ClinVar Miner

Submissions for variant NM_000388.4(CASR):c.196C>T (p.Arg66Cys)

dbSNP: rs121909266
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498645 SCV000589628 likely pathogenic not provided 2017-06-07 criteria provided, single submitter clinical testing The R66C variant in the CASR gene has been reported previously in the homozygous state in a newborn diagnosed with neonatal severe hyperparathyroidism (NSHPT), which prior to a parathyroidectomy had elevated concentrations of serum calcium and PTH (Pidasheva et al., 2006). This variant has also been reported in the heterozygous state in an individual with with familial hypocalciuric hypercalcemia (Chou et al., 1995). An in vitro transfection study demonstrated the R66C variant impairs cell signaling response to extracellular increases in CASR agonists in HEK293 cells (Pidasheva et al., 2006). The R66C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R66C 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. Additionally, a missense variant at the same residue (R66H) has been reported as homozygous in two siblings with NSHPT (Pidasheva et al., 2006). We interpret R66C as a likely pathogenic variant.
Invitae RCV001851747 SCV002107727 likely pathogenic Familial hypocalciuric hypercalcemia; Autosomal dominant hypocalcemia 1 2021-10-05 criteria provided, single submitter clinical testing In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg66 amino acid residue in CASR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16740594, 25104082). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects CASR function (PMID: 8702647, 16740594, 17284438, 21239511). 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: 8335). This variant is also known as p.Arg67Cys. This missense change has been observed in individual(s) with CASR-related conditions (PMID: 7726161, 16740594). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with cysteine at codon 66 of the CASR protein (p.Arg66Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003398474 SCV004122673 pathogenic Familial hypocalciuric hypercalcemia 2023-10-10 criteria provided, single submitter clinical testing Variant summary: CASR c.196C>T (p.Arg66Cys) 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 251326 control chromosomes (gnomAD). c.196C>T has been reported in the literature in the heterozygous state in five related individuals with Familial Hypocalciuric Hypercalcemia (FHH) and in the homozygous state in one additional family member with Neonatal Severe Hyperparathyroidism (NSHPT) who had elevated calcium and parathyroid hormone levels and subsequently underwent a parathyroidectomy (e.g. Pollak_1994, Chou_1995). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function in vitro (e.g. Pidasheva_2006, Huang_2007). The variant showed reduced cell surface expression compared to the wild type protein, lacked mature glycosylation and was deficient in cell signalling responses to extracellular CASR ligands, exhibiting a response approximately 10-30% that of wild type CASR. Additionally, another variant affecting the same amino acid (p.R66H) was found to severely impact protein function and has been observed in multiple affected individuals in a family with FHH/NSHPT (Pidasheva_2006), further supporting that R66 is important for CASR function. The following publications have been ascertained in the context of this evaluation (PMID: 7726161, 17284438, 16740594, 8132750). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000008837 SCV000029047 pathogenic Familial hypocalciuric hypercalcemia 1 1995-05-01 no assertion criteria provided literature only

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