Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Rady Children's Institute for Genomic Medicine, |
RCV000008851 | SCV000996253 | pathogenic | Autosomal dominant hypocalcemia 1 | 2019-02-28 | criteria provided, single submitter | clinical testing | This variant has been previously reported as a heterozygous change in patients with hypocalcemia (PMID: 11013439 12107202 12191970). Functional analysis revealed that the kinetics of activation of the p.Leu125Pro receptor expressed in HEK-293 cells, as assessed by measuring CaSR-stimulated changes in intracellular Ca(2+) and ERK activity, showed a dramatic reduction in the EC(50) for extracellular Ca(2+) compared with the wild-typ (PMID 12191970). The p.Leu125Pro variant is proposed to reduce NaCl reabsorption in the cortical thick ascending limb sufficiently to result in renal loss of NaCl with secondary hyperaldosteronism and hypokalemia (PMID 12191970). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.374T>C, p.Leu125Pro variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.374T>C, p.Leu125Pro variant is classified as Pathogenic. |
| Revvity Omics, |
RCV001781207 | SCV002025075 | likely pathogenic | not provided | 2021-05-11 | criteria provided, single submitter | clinical testing | |
| Fulgent Genetics, |
RCV002482843 | SCV002779038 | pathogenic | Familial hypocalciuric hypercalcemia 1; Neonatal severe primary hyperparathyroidism; Epilepsy, idiopathic generalized, susceptibility to, 8; Autosomal dominant hypocalcemia 1 | 2021-11-16 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV003764538 | SCV004569660 | uncertain significance | Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1 | 2023-11-06 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 125 of the CASR protein (p.Leu125Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant hypocalcemia (PMID: 11701698, 12107202, 12191970). ClinVar contains an entry for this variant (Variation ID: 8346). 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: 12191970, 25506941). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| OMIM | RCV000008851 | SCV000029061 | pathogenic | Autosomal dominant hypocalcemia 1 | 2002-09-01 | no assertion criteria provided | literature only | |
| OMIM | RCV000190877 | SCV000245749 | pathogenic | Bartter syndrome with hypocalcemia | 2002-09-01 | no assertion criteria provided | literature only |