ClinVar

Description

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.