Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003387911 | SCV004100134 | uncertain significance | not specified | 2025-07-24 | criteria provided, single submitter | clinical testing | Variant summary: CASR c.494T>G (p.Val165Gly) results in a non-conservative amino acid change located in the Receptor, ligand binding region of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251094 control chromosomes. c.494T>G has been observed in individual(s) affected with clinical features of familial hypocalciuric hypercalcemia and/or hyperparathyroidism (internal data). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 566469). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| Ambry Genetics | RCV004026232 | SCV002642594 | uncertain significance | Nephrolithiasis/nephrocalcinosis | 2021-09-02 | criteria provided, single submitter | clinical testing | The p.V165G variant (also known as c.494T>G), located in coding exon 3 of the CASR gene, results from a T to G substitution at nucleotide position 494. The valine at codon 165 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV000686284 | SCV000813796 | likely pathogenic | Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1 | 2025-03-17 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 165 of the CASR protein (p.Val165Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of familial hypocalciuric hypercalcemia and/or hyperparathyroidism (internal data). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this CASR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 606,512 individuals referred to our laboratory for CASR testing. ClinVar contains an entry for this variant (Variation ID: 566469). 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. 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. |
| Genome |
RCV003483704 | SCV004228615 | not provided | Neonatal severe primary hyperparathyroidism; Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1; Bartter syndrome with hypocalcemia | no classification provided | phenotyping only | Variant interpreted as Uncertain significance and reported on 02-17-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. |