ClinVar Miner

Submissions for variant NM_000388.4(CASR):c.2254C>T (p.Arg752Cys) (rs193922434)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000029442 SCV000052092 uncertain significance not specified 2019-01-22 criteria provided, single submitter clinical testing Variant summary: The variant, CASR c.2254C>T (p.Arg752Cys) results in a non-conservative amino acid change located in the GPCR family 3, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245378 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant c.2254C>T has been reported in the literature in individuals affected with Familial Hypocalciuric Hypercalcemia (Hannan_2012). However, this report does not provide unequivocal conclusions about association of the variant with Familial Hypocalciuric Hypercalcemia (FHH). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000639459 SCV000761034 uncertain significance Hypocalciuric hypercalcemia, familial, type 1; Hypocalcemia, autosomal dominant 1 2017-08-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 752 of the CASR protein (p.Arg752Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with familial hypocalciuric hypercalcemia (PMID: 22422767). ClinVar contains an entry for this variant (Variation ID: 35790). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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.