Submissions for variant NM_000388.4(CASR):c.566A>G (p.Asn189Ser)

gnomAD frequency: 0.00003  dbSNP: rs762998933

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480926	SCV000568141	uncertain significance	not provided	2016-10-21	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the CASR gene. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. N189S is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Asparagine are tolerated across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function, and a study by Stewart et al. found no detectable difference in activity from wild type when N189S is assessed in a calcium-dependent MAP kinase activation model (Stewart et al., 2004). Missense variants in nearby residues (R185Q, D190G/E, D191K) have been reported in the Human Gene Mutation Database in association with CASR-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000694537	SCV000822987	uncertain significance	Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1	2023-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 189 of the CASR protein (p.Asn189Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of familial hypocalciuric hypercalcemia (PMID: 31672324). ClinVar contains an entry for this variant (Variation ID: 419926). 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.
Genetics and Molecular Pathology, SA Pathology	RCV002272251	SCV002556633	uncertain significance	Hypercalcemia	2020-08-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226303	SCV003922647	uncertain significance	not specified	2023-03-07	criteria provided, single submitter	clinical testing	Variant summary: CASR c.566A>G (p.Asn189Ser) results in a conservative amino acid change located in the Receptor, ligand binding region (IPR001828) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251222 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.566A>G has been reported in the literature as a VUS in settings of multigene panel testing at-least one individual reportedly affected with Familial Benign Hypercalcemia (example, Hureaux_2019). This report does not provide unequivocal conclusions about association of the variant with Familial Hypocalciuric Hypercalcemia. Three ClinVar submitters have assessed the variant since 2014: all three classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.