Von Hippel-Lindau (VHL) syndrome is a disorder that puts patients at increased risk of developing benign and malignant tumors within various organs. While current genetic tests demonstrate successful detection of minor mutations, large structural rearrangements of the genome are undetectable by existing tests, indicating need for custom test to confirm these large alterations. We validated a test using that evaluates a large (291 kb) inversion found within the VHL gene in patients. Validation results achieved 100% match.  This report demonstrates that specialized methodologies are essential for managing hereditary diseases and promoting early symptom detection. Our test allows for greater confidence in diagnosis for families dealing with large structural alterations and may aid in future efforts at corrective therapies to ease patient suffering. Work was performed in a Clinical Laboratory Improvement Amendments-certified laboratory (CLIA ID # 21D0947274). (https://jmg.bmj.com/content/early/2026/04/24/jmg-2026-111493)