ClinVar Genomic variation as it relates to human health

The R544Q variant previously has been reported previously as a rare variant in association with familial hypocalciuric hypercalcemia (FHH) (Nissen et al., 2012). It is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). R544Q is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties and occurs at a position that is conserved in mammals. Missense variants in nearby residues (C542R, C546S, G549R) have been reported in the Human Gene Mutation Database in association with hypocalciuric hypercalcaemia (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

DNA sequence analysis of the CASR gene demonstrated a sequence change, c.1631G>A, in exon 6 that results in an amino acid change, p.Arg544Gln. This sequence change has been described in the gnomAD database with a frequency of 0.6% in the Ashkenazi Jewish subpopulation (dbSNP rs115230894). The p.Arg544Gln change affects a moderately conserved amino acid residue located in a domain of the CASR protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg544Gln substitution. This variant has been reported in the homozygous state in an individual with hypocalcemic hypoparathyroidism (PMID: 29846619). The authors suggest this variant may be pathogenic in the homozygous state but is unlikely to contribute to disease in the heterozygous state. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg544Gln change remains unknown at this time.

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

The CASR c.1631G>A; p.Arg544Gln variant (rs115230894) is reported in the literature in individuals with primary hyperparathyroidism or familial hypocalciuric hypercalcemia (Bhangu 2022, Cavaco 2018, Nissen 2012). This variant is also reported in ClinVar (Variation ID: 237758). It is observed in the general population with an overall allele frequency of 0.087% (245/282890 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.337). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Bhangu JS et al. Novel mutations of the calcium-sensing receptor impede differential diagnosis of primary hyperparathyroidism and familial hypocalciuric hypercalcemia. Gland Surg. 2022 Jan;11(1):12-22. PMID: 35242665. Cavaco BM et al. Homozygous Calcium-Sensing Receptor Polymorphism R544Q Presents as Hypocalcemic Hypoparathyroidism. J Clin Endocrinol Metab. 2018 Aug 1;103(8):2879-2888. PMID: 29846619. Nissen PH et al. Identification of rare and frequent variants of the CASR gene by high-resolution melting. Clin Chim Acta. 2012 Mar 22;413(5-6):605-11. PMID: 22192860.

CASR: BP4