ClinVar Miner

Submissions for variant NM_000388.4(CASR):c.1394G>A (p.Arg465Gln)

dbSNP: rs104893716
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000459271 SCV000550959 pathogenic Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1 2023-12-11 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 465 of the CASR protein (p.Arg465Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with benign familial hypocalciuric hypercalcemia (PMID: 16598859, 26646938, 26963950, 28176280, 30407919; Invitae). ClinVar contains an entry for this variant (Variation ID: 8352). 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. Experimental studies have shown that this missense change affects CASR function (PMID: 16598859). 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: 20164288, 29026550, 31672324; Invitae). 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.
Ambry Genetics RCV004018600 SCV002701672 likely pathogenic Nephrolithiasis/nephrocalcinosis 2024-06-03 criteria provided, single submitter clinical testing The p.R465Q variant (also known as c.1394G>A), located in coding exon 4 of the CASR gene, results from a G to A substitution at nucleotide position 1394. The arginine at codon 465 is replaced by glutamine, an amino acid with highly similar properties. This variant has been identified in individuals with hyperparathyroidism as well as individuals with familial hypocalciuric hypercalcemia (Leech C et al. Biochem. Biophys. Res. Commun., 2006 Apr;342:996-1002; Mayr B et al. Eur. J. Endocrinol., 2016 May;174:R189-208; Vargas-Poussou R et al. J. Clin. Endocrinol. Metab., 2016 05;101:2185-95; Szalat A et al. Endocrine, 2017 Mar;55:741-747Asla Q et al. Endocrine, 2024 Mar;83:747-756; García-Castaño A et al. Front Endocrinol (Lausanne), 2024 Mar;15:1297614). 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 the supporting evidence, this variant is likely pathogenic for FHH1; however, the association of this variant with ADH1 is unlikely.
Athena Diagnostics RCV003482226 SCV004229515 pathogenic not provided 2023-03-07 criteria provided, single submitter clinical testing This variant has been identified in multiple unrelated individuals with clinical features associated with autosomal dominant hypocalciuric hypercalcemia. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. 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. (PMID: 16598859)
Fulgent Genetics, Fulgent Genetics RCV005025038 SCV005657412 likely pathogenic Familial hypocalciuric hypercalcemia 1; Neonatal severe primary hyperparathyroidism; Epilepsy, idiopathic generalized, susceptibility to, 8; Autosomal dominant hypocalcemia 1 2024-04-30 criteria provided, single submitter clinical testing
OMIM RCV000008857 SCV000029067 pathogenic Familial hypocalciuric hypercalcemia 1 2006-04-14 no assertion criteria provided literature only
Molecular Genetics Laboratory, Biobizkaia Health Research Institute RCV000008857 SCV004708178 pathogenic Familial hypocalciuric hypercalcemia 1 2024-03-08 no assertion criteria provided clinical testing

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