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

gnomAD frequency: 0.00001  dbSNP: rs200620134

Total submissions: 11

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000525899	SCV000638059	uncertain significance	Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1	2023-11-07	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). 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 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	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	RCV004021880	SCV001177929	uncertain significance	Nephrolithiasis/nephrocalcinosis	2024-03-18	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. 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 available evidence, 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)
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000664401	SCV004807421	uncertain significance	Familial hypocalciuric hypercalcemia 1	2024-03-26	criteria provided, single submitter	clinical testing
OMIM	RCV000664401	SCV000788331	pathogenic	Familial hypocalciuric hypercalcemia 1	2018-07-25	no assertion criteria provided	literature only