ClinVar Miner

Submissions for variant NM_000388.4(CASR):c.659G>A (p.Arg220Gln) (rs1202110240)

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
GeneDx RCV000523669 SCV000616672 likely pathogenic not provided 2017-09-18 criteria provided, single submitter clinical testing The R220Q variant in the CASR gene has previously been reported in at least one individual with familial hypocalciuric hypercalcemia (Pearce et al., 1996). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R220Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Arginine 220 is highly conserved across species at this position within the extracellular domain and functional studies have suggested that it is important for ligand-receptor interactions (D'Souza-Li et al., 2002). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein tructure/function. Alternate missense variants in the same residue (R220W, R220P) have been reported in association with familial hypocalciuric hypercalcemia, supporting the functional importance of this region of the protein (D'Souza-Li et al., 2002; Hannan et al., 2012). Based on currently available evidence, R220Q is a strong candidate for a pathogenic variant. However, the possibility it may be a rare benign variant cannot be excluded.
Invitae RCV000639448 SCV000761023 uncertain significance Hypocalciuric hypercalcemia, familial, type 1; Hypocalcemia, autosomal dominant 1 2017-12-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 220 of the CASR protein (p.Arg220Gln). 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 (ExAC no frequency). This variant has been reported in an individual and a single family presenting with features consistent with familial hypocalciuric hypercalcemia (PMID: 20495831, 9039332). 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. A different missense substitution at this codon (p.Arg220Trp) has been reported to segregate with disease in three unrelated families (PMID: 10885494, 11889203, 22142470). In addition, experimental studies have shown that this missense change has a significant difference in the internal calcium response to increasing concentration of extracellualar calcium when compared to wild type (PMID: 11763315, 1889203). This suggests that the arginine residue is critical for CASR protein function and that other missense substitutions at this position may also be damaging. 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.