ClinVar

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 249 of the CTSK protein (p.Ile249Asn). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individuals with pycnodysostosis (PMID: 35315254). ClinVar contains an entry for this variant (Variation ID: 1301984). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CTSK protein function. This variant disrupts the p.Ile249 amino acid residue in CTSK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17397052, 24767306, 25725806, 26892377, 30199612). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.