ClinVar Miner

Submissions for variant NM_000388.4(CASR):c.106G>A (p.Gly36Arg) (rs193922420)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000705981 SCV000835007 uncertain significance Familial hypocalciuric hypercalcemia; Hypocalcemia, autosomal dominant 1 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 36 of the CASR protein (p.Gly36Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CASR-related disease. ClinVar contains an entry for this variant (Variation ID: 35774). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 Inc RCV000341520 SCV001143427 uncertain significance not provided 2018-09-24 criteria provided, single submitter clinical testing

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