Recommendations from the ClinGen SCID VCEP: Implementation of ACMG/AMP Variant Curation Guidelines for Severe Combined Immunodeficiency Disease

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 was created to develop specifications-rules for SCIDassociated genes because the American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) guidelines from 2015 are not gene-specific. The panel has focused on IL2RG, JAK3, ADA, DCLRE1C, IL7R, RAG1, and RAG2 to aid in precise diagnosis, clinical management, and genetic counseling. Methods and Results: Of the 28 ACMG/AMP criteria, the SCID VCEP adapted 18 rules to the 7 selected genes and determined that 10 rules were not applicable (with slight differences between each gene). The key specifications of the rules included setting thresholds for minor allele frequency, developing a method for counting probands and segregations, reviewing functional assays, and determining phenotypic characteristics specific to each gene. Pilot testing of the rules modifications demonstrated appropriate performance as determined by the VCEP. The VCEP will curate 5,460 variants using these gene-specific rules and categorize them into five groups: pathogenic, likely pathogenic, uncertain significance, likely benign, and benign. The pathogenicity classifications will be published in ClinVar with 3-star review status. This standardized and evidence-based interpretation of genetic variants associated with SCID is crucial to ensure accurate diagnosis, effective clinical management and informed genetic counseling for affected individuals and their families.