Perspective: Application of the American College of Medical Genetics Variant Interpretation Criteria to Common Variable Immunodeficiency Disorders

Clin Rev Allergy Immunol. 2021 Oct;61(2):226-235. doi: 10.1007/s12016-020-08828-z. Epub 2021 Apr 5.


Common variable immunodeficiency disorders (CVIDs) are rare primary immunodeficiency diseases (PIDs) mostly associated with late onset antibody failure leading to immune system failure. Patients with CVID are predisposed to disabling complications such as bronchiectasis and systemic autoimmunity. In recent years a large number of genetic defects have become associated with these disorders. Patients with a causative mutation are deemed to have CVID-like disorders, while those with mutations predisposing to or modifying disease severity remain within the spectrum of CVID as defined by current diagnostic criteria. Next-generation sequencing (NGS) allows simultaneous analysis of multiple genes. Potential mutations identified from NGS are commonly evaluated with the American College of Medical Genetics (ACMG) variant interpretation criteria to determine their pathogenicity (causality). Patients with CVID and CVID-like disorders have marked genetic, allelic, and phenotypic heterogeneity. Although all patients with a CVID phenotype should undergo genetic testing, the complexity of the genetics associated with these disorders is challenging. Variants of unknown significance (VUS) remain a significant barrier to realising the full potential of NGS in CVID and CVID-like disorders. Here we explore the nuances of applying the ACMG criteria to patients with CVID and CVID-like disorders. Close collaboration between the clinician, bioinformatics, and genetics professionals will improve the diagnostic yield from genetic testing and reduce the frequency of VUS.

Keywords: ACMG criteria; CVID; CVID-like disorders.

Publication types

  • Review

MeSH terms

  • Common Variable Immunodeficiency / diagnosis*
  • Common Variable Immunodeficiency / genetics*
  • Genetic Predisposition to Disease*
  • Genetic Variation*
  • Genetics, Medical*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Phenotype