ClinVar Miner

Submissions for variant NM_000388.4(CASR):c.164C>T (p.Pro55Leu)

dbSNP: rs886041154
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000401051 SCV000329200 pathogenic not provided 2018-05-23 criteria provided, single submitter clinical testing The P55L pathogenic variant in the CASR gene has been reported previously in association with familial hypocalciuric hypercalcemia (Pearce et al., 1995; Hannan et al., 2012). This variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Functional studies demonstrate that this substitution reduces calcium ion binding affinity of the extracellular domain of the CASR protein and leads to abnormal moderation of calcium homeostasis (Pearce et al., 1996; White et al., 2009; Lu et al., 2009). We interpret P55L as a pathogenic variant.
Athena Diagnostics Inc RCV000401051 SCV000841348 pathogenic not provided 2022-11-16 criteria provided, single submitter clinical testing This variant has been identified in multiple unrelated individuals with autosomal dominant hypocalciuric hypercalcemia and segregates with disease in multiple families. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 8878438, 10468915, 11763315, 19759318, 8636323, 8675635).
Invitae RCV000815977 SCV000956461 pathogenic Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1 2023-11-08 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 55 of the CASR protein (p.Pro55Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial hypocalciuric hypercalcemia (PMID: 8675635, 11763315, 12580936, 20164288, 22422767, 24947037). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 279731). 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 disruptive. Experimental studies have shown that this missense change affects CASR function (PMID: 8878438, 19389809, 19759318). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV002392790 SCV002703464 pathogenic Inborn genetic diseases; Nephrolithiasis/nephrocalcinosis 2022-10-24 criteria provided, single submitter clinical testing The p.P55L pathogenic mutation (also known as c.164C>T), located in coding exon 1 of the CASR gene, results from a C to T substitution at nucleotide position 164. The proline at codon 55 is replaced by leucine, an amino acid with similar properties. This mutation has been reported in multiple unrelated individuals and families with familial hypocalciuric hypercalcemia (Pearce SH et al. J Clin Invest, 1995 Dec;96:2683-92; Heath H et al. J Clin Endocrinol Metab, 1996 Apr;81:1312-7; Cetani F et al. Clin Endocrinol (Oxf), 2003 Feb;58:199-206; Speer G et al. Exp Clin Endocrinol Diabetes, 2003 Dec;111:486-90; Guarnieri V et al. J Clin Endocrinol Metab, 2010 Apr;95:1819-29; Hannan FM et al. Hum Mol Genet, 2012 Jun;21:2768-78). In vitro studies showed that P55L reduces the ability of the calcium-sensing receptor to sense extracellular calcium (Pearce SH et al. J Clin Invest, 1996 Oct;98:1860-6; Heath H et al. J Clin Endocrinol Metab, 1996 Apr;81:1312-7; Lu JY et al. J Pharmacol Exp Ther, 2009 Dec;331:775-86). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002469093 SCV002766022 pathogenic Familial hypocalciuric hypercalcemia 2022-11-15 criteria provided, single submitter clinical testing Variant summary: CASR c.164C>T (p.Pro55Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250952 control chromosomes. c.164C>T has been widely reported in the literature in multiple individuals affected with Familial Hypocalciuric Hypercalcemia (example, Pearce_1995, Sumida_2022). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in reduced responsiveness of the calcium receptor to ionic calcium levels consistent with a loss of function mechanism of disease (example, Pearce_1996). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000401051 SCV004226751 pathogenic not provided 2023-02-28 criteria provided, single submitter clinical testing PP1, PP2, PP3, PM2_supporting, PS3, PS4_moderate

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