Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000806048 | SCV000946028 | likely pathogenic | Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1 | 2023-08-22 | criteria provided, single submitter | clinical testing | This missense change has been observed in individual(s) with familial hypocalciuric hypercalcemia (FHH) and/or neonatal severe hyperparathyroidism (NSHPT) (PMID: 16740594, 32347971, 32386559). It has also been observed to segregate with disease in related individuals. 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. Experimental studies have shown that this missense change affects CASR function (PMID: 16740594, 25104082). 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. ClinVar contains an entry for this variant (Variation ID: 650821). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 66 of the CASR protein (p.Arg66His). |
| Gene |
RCV002264984 | SCV002547123 | pathogenic | not provided | 2022-01-07 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate disruption of protein trafficking to the cell surface and impaired cell singling response (Pidasheva et al., 2006; Dershem et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16740594, 25525159, 32347971, 32386559, 25104082, 27434672, 31778168) |
| Ambry Genetics | RCV002422761 | SCV002722905 | likely pathogenic | Inborn genetic diseases; Nephrolithiasis/nephrocalcinosis | 2020-01-22 | criteria provided, single submitter | clinical testing | The p.R66H variant (also known as c.197G>A), located in coding exon 2 of the CASR gene, results from a G to A substitution at nucleotide position 197. The arginine at codon 66 is replaced by histidine, an amino acid with highly similar properties. This variant was identified in the homozygous state in two siblings with neonatal severe hyperparathyroidism and was confirmed heterozygous in both parents with familial hypocalciuric hypercalcemia (Pidasheva S et al. Hum. Mol. Genet., 2006 Jul;15:2200-9). In HEK293 cells, this variant demonstrated impaired trafficking from the endoplasmic reticulum, reduced levels of mature fully glycosylated protein, and was unresponsive to high calcium levels, with little or no activation of ERK1/2 compared to wild type (Pidasheva S et al. Hum. Mol. Genet., 2006 Jul;15:2200-9; Stratta P et al. Nephrol. Dial. Transplant., 2014 Oct;29:1902-9). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |