ClinVar Miner

Submissions for variant NM_000388.4(CASR):c.196C>T (p.Arg66Cys) (rs121909266)

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Total submissions: 2
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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.
OMIM RCV000008837 SCV000029047 pathogenic Hypocalciuric hypercalcemia, familial, type 1 1995-05-01 no assertion criteria provided literature only

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