Reclassification of variants of uncertain significance in type I collagen genes: a national reference laboratory...

The availability of large volumes of data from genetic testing has enabled the interpretation of more DNA variants, contributing to a greater number of identified variants of uncertain significance (VUS). The growing number of VUS causes a burden of inconclusive findings in clinical practice. Osteogenesis imperfecta (OI) is a genetically heterogeneous connective tissue disorder causing bone fragility and limb deformity. Pathogenic variants in two collagen genes, COL1A1 and COL1A2, account for around 90% of all OI.

Data mining of the variants from Sheffield Diagnostic Genetics Service, the national OI testing hub (UK), was conducted to collate all VUS in COL1A1 and COL1A2 identified. All VUS were then reclassified according to the latest 2024 ACGS (Association for Clinical Genomic Science) best practice guidelines.

A total of 161 VUS in COL1A1 and 98 VUS in COL1A2 were identified and reanalysed. For COL1A1, we found that 2% VUS were upgraded to likely pathogenic (LP), 23% of the VUS were downgraded to likely benign and benign, 12% were reclassified as hot VUS and the remaining 63% have not changed classification as VUS. With regard to COL1A2, only 1% of the VUS were upgraded to LP, 25% were downgraded to likely benign and benign, 13% were reclassified as hot VUS and 61% remained as VUS.

From this study, we demonstrated that iterative reanalysis of VUS is crucial in clinical practice as new data and evidence become available. This dynamic process will significantly improve diagnostic accuracy and inform patient care decisions.