Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001233441 | SCV001406035 | likely pathogenic | Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1 | 2023-07-08 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 959995). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 767 of the CASR protein (p.Glu767Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypocalcemia and/or hypoparathyroidism (PMID: 15551332; Invitae). It has also been observed to segregate with disease in related individuals. 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: 22798347, 23372019). 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. |
| Ambry Genetics | RCV003353236 | SCV004070927 | likely pathogenic | Nephrolithiasis/nephrocalcinosis | 2023-08-02 | criteria provided, single submitter | clinical testing | The c.2299G>A (p.E767K) alteration is located in exon 7 (coding exon 6) of the CASR gene. This alteration results from a G to A substitution at nucleotide position 2299, causing the glutamic acid (E) at amino acid position 767 to be replaced by a lysine (K)._x000D_ Based on the available evidence, the CASR c.2299G>A (p.E767K) alteration is classified as likely pathogenic for autosomal dominant CASR-related hypocalcemia; however, it is unlikely to be causative of autosomal recessive neonatal hyperparathyroidism and autosomal dominant hypocalciuric hypercalcemia. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was reported in the heterozygous state in multiple relatives from a family with CASR-related hypocalcemia (Uckun-Kitapci, 2005). Additionally, another alteration at the same codon, c.2299G>C (p.E767Q), has been detected in individuals with hypocalcemia (Letz, 2010; Taylor, 2015). This amino acid position is highly conserved in available vertebrate species. Functional studies indicate this alteration increases sensitivity to extracellular calcium (Leach, 2012). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. |