Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
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 | likely pathogenic | Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1 | 2023-06-15 | criteria provided, single submitter | clinical testing | An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 448997). This missense change has been observed in individuals with familial hypocalciuric hypercalcaemia (PMID: 9039332, 20495831, 32347971). This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 220 of the CASR protein (p.Arg220Gln). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg220 amino acid residue in CASR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10885494, 11889203, 22142470). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. |
| Molecular Genetics Laboratory, |
RCV003983103 | SCV004708175 | pathogenic | Familial hypocalciuric hypercalcemia 1 | 2024-03-08 | no assertion criteria provided | clinical testing |