Genetic variants, regardless of the method used for their detection, are categorised broadly by the likelihood that they are responsible for an individual’s clinical phenotype. These are summarily termed categories 1 to 5 on the joint recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology [173]. In brief, variants that have previously been confirmed as benign in published literature, curated databases of genetic variants, or unpublished in-house laboratory data are termed category 1 “benign” variants. Those that are predicted by computational (in silico) or other means to be benign are termed category 2 “likely benign” variants. “Variants of uncertain significance” (VUS), which differ from the reference genome but cannot be confirmed or ruled out as responsible for the phenotype in question are classified as category 3 variants. Category 4 “likely pathogenic” variants are predicted computationally or otherwise to be pathogenic, but have not been conclusively proven as such in existing data sources, as listed above. Lastly, category 5 “pathogenic” variants are confirmed to be disease-causing in published literature or databases.           For the purposes of clinical practice, category 4 and 5 variants are generally considered diagnostic positive, and category 1 and 2 variants are considered negative. By consensus, category 3 VUS should not be used to guide clinical decision-making for affected individuals [173]. Interpretation of VUS can be aided by trio and segregation studies in individual cases, and functional testing of suspected variants expressed in in vitro systems within experienced research settings [174]. Different labs and genomic testing pipelines may manage VUS differently, e.g., in reporting pre-test probability of finding VUS in their panel, or may not report VUS at all [172]. Of note, reference databases for variant classification are gradually refined over time, and most VUS are eventually reclassified into other categories, prompting many genomic laboratories to periodically re-analyse historic clinical sequencing data, and issue supplementary reports where reclassification impacts the interpretation of genetic findings in individual cases [175]. In the context of CGD, clinical symptoms alone are insufficient to confirm pathogenicity of a novel CGD gene variant without first demonstrating an oxidative burst defect [108].