The Enigma of Clinical Next Generation Sequencing (NGS) based Genetic Testing Variant Annotation Tools: A Performance Evaluation Study

As the scientific community continues to discover novel genetic variants associated with human constitutional disorders, there is a growing need for a standardized approach for reporting of genetic variants, as accurate variant identification is crucial for effective diagnosis and treatment. Robust identification and annotation of genetic variants relevant for human germline disorders is foundational for clinical Next Generation Sequencing (NGS) assays. Using a manually curated set of 296 variants, generated by targeted gene panel sequencing using the ~4700 gene medical exome panel on 105 patients, we evaluated the performance of two variant annotation tools (Variant Effect Predictor and Alamut Batch) for implementation in our clinical bioinformatics pipeline at the Molecular Diagnostics Laboratory at Lurie Children’s Hospital. With respect to HGVS nomenclature standards and clinical integrity, VEP produces more accurate variant annotations due to usage of updated gene transcript versions within the algorithm