Submissions for variant NM_000388.4(CASR):c.106G>A (p.Gly36Arg)

gnomAD frequency: 0.00001  dbSNP: rs193922420

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029426	SCV000052076	uncertain significance	not specified	2019-02-14	criteria provided, single submitter	clinical testing	Variant summary: CASR c.106G>A (p.Gly36Arg) 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. A study utilizing three dimensional protein structure analysis to discern and prioritize damaging variants in genes causing endocrine and metabolic disorders predicted this variant to disrupt the CASR protein structure due to a steric clash attibuted to the substitution of glycine at position 36 by a large arginine residue (Ittisoponpisan_CASR_JES_2018). The variant was absent in 246060 control chromosomes (gnomAD). 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.106G>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 ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV000341520	SCV000329199	uncertain significance	not provided	2016-05-17	criteria provided, single submitter	clinical testing	The G36R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G36R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G36R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000705981	SCV000835007	uncertain significance	Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1	2023-11-09	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 36 of the CASR protein (p.Gly36Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CASR-related conditions. ClinVar contains an entry for this variant (Variation ID: 35774). 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. 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	RCV000341520	SCV001143427	uncertain significance	not provided	2019-12-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004018678	SCV005035206	uncertain significance	Nephrolithiasis/nephrocalcinosis	2023-07-14	criteria provided, single submitter	clinical testing	The p.G36R variant (also known as c.106G>A), located in coding exon 1 of the CASR gene, results from a G to A substitution at nucleotide position 106. The glycine at codon 36 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is highly 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000341520	SCV005410366	uncertain significance	not provided	2024-04-25	criteria provided, single submitter	clinical testing	PP2, PP3, PM2