Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002230400 | SCV000550985 | pathogenic | Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1 | 2023-11-13 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 680 of the CASR protein (p.Arg680Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with familial hypocalciuric hypercalcemia and/or neonatal severe hyperparathyroidism (PMID: 8675635, 15241688, 32347971, 32386559). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 410347). 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. Experimental studies have shown that this missense change affects CASR function (PMID: 8878438, 17284438, 19389809, 22798347, 23372019, 32386559). This variant disrupts the p.Arg680 amino acid residue in CASR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19179454, 22798347, 23372019, 26646938, 26963950, 27666534, 32347971; Invitae). 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. |
| Athena Diagnostics | RCV001289355 | SCV001477106 | pathogenic | not provided | 2022-01-27 | criteria provided, single submitter | clinical testing | The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant appears to be associated with disease in at least one family. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant caused significant alterations in calcium potency and/or efficacy (PMID: 8878438, 22798347, 17284438). Computational tools predict that this variant is damaging. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002307504 | SCV002600597 | pathogenic | Familial hypocalciuric hypercalcemia | 2022-10-20 | criteria provided, single submitter | clinical testing | Variant summary: CASR c.2038C>T (p.Arg680Cys) results in a non-conservative amino acid change located in the GPCR family 3, C-terminal domain (IPR017978) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251154 control chromosomes. c.2038C>T has been widely reported in the literature in individuals affected with features of Familial Hypocalciuric Hypercalcemia/Familial benign hypercalcemia (example, Pearce_1995, Mouly_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Pearce_1996). The most pronounced variant effect results in lack of responsiveness to gadolinium or calcium ions (<10% of normal activity) and severely reduced N-linked glycosylation despite normal receptor expression on the cell membrane. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |