ClinVar

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu309 amino acid residue in CTSK. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 8426). This missense change has been observed in individual(s) with pycnodysostosis (PMID: 10878663). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs29001685, gnomAD 0.002%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 309 of the CTSK protein (p.Leu309Pro).