ClinVar

Description

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.