Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000029452 | SCV000052102 | uncertain significance | not specified | 2019-02-05 | criteria provided, single submitter | clinical testing | Variant summary: CASR c.496A>G (p.Ser166Gly) results in a non-conservative amino acid change located in the ligand binding region (IPR001828) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245912 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.496A>G has been reported in the literature in an individual affected with Familial Hypocalciuric Hypercalcemia, who had a strong family history of hypocalciuric hypercalcemia on the fathers side, with nine hypercalcemic family members, however the family members were not tested for the variant (Cole 2009). These data therefore do not allow unequivocal conclusions about the variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| Invitae | RCV002228057 | SCV000761043 | uncertain significance | Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1 | 2022-09-13 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 35800). This missense change has been observed in individual(s) with familial hypocalciuric hypercalcemia (PMID: 19179454). This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 166 of the CASR protein (p.Ser166Gly). |