ClinVar Miner

Submissions for variant NM_000388.4(CASR):c.3091G>A (p.Gly1031Ser) (rs142704083)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000503233 SCV000052099 likely benign not specified 2019-03-13 criteria provided, single submitter clinical testing Variant summary: CASR c.3091G>A (p.Gly1031Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function (ACMG BP4). The variant allele was found at a frequency of 0.00022 in 277196 control chromosomes, predominantly at a frequency of 0.0022 within the African subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African control individuals in the gnomAD database is approximately 176 fold of the estimated maximal expected allele frequency for a pathogenic variant in CASR causing Familial Hypocalciuric Hypercalcemia phenotype (1.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin (ACMG BS1). To our knowledge, no occurrence of c.3091G>A in individuals affected with Familial Hypocalciuric Hypercalcemia and no experimental evidence demonstrating its impact on protein function have been reported. This variant was previously classified as a VUS-possibly pathogenic variant that was converted during ClinVar submission to likely pathogenic in 2011. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. No new evidence supporting a pathogenic outcome has emerged over a span of eight years (2011-2019). Based on the evidence outlined above, the variant was classified as likely benign.
Genetic Services Laboratory, University of Chicago RCV000503233 SCV000593860 uncertain significance not specified 2017-05-08 criteria provided, single submitter clinical testing
Invitae RCV001085495 SCV000761076 likely benign Familial hypocalciuric hypercalcemia; Hypocalcemia, autosomal dominant 1 2020-12-04 criteria provided, single submitter clinical testing
Mendelics RCV000987315 SCV001136580 benign Hypocalciuric hypercalcemia, familial, type 1 2019-05-28 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000639501 SCV001143442 benign not provided 2019-03-30 criteria provided, single submitter clinical testing
Ambry Genetics RCV001018559 SCV001179813 uncertain significance Inborn genetic diseases 2018-12-04 criteria provided, single submitter clinical testing The p.G1031S variant (also known as c.3091G>A), located in coding exon 6 of the CASR gene, results from a G to A substitution at nucleotide position 3091. The glycine at codon 1031 is replaced by serine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species, and serine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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