BACKGROUND: The Clinical Genome Resource (ClinGen) is an international consortium with the goal of creating a publicly available genomic knowledge database for laboratories and clinicians. Within ClinGen, the Antibody Deficiencies Variant Expert Panel (AD-VCEP) curates variants associated with Inborn Errors of Immunity (IEIs).
Inborn errors of immunity (IEIs) are a group of heterogeneous diseases with broad phenotypes. Genetic testing has become the principal method of diagnosis for IEIs. However, confirmatory diagnostics rely on previous documentation of the variant, leaving clinicians and genetic counselors with a tremendous task when the variant is of uncertain significance (VUS). The American College of Medical Genetics and The Association for Molecular Pathology (ACMG/AMP) have published guidelines to determine whether a variant is pathogenic, VUS, or benign. However, in the context of IEIs, the ACMG/AMP guidelines might only fit partially due to the incomplete penetrance, high genetic heterogeneity, and extensive overlap between conditions seen in IEIs.
METHODS: The AD-VCEP developed gene-specific variant curation rules for twenty ACMG/AMP codes applicable to the CTLA4 gene. Modifications have included creating a point system to define probands with a phenotype highly specific to the disorder, setting allele frequencies in control populations, and defining potential hot spots based on functional data.
RESULTS: Thirty-seven CTLA4 variants have been subjected to a pilot study of the rule specifications, with seventeen nominated as suspected pathogenic, eleven as suspected benign, and ten as VUS. Preliminary results indicate that gene-specific modifications to the proband-counting (PS4), functional assay (PS3), population frequency (BS1, BA1), and functional domain (PM1) codes have helped resolve ClinVar ambiguities and classify variants for CTLA4 insufficiency that were previously absent from ClinVar.
In summary, the work of the AD-VCEP represents the first comprehensive adaptation of the ACMG-AMP guidelines to the IEIs. It will help standardize IEI variant curation for subsequent genes.
