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UniProtKB/Swiss-Prot P41180: Variant p.Arg66Cys

Extracellular calcium-sensing receptor
Gene: CASR
Chromosomal location: 3q21-q24
Variant information

Variant position:  66
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  Disease [Disclaimer]
The variants are classified into three categories: Disease, Polymorphism and Unclassified.
  • Disease: Variants implicated in disease according to literature reports.
  • Polymorphism: Variants not reported to be implicated in disease.
  • Unclassified: Variants with uncertain implication in disease according to literature reports. Evidence against or in favor of a pathogenic role is limited and/or conflicting.

Residue change:  From Arginine (R) to Cysteine (C) at position 66 (R66C, p.Arg66Cys).
Indicates the amino acid change of the variant. The one-letter and three-letter codes for amino acids used in UniProtKB/Swiss-Prot are those adopted by the commission on Biochemical Nomenclature of the IUPAC-IUB.

Physico-chemical properties:  Change from large size and basic (R) to medium size and polar (C)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  -3
The score within a Blosum matrix for the corresponding wild-type to variant amino acid change. The log-odds score measures the logarithm for the ratio of the likelihood of two amino acids appearing by chance. The Blosum62 substitution matrix is used. This substitution matrix contains scores for all possible exchanges of one amino acid with another:
  • Lowest score: -4 (low probability of substitution).
  • Highest score: 11 (high probability of substitution).
More information can be found on the following page

Involvement in 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.
The name and a short description of the disease associated with the variant. For more information about the disease, the user can refer to OMIM, following the link provided after the disease acronym.

Variant description:  In HHC1; does not affect homodimerization; impaired N-glycosylation; impaired cell membrane localization; decreased G-protein coupled receptor signaling pathway.
Any additional useful information about the variant.

Other resources:  
Links to websites of interest for the variant.



Sequence information

Variant position:  66
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  1078
The length of the canonical sequence.

Location on the sequence:   AKDQDLKSRPESVECIRYNF  R GFRWLQAMIFAIEEINSSPA
The residue change on the sequence. Unless the variant is located at the beginning or at the end of the protein sequence, both residues upstream (20) and downstream (20) of the variant will be shown.

Residue conservation: 
The multiple alignment of the region surrounding the variant against various orthologous sequences.

Human                         AKDQDLKSRPESVECIRYNFRGFRWLQAMIFAIEEINSSPA

Mouse                         AKDQDLKSRPESVECIRYNFRGFRWLQAMIFAIEEINSSPA

Rat                           AKDQDLKSRPESVECIRYNFRGFRWLQAMIFAIEEINSSPS

Pig                           AKDQNLESRPESVECIRYNFRGFRWLQAMIFAIEEINSSPA

Bovine                        VKDQDLKSRPESVECIRYNFRGFRWLQAMIFAIEEINSSPA

Sequence annotation in neighborhood:  
The regions or sites of interest surrounding the variant. In general the features listed are posttranslational modifications, binding sites, enzyme active sites, local secondary structure or other characteristics reported in the cited references. The "Sequence annotation in neighborhood" lines have a fixed format:
  • Type: the type of sequence feature.
  • Positions: endpoints of the sequence feature.
  • Description: contains additional information about the feature.

TypePositionsDescription
Chain 20 – 1078 Extracellular calcium-sensing receptor
Topological domain 20 – 612 Extracellular
Region 22 – 188 Ligand-binding 1 (LB1)
Region 66 – 70 Anion binding
Metal binding 81 – 81 Calcium; via carbonyl oxygen
Metal binding 84 – 84 Calcium
Disulfide bond 60 – 101
Mutagenesis 69 – 69 R -> E. Abolishes G-protein coupled receptor signaling pathway.
Helix 65 – 82


Literature citations

Mutations in the human Ca(2+)-sensing-receptor gene that cause familial hypocalciuric hypercalcemia.
Chou Y.-H.W.; Pollak M.R.; Brandi M.L.; Toss G.; Arnqvist H.; Atkinson A.B.; Papapoulos S.E.; Marx S.; Brown E.M.; Seidman J.G.; Seidman C.E.;
Am. J. Hum. Genet. 56:1075-1079(1995)
Cited for: VARIANTS HHC1 MET-62; CYS-66; MET-138; GLU-143 AND GLN-227;

Expression and characterization of inactivating and activating mutations in the human Ca2+o-sensing receptor.
Bai M.; Quinn S.; Trivedi S.; Kifor O.; Pearce S.H.S.; Pollak M.R.; Krapcho K.; Hebert S.C.; Brown E.M.;
J. Biol. Chem. 271:19537-19545(1996)
Cited for: VARIANTS HHC1 MET-62; CYS-66; MET-138; GLU-143; GLN-185; LYS-297 AND TRP-795; VARIANT HYPOC1 ALA-127; FUNCTION; SUBCELLULAR LOCATION; GLYCOSYLATION; CHARACTERIZATION OF VARIANTS HHC1 MET-62; CYS-66; MET-138; GLU-143; GLN-185; LYS-297 AND TRP-795; CHARACTERIZATION OF VARIANT HYPOC1 ALA-127;

Calcium-sensing receptor dimerizes in the endoplasmic reticulum: biochemical and biophysical characterization of CASR mutants retained intracellularly.
Pidasheva S.; Grant M.; Canaff L.; Ercan O.; Kumar U.; Hendy G.N.;
Hum. Mol. Genet. 15:2200-2209(2006)
Cited for: VARIANTS HHC1 CYS-66; HIS-66 AND 583-ASN--SER-1078 DEL; SUBCELLULAR LOCATION; SUBUNIT; GLYCOSYLATION; CHARACTERIZATION OF VARIANTS CYS-66; HIS-66 AND 583-ASN--SER-1078 DEL;

Disclaimer: Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. They are not in any way intended to be used as a substitute for professional medical advice, diagnostic, treatment or care.