ClinVar Genomic variation as it relates to human health

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 143 of the CASR protein (p.Gly143Arg). This variant is present in population databases (rs769256610, gnomAD 0.0009%). This missense change has been observed in individuals with familial hypocalciuric hypercalcemia (PMID: 19179454, 32347971, 32430905; Invitae). ClinVar contains an entry for this variant (Variation ID: 237770). 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. This variant disrupts the p.Gly143 amino acid residue in CASR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7726161, 8702647, 19389809, 23077345). 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 frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic. Computational tools yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Computational tools predict that this variant is damaging.

The p.G143R variant (also known as c.427G>A), located in coding exon 2 of the CASR gene, results from a G to A substitution at nucleotide position 427. The glycine at codon 143 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been identified in multiple individuals diagnosed with hyperparathyroidism (Ambry internal data; Cole DE et al. J Mol Endocrinol, 2009 Apr;42:331-9; Mariathasan S et al. Clin Endocrinol (Oxf), 2020 Oct;93:409-418).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. Loss-of-function variants in CASR are known to cause familial hypocalciuric hypercalcemia (FHH1); however, such associations with CASR-related hypocalcemia (ADH1) have not been reported (Hannan F et al. Nat Rev Endocrinol. 2018 Dec 1; 15(1): 33–51). Based on the supporting evidence, this variant is likely pathogenic for FHH1; however, the association of this variant with ADH1 is unlikely.

Variant summary: CASR c.427G>A (p.Gly143Arg) results in a non-conservative amino acid change located in the Receptor, ligand binding region domain (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 4e-06 in 251306 control chromosomes. c.427G>A has been reported in the literature in individuals affected with Familial Hypocalciuric Hypercalcemia (e.g. Cole_2009, Mouly_2020, Mariathasan_2020). These data indicate that the variant may be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.428G>A,p.Gly143Glu), supporting the critical relevance of codon 143 to CASR protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19179454, 31189130, 32430905, 32347971, 34088669). ClinVar contains an entry for this variant (Variation ID: 237770). Based on the evidence outlined above, the variant was classified as pathogenic.

The CASR c.427G>A variant is predicted to result in the amino acid substitution p.Gly143Arg. The p.Gly143Arg variant has been reported to be causative for familial hypocalciuric hypercalcemia (Cole et al. 2009. PubMed ID: 19179454; Mouly et al. 2020. PubMed ID: 32347971). In addition, a different substitution of this same amino acid (p.Gly143Glu) has also been reported to be pathogenic (Zhang et al. 2002. PubMed ID: 12114500) and several functional studies indicate the p.Gly143 residue is important for normal protein function (Bai et al. 1996. PubMed ID: 8702647; Grant et al. 2012. PubMed ID: 23077345). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic.