The Clinical Genome Resource (ClinGen) is a National Institutes of Health (NIH)-funded program that aims to improve our understanding of the relationship between genetic variations and human health. ClinGen has formed Variant Curation Expert Panels(VCEPs) that provide evidence-based interpretations of genomic variants associated with specific diseases. The ClinGen Severe Combined Immunodeficiency Disease(SCID) VCEP aimed to establish gene-specific guidelines for SCID-associated genes due to the lack of gene-specificity in the 2015 guidelines provided by the American College of Medical Genetics and Genomics(ACMG) and Association for Molecular Pathology(AMP).
The SCID-VCEP adapted 20 rules from the 28 ACMG/AMP criteria to the seven SCID-associated genes most commonly identified as defective in North American SCID cases: IL2RG, JAK3, ADA, DCLRE1C, IL7R, RAG1, and RAG2, with slight differences between each gene. The key specifications of the rules included setting thresholds for populational allele frequency, developing a method for counting probands and segregations, reviewing functional assays, and determining phenotypic characteristics specific to each gene. To ensure the effectiveness of the specifications, the VCEP selected well-known variants and curated them in pairs to ensure validity and reproducibility. Immunology and genetics experts reviewed the curations, and their feedback led to iterative refinements of the specifications during pilot testing of the specifications. Comprehensive guidelines for implementation in the sustained curation phase were produced as a result of this process.
The VCEP has successfully developed and tested specific parameters for determination of variant pathogenicity in 7 key SCID-associated genes. These curation rules will enable publication of ClinGen VCEP variant classifications in ClinVar with a 3-star rating. They may also be used independently by investigators, clinicians, and clinical laboratories. The efforts of the SCID-VCEP represent a significant step forward in our understanding of SCID and its associated genes, and it has the potential to enhance clinical decision-making and improve overall patient outcomes.