CASR R990G - GET-Evidence

Note: This variant has not been sufficiently evaluated by a GET-Evidence editor.

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Curation:
Currentness:

CASR R990G

(CASR Arg990Gly)


Short summary

 

Variant evidence
Computational 5

PolyPhen: Possibly damaging 0.388
SIFT: Affect protein function 0.02
GVGD: GV 0.00; GD 125.13; Class C65
Variant Effect Predictor (Ensembl ):
SIFT=deleterious(0);
PolyPhen=possibly_damaging(0.388);
Condel=deleterious(0.744)
Mutation Tasting Prediction: Polymorphism, P value: 0. 588690; protein features (might be) affected (aa 863-1078 TOPO_DOM Cytoplasmic (potential) gets lost)

Functional 3

990G appears to be a gain-of-function allele, that increases response to extracellular calcium ions and sensitivity to R-568.

See Vezzoli G et al. 2007 (17332735), Terranegra A et al. 2010 (20682641), Reyes M et al. 2012 (22166946).

Case/Control -
Familial -
 
Clinical importance
Severity 2

See Muddana V et al. 2008 (18680227), Hibler EA et al. 2012 (22144504).

Treatability -
Penetrance -
 

Impact

Insufficiently evaluated pharmacogenetic

(The "insufficiently evaluated" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

unknown

Summary of published research, and additional commentary

Rare allele among people of European ancestry, but common among East Asians.

Allele frequency

  • G @ chr3:122003769: 6.4% (690/10758) in EVS
  • G @ chr3:123486458: 11.7% (15/128) in GET-Evidence
  • Frequency shown in summary reports: 6.4% (690/10758)

Publications
 

Vezzoli G, Terranegra A, Arcidiacono T, Biasion R, Coviello D, Syren ML, Paloschi V, Giannini S, Mignogna G, Rubinacci A, Ferraretto A, Cusi D, Bianchi G, Soldati L. R990G polymorphism of calcium-sensing receptor does produce a gain-of-function and predispose to primary hypercalciuria. Kidney Int. 2007 Jun;71(11):1155-62. Epub 2007 Feb 28. PubMed PMID: 17332735.

 

Muddana V, Lamb J, Greer JB, Elinoff B, Hawes RH, Cotton PB, Anderson MA, Brand RE, Slivka A, Whitcomb DC. Association between calcium sensing receptor gene polymorphisms and chronic pancreatitis in a US population: role of serine protease inhibitor Kazal 1type and alcohol. World J Gastroenterol. 2008 Jul 28;14(28):4486-91. PubMed PMID: 18680227; PubMed Central PMCID: PMC2731274.

 

Schwartz GG, John EM, Rowland G, Ingles SA. Prostate cancer in African-American men and polymorphism in the calcium-sensing receptor. Cancer Biol Ther. 2010 Jun;9(12):994-9. Epub 2010 Jun 4. PubMed PMID: 20364112.

 

Terranegra A, Ferraretto A, Dogliotti E, Scarpellini M, Corbetta S, Barbieri AM, Spada A, Arcidiacono T, Rainone F, Aloia A, Cusi D, Vezzoli G, Soldati L. Calcimimetic R-568 effects on activity of R990G polymorphism of calcium-sensing receptor. J Mol Endocrinol. 2010 Oct;45(4):245-56. Epub 2010 Aug 3. PubMed PMID: 20682641.

 

Hibler EA, Hu C, Jurutka PW, Martinez ME, Jacobs ET. Polymorphic variation in the GC and CASR genes and associations with vitamin D metabolite concentration and metachronous colorectal neoplasia. Cancer Epidemiol Biomarkers Prev. 2012 Feb;21(2):368-75. Epub 2011 Dec 5. PubMed PMID: 22144504; PubMed Central PMCID: PMC3275650.

 

Reyes M, Rothe HM, Mattar P, Shapiro WB, Cifuentes M. Antilipolytic effect of calcimimetics depends on the allelic variant of calcium-sensing receptor gene polymorphism rs1042636 (Arg990Gly). Eur J Hum Genet. 2012 Apr;20(4):480-2. doi: 10.1038/ejhg.2011.221. Epub 2011 Dec 14. PubMed PMID: 22166946; PubMed Central PMCID: PMC3306864.

