ClinVar Miner

Submissions for variant NM_000388.4(CASR):c.554G>A (p.Arg185Gln) (rs104893689)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000412784 SCV000490454 pathogenic not provided 2018-05-04 criteria provided, single submitter clinical testing The R185Q variant has been reported in association with CASR-related disorders (Pollak et al., 1993; Bai et al., 1997; Reh et al., 2011). In vitro functional studies demonstrated that the R185Q variant results in substantially decreased signaling capacity (Bai et al., 1996; Leach et al., 2012). The R185Q variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R185Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is pathogenic.
Invitae RCV000627760 SCV000550968 pathogenic Familial hypocalciuric hypercalcemia; Hypocalcemia, autosomal dominant 1 2019-11-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 185 of the CASR protein (p.Arg185Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (rs104893689, ExAC no frequency). This variant has been reported to segregate with familial hypocalciuric hypercalcemia and neonatal hyperparathyroidism in two families (PMID: 7916660, 24203066). It has also been reported to occur de novo in individuals with neonatal hyperparathyroidism (PMID: 21289269, 25091521, 9011580) and in additional individuals with familial hypocalciuric hypercalcemia or neonatal hyperparathyroidism (PMID: 26161261, 18751724, 22422767). However, none of the individuals with neonatal hyperparathyroidism carried a second CASR variant. This variant is also known as p.Arg186Glu in the literature. ClinVar contains an entry for this variant (Variation ID: 8314). Experimental studies have shown that this missense change disrupts the ability of the CASR protein to respond to extracellular calcium in cell culture (PMID: 19759318, 22798347, 12114500, 17284438, 12095982, 25091521). For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000008813 SCV000590874 pathogenic Hypocalciuric hypercalcemia, familial, type 1 2016-03-14 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV000008813 SCV001427174 pathogenic Hypocalciuric hypercalcemia, familial, type 1 2019-02-04 criteria provided, single submitter clinical testing A heterozygous missense variant, NM_000388.3(CASR):c.554G>A, has been identified in exon 4 of 7 of the CASR gene. The variant is predicted to result in a minor amino acid change from arginine to glutamine at position 185 of the protein (NP_000379.2(CASR):p.(Arg185Gln)). The arginine at this position has very high conservation (100 vertebrates, UCSC), and is located within the ligand-binding functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in population databases (gnomAD, dbSNP, 1000G). The variant has been previously described as pathogenic in multiple patients (ClinVar). Additionally, studies showed altered protein function (Bai, M. et al., 1996; Glaudo, M. et al., 2016). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
OMIM RCV000008813 SCV000029023 pathogenic Hypocalciuric hypercalcemia, familial, type 1 1997-01-01 no assertion criteria provided literature only
OMIM RCV000008814 SCV000029024 pathogenic Neonatal severe hyperparathyroidism 1997-01-01 no assertion criteria provided literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.