ClinVar

Description

The P748H variant has been published previously in association with familial hypocalciuric hypercalcemia (Cetani et al. 2009). It is reported as likely pathogenic in ClinVar by a different clinical laboratory, but additional evidence is not available (ClinVar SCV000052090.1; Landrum et al., 2015). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). P748H is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, functional studies have shown the P748H receptor shows a reduced response to calcium in comparison to wild type (Cetani et al. 2009). In summary, this variant is likely pathogenic.