Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000474973 | SCV000550984 | pathogenic | Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1 | 2023-12-16 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 798 of the CASR protein (p.Pro798Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypocalciuric hypercalcemia (PMID: 15963484, 22422767, 31672324; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 410346). 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. This variant disrupts the p.Pro798 amino acid residue in CASR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15963484, 19389809). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002265771 | SCV002548002 | likely pathogenic | Familial hypocalciuric hypercalcemia | 2022-05-03 | criteria provided, single submitter | clinical testing | Variant summary: CASR c.2393C>T (p.Pro798Leu) results in a non-conservative amino acid change located in the GPCR family 3, C-terminal domain (IPR017978) of the encoded protein sequence. Proline 798 is conserved among different species, suggesting its crucial role in the normal functioning of CASRs. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251304 control chromosomes. c.2393C>T has been reported in the literature in individuals affected with Familial Hypocalciuric Hypercalcemia (example, Hannan_2012, Hureaux_2019, Gorvin_2019, Mariathasan_2020). These data indicate that the variant is likely to be associated with disease. 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 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Center for Genomic Medicine, |
RCV002465660 | SCV002760319 | likely pathogenic | not provided | 2023-08-15 | criteria provided, single submitter | clinical testing | |
| Athena Diagnostics Inc | RCV002465660 | SCV004229518 | likely pathogenic | not provided | 2023-04-21 | criteria provided, single submitter | clinical testing | In some published literature, this variant is referred to as c.2423C>T p.(Pro808Leu). This variant has been identified in multiple unrelated individuals with clinical features of hypocalciuric hypercalcemia. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Computational tools predict that this variant is damaging. |