ClinVar

Description

Variant summary: CASR c.2096C>G (p.Thr699Ser) results in a conservative amino acid change located in the C-terminal domain (IPR017978) 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 251452 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2096C>G in individuals affected with Autosomal Dominant Hypocalcemia and no experimental evidence demonstrating its impact on protein function have been reported. However, a different missense affecting the same amino acid position (Thr699Asn) has been reported in an individual affected with hypocalciuric hypercalcaemia, and in vitro functional characterization supported the causal role of this variant (PMID 35356007); these data suggest that the Thr699 residue might be important for protein function. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.