ClinVar

Description

Variant summary: CASR c.1393C>T (p.Arg465Trp) results in a non-conservative amino acid change located in the ligand binding region (IPR001828) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251282 control chromosomes (gnomAD). c.1393C>T has been reported in the literature in the heterozygous state in multiple individuals affected with Familial Hypocalciuric Hypercalcemia, but often without segregation data (e.g. Guarnieri_2010, Vargas-Poussou_2016, Hureaux_2019, Mouly_2020). It has also been reported as a homozygous genotype in a woman with no family history of calcium distrubances who was asymptomatic until during her second pregnancy, but whose two heterozygous daughters were affected (Maltese_2017). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found the variant was associated with reduced maturation, cell surface expression, and cell signaling compared to the wild-type protein, however, it does not allow strong conclusions about the variant effect (Guarnieri_2010). The following publications have been ascertained in the context of this evaluation (PMID: 20164288, 29026550, 32347971, 26963950, 31672324). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified it as either likely pathogenic (n=3) or VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.