ClinVar

Description

The c.913C>A (p.Pro305Thr) variant has been described in at least four studies in which it was found in a total of 19 generalized arterial calcification of infancy individuals, including seven in a homozygous state and 12 in a compound heterozygous state (including three sibling pairs) with most patients reported to have died in infancy (Ruf et al. 2005; Ciana et al. 2006; Rutsch et al. 2008; Stella et al. 2016). The p.Pro305Thr variant was absent from 85 controls. The variant is reported at a frequency of 0.00023 in the African American population of the Exome Sequencing Project but this is based on one allele only so the variant is presumed to be rare. The Pro305 residue is highly conserved and located in the catalytic domain of the protein. Functional studies in which the variant was transfected into HEK293 cells show that the p.Pro305Thr variant results in a complete loss of activity and extracellular PPi generation compared to wildtype. The variant localized to the plasma membrane similarly to wild type but is predicted to have a structural impact effect on protein stability (Stella et al. 2016). Based on the collective evidence, the p.Pro305Thr variant is classified as pathogenic for generalized arterial calcification of infancy.