Common Variable Immunodeficiency Disorders (CVIDs) are rare Primary Immunodeficiency diseases (PIDs) associated with late onset antibody failure leading to immune system failure. Most patients suffer recurrent and severe infections, while some have predominantly autoimmune and inflammatory disorders. In recent years a large number of genetic defects have become associated with these disorders. Next Generation Sequencing (NGS) allows the analysis of multiple genes simultaneously. The mutations identified from NGS are evaluated with the American College of Medical Genetics (ACMG) variant interpretation criteria to determine their pathogenicity (causality). We have advocated all patients with a CVID phenotype should undergo genetic testing but acknowledge the complexity of the genetics associated with these disorders. Variants of Unknown Significance (VUS) remain a significant barrier to realising the full potential of NGS in CVID and CVID-like disorders. We review the nuances of the application of the ACMG variant interpretation criteria to patients with a CVID phenotype.