ClinVar Miner

Submissions for variant NM_000388.4(CASR):c.40A>G (p.Thr14Ala)

gnomAD frequency: 0.00001  dbSNP: rs199515839
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000524604 SCV000638073 uncertain significance Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1 2023-12-12 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 14 of the CASR protein (p.Thr14Ala). This variant is present in population databases (rs199515839, gnomAD 0.004%). This missense change has been observed in individual(s) with primary hyperparathyroidism (PMID: 15879434). ClinVar contains an entry for this variant (Variation ID: 463950). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect CASR function (PMID: 15879434). 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.
GeneDx RCV001770431 SCV001993418 uncertain significance not provided 2020-02-27 criteria provided, single submitter clinical testing Published functional studies demonstrate no damaging effect on protein expression, processing, and localization, or response to extracellular calcium (Pidasheva 2005); Observed in individuals with a personal or family history including parathyroid adenoma (Pidasheva 2005); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17274009, 15879434, 17320849)
Fulgent Genetics, Fulgent Genetics RCV002483414 SCV002776051 uncertain significance Familial hypocalciuric hypercalcemia 1; Neonatal severe primary hyperparathyroidism; Epilepsy, idiopathic generalized, susceptibility to, 8; Autosomal dominant hypocalcemia 1 2021-11-29 criteria provided, single submitter clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV003320679 SCV004024942 uncertain significance not specified 2023-08-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV004023965 SCV005034806 likely benign Nephrolithiasis/nephrocalcinosis 2023-12-27 criteria provided, single submitter clinical testing 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.

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