ClinVar Miner

Submissions for variant NM_000388.4(CASR):c.2216G>A (p.Cys739Tyr)

gnomAD frequency: 0.00001  dbSNP: rs375468610
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000517161 SCV000612660 uncertain significance not specified 2016-08-16 criteria provided, single submitter clinical testing
Invitae RCV000529628 SCV000638039 uncertain significance Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1 2023-12-08 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 739 of the CASR protein (p.Cys739Tyr). This variant is present in population databases (rs375468610, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of hypocalciuric hypercalcemia (PMID: 32638038). ClinVar contains an entry for this variant (Variation ID: 446992). 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 does not substantially affect CASR function (PMID: 32638038). 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.
Ambry Genetics RCV004023497 SCV001175531 uncertain significance Nephrolithiasis/nephrocalcinosis 2024-03-13 criteria provided, single submitter clinical testing The p.C739Y variant (also known as c.2216G>A), located in coding exon 6 of the CASR gene, results from a G to A substitution at nucleotide position 2216. The cysteine at codon 739 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration was identified in two siblings diagnosed with familial hypocalciuric hypercalcemia (FHH) however functional studies indicated that this variant most likely was not causing FHH (Magno AL et al. Calcif Tissue Int, 2020 09;107:230-239). 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002481665 SCV002799634 uncertain significance Familial hypocalciuric hypercalcemia 1; Neonatal severe primary hyperparathyroidism; Epilepsy, idiopathic generalized, susceptibility to, 8; Autosomal dominant hypocalcemia 1 2022-03-15 criteria provided, single submitter clinical testing

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