Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000498268 | SCV000590420 | likely pathogenic | not provided | 2017-06-20 | criteria provided, single submitter | clinical testing | The E558G variant in the CASR gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The E558G variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E558G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (G553R, I554N, I555T, E556K, G557E, C562Y) have been reported in the Human Gene Mutation Database in association with a CASR-related disorder (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret E558G as a likely pathogenic variant. |
Invitae | RCV003766803 | SCV004606868 | uncertain significance | Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1 | 2024-01-03 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 558 of the CASR protein (p.Glu558Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CASR-related conditions. ClinVar contains an entry for this variant (Variation ID: 432667). 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 tolerated. 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. |