ClinVar Genomic variation as it relates to human health

The best available variant frequency is uninformative because there are too few occurrences in population data. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. Damaging to protein function(s) relevant to disease mechanism.

The c.1393C>T;p.(Arg465Trp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (PMID: 20164288) - PS4_supporting. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 29026550) - PS3_supporting. The variant is present at low allele frequencies population databases (rs751217000 – gnomAD 0.00006570%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. Pathogenic missense variant in this residue have been reported (ClinVar ID: 8352 - c.1394G>A (p.Arg465Gln)) - PM5. The variant co-segregated with disease in multiple affected family members (PMID: 29026550) - PP1_supporting. In summary, the currently available evidence indicates that the variant is likely pathogenic.

Variant summary: CASR c.1393C>T (p.Arg465Trp) results in a non-conservative amino acid change located in the ligand binding region (IPR001828) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251282 control chromosomes (gnomAD). c.1393C>T has been reported in the literature in the heterozygous state in multiple individuals affected with Familial Hypocalciuric Hypercalcemia, but often without segregation data (e.g. Guarnieri_2010, Vargas-Poussou_2016, Hureaux_2019, Mouly_2020). It has also been reported as a homozygous genotype in a woman with no family history of calcium distrubances who was asymptomatic until during her second pregnancy, but whose two heterozygous daughters were affected (Maltese_2017). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found the variant was associated with reduced maturation, cell surface expression, and cell signaling compared to the wild-type protein, however, it does not allow strong conclusions about the variant effect (Guarnieri_2010). The following publications have been ascertained in the context of this evaluation (PMID: 20164288, 29026550, 32347971, 26963950, 31672324). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified it as either likely pathogenic (n=3) or VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 465 of the CASR protein (p.Arg465Trp). This variant is present in population databases (rs751217000, gnomAD 0.007%). This missense change has been observed in individuals with clinical features of familial hypocalciuric hypercalcemia (FHH) (PMID: 20164288, 29026550, 31672324, 32347971; Invitae). ClinVar contains an entry for this variant (Variation ID: 410348). 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: 20164288). This variant disrupts the p.Arg465 amino acid residue in CASR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16598859, 26646938, 26963950, 28176280, 30407919; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

The p.R465W variant (also known as c.1393C>T), located in coding exon 4 of the CASR gene, results from a C to T substitution at nucleotide position 1393. The arginine at codon 465 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been identified in individuals with hypercalcemia and inappropriately normal parathyroid hormone levels; however, if has also been identified in first degree relatives without hypercalcemia (Guarnieri V et al. J. Clin. Endocrinol. Metab., 2010 Apr;95:1819-29; Maltese G et al. Clin Case Rep, 2017 10;5:1587-1590). This variant has also been reported in additional familial hypocalciuric hypercalcemia cohorts (Hureaux M et al. Kidney Int, 2019 Dec;96:1408-1416; Mouly C et al. Clin Endocrinol (Oxf), 2020 Sep;93:248-260). In HEK293 cells, this variant was impaired relative to the wild type CASR with respect to maturation, cell surface expression, and signaling (Guarnieri V et al. J. Clin. Endocrinol. Metab., 2010 Apr;95:1819-29). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, the evidence for the gene-disease relationship is limited for pancreatitis and cancer predisposition; therefore, the clinical significance of this variant for CASR-related pancreatitis and cancer predisposition is unclear. Based on available evidence to date, the clinical significance of this alteration remains unclear.

PP2, PP3, PS3_moderate, PS4_moderate