 

Genomes
 

hu241DEA - CGI sample GS01175-DNA_D05 from PGP sample 1205491
het G @ chr3:122003769

 

hu38168C - CGI sample GS01173-DNA_H06 from PGP sample 91708424
het G @ chr3:122003769

 

 

hu8229AE - CGI sample GS01173-DNA_A07 from PGP sample 96240009
het G @ chr3:122003769

 

hu92C40A - CGI sample GS01175-DNA_G03 from PGP sample 92527586
het G @ chr3:122003769

 

hu92FD55 - CGI sample GS01669-DNA_A04 from PGP sample 08188426
hom G @ chr3:122003769

 

 

huAE4A11 - CGI sample GS01669-DNA_F02 from PGP sample 40767107
het G @ chr3:122003769

 

huBEDA0B - CGI sample GS00253-DNA_C01_200_37
het G @ chr3:122003769

 

huCA017E - CGI sample GS01175-DNA_B01 from PGP sample 86206034
het G @ chr3:122003769

 

huE80E3D - CGI sample GS00253-DNA_D01_200_37
het G @ chr3:122003769

 

GS07357 - var-GS07357-1100-36-ASM
het G @ chr3:123486459

 

GS10851 - var-GS10851-1100-36-ASM
het G @ chr3:123486459

 

GS18537 - var-GS18537-1100-36-ASM
hom G @ chr3:123486459

 

GS18555 - var-GS18555-1100-36-ASM
het G @ chr3:123486459

 

GS18558 - var-GS18558-1100-36-ASM
hom G @ chr3:123486459

 

GS18942 - var-GS18942-1100-36-ASM
het G @ chr3:123486459

 

GS18956 - var-GS18956-1100-36-ASM
het G @ chr3:123486459

 

Other external references
 

    dbSNP
  • rs1042636
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    GeneTests
  • GeneTests records for the CASR gene
    Autosomal Dominant Hypocalcemia
    CASR-Associated Familial Isolated Hypoparathyroidism
    CASR-Related Disorders
    CASR-Related Familial Isolated Hypoparathyroidism
    Familial Hypocalciuric Hypercalcemia, Type I
    Familial Isolated Hypoparathyroidism
    Neonatal Severe Primary Hyperparathyroidism
    www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/CASR
    PharmGKB
  • [Pancreatic Diseases]
    One study at 115 subjects with pancreatitis and 66 controls found that the CASR R990G variant is a significant risk factor for chronic pancreatitis.
    www.ncbi.nlm.nih.gov/pubmed/18680227
    PolyPhen-2
  • Score: 0.939 (probably damaging)
    Web search results (149 hits -- see all)
  • CASR [PharmGKB]
    One study at 115 subjects with pancreatitis and 66 controls found that the CASR R990G variant is a significant risk factor for chronic pancreatitis. Variant Name: ...
    www.pharmgkb.org/do/serve?objId=PA26097&objCls=Gene
  • Association between calcium sensing receptor gene ...
    RESULTS: The CASR exon 7 R990G polymorphism was significantly associated with CP ... The association between CASR R990G and CP was stronger in subjects who reported ...
    www.ncbi.nlm.nih.gov/pubmed/18680227
  • World J Gastroenterol
    RESULTS: The CASR exon 7 R990G polymorphism was significantly associated with CP ... The association between CASR R990G and CP was stronger in subjects ...
    www.wjgnet.com/1007-9327/14/4486.asp
  • Primary Hyperparathyroidism and the Presence of Kidney Stones ...
    Thus, the CASR is a candidate gene for association with disorders of ... Vezzoli et al. (10) found that CASR R990G was associated with urinary calcium excretion ...
    jcem.endojournals.org/cgi/content/full/92/1/277
  • R990G polymorphism of the calcium-sensing receptor and renal ...
    R990G polymorphism of the calcium-sensing receptor and renal calcium excretion in ... No mutations in CaSR coding sequence have been found in parathyroid tumors (10, ...
    www.eje-online.org/cgi/content/full/155/5/687
  • Rs1042636 - SNPedia
    Defects in CASR are the cause of autosomal dominant hypoparathyroidism (FIH) (MIM:146200) ... 66 controls found that the CASR R990G variant is a significant risk ...
    www.snpedia.com/index.php?title=Rs1042636
  • R990G polymorphism of the calcium-sensing receptor and renal ...
    sensing receptor (CaSR) and clinical characteristics of PHPT are not conclusive. ... between CaSR A986S and R990G genotypes in patients affected ...
    www.eje-online.org/cgi/reprint/155/5/687.pdf
  • Association of genetic variants in the calcium-sensing ...
    We assessed the associations between CASR gene variants and risk for colorectal adenoma, a cancer precursor. ... signaling region of CASR (A986S, R990G, Q1011E) were analyzed by ...
    www.ncbi.nlm.nih.gov/pubmed/15598778
  • FHA - The clinical significance of parathyroid tissue calcium ...
    In the present report, we examined the relationship between CaSR... METHODS: We genotyped the CaSR R990G and Q1011E variants in 192 end-stage renal disease (ESRD) patients by ...
    find-health-articles.com/rec_pub_19640368-the-clinical-si...
  • Functional characterization of calcium sensing receptor ...
    R990G polymorphism of calcium-sensing receptor does produce a ... Methods: We genotyped the CaSR R990G and Q1011E variants in 192 end-stage renal disease (ESRD) patients by ...
    lib.bioinfo.pl/pmid:17054460

Other in silico analyses
 

  • NBLOSUM100 score = 6
  • GET-Evidence autoscore = 4

Edit history
 

Gene search

"GENE" or "GENE A123C":

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