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

dbSNP: rs886041154

Total submissions: 7

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	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).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000815977	SCV000956461	pathogenic	Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1	2024-12-08	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. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this CASR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 606,512 individuals referred to our laboratory for CASR testing. 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	RCV004021054	SCV002703464	pathogenic	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	2024-09-19	criteria provided, single submitter	clinical testing	PP1, PP2, PP3, PM2, PS3, PS4_moderate
Molecular Genetics Laboratory, Biobizkaia Health Research Institute	RCV003982979	SCV004708207	pathogenic	Familial hypocalciuric hypercalcemia 1	2024-03-08	no assertion criteria provided	clinical testing