Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000480370 | SCV000568685 | uncertain significance | not provided | 2017-02-15 | criteria provided, single submitter | clinical testing | The D1005N variant in the CASR gene has been previously reported in an individual with familial hypocalciuric hypercalcemia; however, functional studies did not demonstrate a significant reduction in receptor calcium response (Rus et al., 2008). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D1005N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position where amino acids with similar properties to Aspartic Acid are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret D1005N as a variant of uncertain significance. |
| Invitae | RCV000543588 | SCV000638066 | uncertain significance | Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1 | 2024-01-27 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1005 of the CASR protein (p.Asp1005Asn). This variant is present in population databases (rs201990892, gnomAD 0.01%). This missense change has been observed in individual(s) with familial hypocalciuric hypercalcemia (PMID: 18796518, 21521328). ClinVar contains an entry for this variant (Variation ID: 420107). 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. Experimental studies have shown that this missense change affects CASR function (PMID: 18796518). 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. |
| Ambry Genetics | RCV002356780 | SCV001179240 | uncertain significance | Inborn genetic diseases; Nephrolithiasis/nephrocalcinosis | 2021-11-26 | criteria provided, single submitter | clinical testing | The p.D1005N variant (also known as c.3013G>A), located in coding exon 6 of the CASR gene, results from a G to A substitution at nucleotide position 3013. The aspartic acid at codon 1005 is replaced by asparagine, an amino acid with highly similar properties. This variant has been reported in 2 individuals with hypercalcaemia (Rus R et al. J. Clin. Endocrinol. Metab., 2008 Dec;93:4797-803; Frank-Raue K et al. Clin. Endocrinol. (Oxf), 2011 Jul;75:50-5). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear. |
| Fulgent Genetics, |
RCV002489155 | SCV002801440 | uncertain significance | Familial hypocalciuric hypercalcemia 1; Neonatal severe primary hyperparathyroidism; Epilepsy, idiopathic generalized, susceptibility to, 8; Autosomal dominant hypocalcemia 1 | 2022-03-23 | criteria provided, single submitter | clinical testing |