ClinVar Miner

Submissions for variant NM_000388.4(CASR):c.1663A>G (p.Ile555Val)

dbSNP: rs777646067
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001037938 SCV001201375 uncertain significance Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1 2021-08-17 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 555 of the CASR protein (p.Ile555Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in an individual with a clinical suspicion of familial hypocalciuric hypercalcemia (PMID: 17698911). This variant is present in population databases (rs777646067, ExAC 0.001%).
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV002465826 SCV002760318 uncertain significance not specified 2025-03-04 criteria provided, single submitter clinical testing
GeneDx RCV005235504 SCV005881972 likely pathogenic not provided 2024-09-09 criteria provided, single submitter clinical testing Observed in an individual with clinical suspicion of familial hypocalciuric hypercalcemia (PMID: 17698911); Observed by whole genome sequencing in a patient with primary hyperparathyroidism, parathyroid adenoma, and family history of hyperparathyroidism in both a parent and a child; patient had a clinical diagnosis of MEN1 but no variant was identified by sequencing of the MEN1 gene (PMID: 31658439); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22192860, 17698911, 31658439)

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