ClinVar

Description

Variant summary: CASR c.554G>A (p.Arg185Gln) results in a conservative amino acid change located in the Receptor, ligand binding region. (IPR001828) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251556 control chromosomes. c.554G>A has been reported in the literature in multiple individuals affected with Neonatal Severe Hyperparathyroidism (NSHPT) and/or Familial Hypocalciuric Hypercalcemia (FHH) (example, Obermannova_2009, Pollak_1993, Heath_1996, Bai_1997). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a significantly higher EC50 in response to calcium agonists (example divalent calcium and trivalent cations such as Gadolimium) in addition to a dominant negative effect when co-expressed with wild-type CASR indicating that the primary abnormality in receptor function is in ligand binding (example Bai_1997). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.