Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001210240 | SCV001381716 | uncertain significance | Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1 | 2023-10-04 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 820 of the CASR protein (p.Ser820Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familialhypocalciuric hypercalcaemia type 1 (PMID: 30052933). ClinVar contains an entry for this variant (Variation ID: 940617). 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: 30052933). 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001420750 | SCV001623093 | uncertain significance | not specified | 2021-04-22 | criteria provided, single submitter | clinical testing | Variant summary: CASR c.2458T>G (p.Ser820Ala) results in a conservative amino acid change located in the GPCR family 3 (third extracellular loop) C-terminal transmembrane domain (IPR017978) of the encoded protein sequence. This variant affects an evolutionarily conserved residue of the CASR protein. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251308 control chromosomes. c.2458T>G has been reported in the literature in at-least one individual affected with Familial Hypocalciuric Hypercalcaemia (example, Gorvin_2018). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in an impairment of calcium ion signalling without altering ERK phosphorylation in an in-vitro experimental system (Gorvin_2018). This finding is consistent with a loss of function mechanism observed in Familial Hypocalciuric Hypercalcaemia. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance citing an overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |