ClinVar Miner

Submissions for variant NM_000388.3(CASR):c.2657G>C (p.Arg886Pro) (rs1057520791)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000443461 SCV000517456 pathogenic not provided 2018-01-19 criteria provided, single submitter clinical testing The R886P missense variant in the CASR gene has been previously reported to segregate with disease in at least one family with familial hypocalciuric hyercalcemia (Simmonds et al., 2002). A functional study of the R886P variant has shown that it results in increased expression with reduced levels of calcium-stimulated ERK 1/2 phosphorylation (Stepanchick et al., 2010). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). R886P 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 where amino acids with similar properties to arginine are tolerated across species. A missense variant at the same codon (R886W) has been reported in association with hypocalciuric hypercalcaemia, supporting the functional importance of this region of the protein (Nissen et al., 2007). Based on currently available evidence, we consider R886P to be pathogenic.
Invitae RCV000694836 SCV000823298 likely pathogenic Hypocalciuric hypercalcemia, familial, type 1; Hypocalcemia, autosomal dominant 1 2018-05-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 886 of the CASR protein (p.Arg886Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with hypocalciuric hypercalcemia in a family (PMID: 11807402). ClinVar contains an entry for this variant (Variation ID: 379932). An experimental study has shown that this missense change results in increased expression of CASR protein and reduced levels of calcium-stimulated ERK1/2 phosphorylation relative to wild-type (PMID: 20798521). The p.Arg886Trp amino acid residue in CASR has been determined to be clinically significant (PMID: 17698911). This suggests that variants that disrupt this residue are likely to be causative of disease. 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.
OMIM RCV000664400 SCV000788330 pathogenic Hypocalciuric hypercalcemia, familial, type 1 2002-01-01 no assertion criteria provided literature only

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