ClinVar Miner

Submissions for variant NM_000388.4(CASR):c.2915C>T (p.Thr972Met)

gnomAD frequency: 0.00001  dbSNP: rs200620134
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services,Illumina RCV000664401 SCV000440131 uncertain significance Familial hypocalciuric hypercalcemia 1 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services,Illumina RCV000288087 SCV000440132 uncertain significance Autosomal dominant hypocalcemia 1 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services,Illumina RCV000345436 SCV000440133 uncertain significance Neonatal severe primary hyperparathyroidism 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services,Illumina RCV000383567 SCV000440134 benign Familial hypoparathyroidism 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae RCV000525899 SCV000638059 uncertain significance Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1 2021-11-02 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 972 of the CASR protein (p.Thr972Met). This variant is present in population databases (rs200620134, gnomAD 0.009%). This missense change has been observed in individual(s) with an atypical presentation of familial benign hypocalciuric hypercalcemia (FHH) and/or hyperparathyroidism (PMID: 25292184, 26646938). ClinVar contains an entry for this variant (Variation ID: 342802). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CASR function (PMID: 25292184). 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.
Athena Diagnostics Inc RCV000711038 SCV000841358 uncertain significance not provided 2018-01-29 criteria provided, single submitter clinical testing
Mendelics RCV000664401 SCV001136578 uncertain significance Familial hypocalciuric hypercalcemia 1 2019-05-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV001016922 SCV001177929 uncertain significance Inborn genetic diseases 2019-05-21 criteria provided, single submitter clinical testing The p.T972M variant (also known as c.2915C>T), located in coding exon 6 of the CASR gene, results from a C to T substitution at nucleotide position 2915. The threonine at codon 972 is replaced by methionine, an amino acid with similar properties. This variant was identified in an individual with hypercalcemia, hypercalciuria, and improperly normal parathyroid hormone levels (Mastromatteo E et al. BMC Endocr Disord, 2014 Oct;14:81). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this alteration remains unclear.
GeneDx RCV000711038 SCV001986154 uncertain significance not provided 2020-12-21 criteria provided, single submitter clinical testing Published functional studies demonstrate intermediate levels of glycosylated mature protein and reduced CaSR signaling activity (Mastromatteo 2014); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25292184, 26646938)
OMIM RCV000664401 SCV000788331 pathogenic Familial hypocalciuric hypercalcemia 1 2018-07-25 no assertion criteria provided literature only

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