Submissions for variant NM_000388.4(CASR):c.725T>C (p.Leu242Pro)

dbSNP: rs1064794676

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003238587	SCV002010662	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001868777	SCV002224690	uncertain significance	Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1	2022-06-09	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1319285). This variant has not been reported in the literature in individuals affected with CASR-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 242 of the CASR protein (p.Leu242Pro).
Ambry Genetics	RCV004040745	SCV002672496	uncertain significance	Nephrolithiasis/nephrocalcinosis	2019-03-18	criteria provided, single submitter	clinical testing	The p.L242P variant (also known as c.725T>C), located in coding exon 3 of the CASR gene, results from a T to C substitution at nucleotide position 725. The leucine at codon 242 is replaced by proline, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003388041	SCV004099760	uncertain significance	not specified	2023-09-12	criteria provided, single submitter	clinical testing	Variant summary: CASR c.725T>C (p.Leu242Pro) results in a non-conservative amino acid change located in the Receptor, ligand binding region (IPR001828) of 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 251274 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.725T>C in individuals affected with Autosomal Dominant Hypocalcemia and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004554870	SCV004109228	uncertain significance	CASR-related disorder	2023-09-21	criteria provided, single submitter	clinical testing	The CASR c.725T>C variant is predicted to result in the amino acid substitution p.Leu242Pro. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Mayo Clinic Laboratories, Mayo Clinic	RCV003238587	SCV004226144	uncertain significance	not provided	2022-09-27	criteria provided, single submitter	clinical testing	PP2, PP3, PM2_supporting