3 (Metabotropic glutamate/pheromone receptors);GPCR ligand binding;E-cadherin signaling in keratinocytes;G alpha (i) signalling events;G alpha (q) signalling events;GPCR downstream signalling
(Consensus)
Recessive Scores
- pRec
- 0.661
Intolerance Scores
- loftool
- 0.00530
- rvis_EVS
- -0.11
- rvis_percentile_EVS
- 45.57
Haploinsufficiency Scores
- pHI
- 0.262
- hipred
- Y
- hipred_score
- 0.693
- ghis
- 0.447
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.711
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Casr
- Phenotype
- muscle phenotype; homeostasis/metabolism phenotype; cellular phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); pigmentation phenotype; endocrine/exocrine gland phenotype; digestive/alimentary phenotype; vision/eye phenotype; immune system phenotype; renal/urinary system phenotype; skeleton phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); hematopoietic system phenotype;
Zebrafish Information Network
- Gene name
- casr
- Affected structure
- cranial vault
- Phenotype tag
- abnormal
- Phenotype quality
- dorso-ventrally flattened
Gene ontology
- Biological process
- ossification;response to ischemia;detection of calcium ion;cellular calcium ion homeostasis;apoptotic process;G protein-coupled receptor signaling pathway;adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway;phospholipase C-activating G protein-coupled receptor signaling pathway;JNK cascade;chemosensory behavior;positive regulation of cell population proliferation;anatomical structure morphogenesis;positive regulation of gene expression;positive regulation of insulin secretion;positive regulation of ATPase activity;bile acid secretion;cellular response to hepatocyte growth factor stimulus;vasodilation;positive regulation of vasoconstriction;branching morphogenesis of an epithelial tube;positive regulation of positive chemotaxis;regulation of calcium ion transport;fat pad development;calcium ion import;cellular response to vitamin D;cellular response to glucose stimulus;cellular response to low-density lipoprotein particle stimulus;cellular response to hypoxia;response to fibroblast growth factor;positive regulation of calcium ion import;cellular response to peptide;chloride transmembrane transport
- Cellular component
- nucleus;cytoplasm;plasma membrane;integral component of plasma membrane;cell surface;basolateral plasma membrane;apical plasma membrane;neuronal cell body;axon terminus
- Molecular function
- magnesium ion binding;phosphatidylinositol phospholipase C activity;G protein-coupled receptor activity;integrin binding;calcium ion binding;protein binding;drug binding;amino acid binding;polyamine binding;protein kinase binding;signaling receptor activity;protein homodimerization activity;ion channel binding