ClinVar

Description

Variant summary: CASR c.2449G>A (p.Val817Ile) results in a conservative amino acid change located in the receptor calcium 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 251330 control chromosomes (gnomAD). c.2449G>A has been reported in the literature in individuals affected with Familial Hypocalciuric Hypercalcemia (examples: Pearce_ 1995 and Vargas-Poussou_ 2016). These data indicate that the variant is likely to be associated with disease. Multiple studies have shown this variant leads to reduced cell surface expression, reduced Ca2+ sensitivity and reduced ERK1/2 phosphorylation compared to wild type (examples: Pearce_1996, Hu_2005, Huang_2007, Leach_2013, White_2018). The following publications have been ascertained in the context of this evaluation (PMID: 8675635, 17284438, 8878438, 15591042, 19389809, 26963950, 23372019). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.