Submissions for variant NM_000388.4(CASR):c.2657G>C (p.Arg886Pro)

dbSNP: rs1057520791

Total submissions: 5

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000694836	SCV000823298	pathogenic	Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1	2024-11-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 886 of the CASR protein (p.Arg886Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial hypocalciuric hypercalcemia (PMID: 11807402). It has also been observed to segregate with disease in related individuals. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this CASR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 606,512 individuals referred to our laboratory for CASR testing. ClinVar contains an entry for this variant (Variation ID: 379932). 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: 20798521). This variant disrupts the p.Arg886 amino acid residue in CASR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17698911). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	RCV000443461	SCV002771677	pathogenic	not provided	2022-04-19	criteria provided, single submitter	clinical testing	This variant appears to segregate with disease in at least one family. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant was shown to impair receptor function (PMID: 20798521).
Mayo Clinic Laboratories, Mayo Clinic	RCV000443461	SCV005413617	pathogenic	not provided	2023-09-12	criteria provided, single submitter	clinical testing	PP1_strong, PP3, PM2, PM5_supporting, PS3_supporting, PS4_moderate
OMIM	RCV000664400	SCV000788330	pathogenic	Familial hypocalciuric hypercalcemia 1	2002-01-01	no assertion criteria provided	literature only