The focus of the Antibody Deficiencies Variant Curation Expert Panel will be to curate variants in genes associated with various inborn errors of immunity that result in antibody deficiencies (decrease in one or more immunoglobulin isotypes) with or without quantitative B cell defects and other phenotypic manifestations. The VCEP will consider genes found to be associated with antibody immunodeficiencies, as outlined by the International Union of Immunological Societies (IUIS) Expert Committee 2019 publication: (PMID: 31953710).  To start, the VCEP will consider the following three genes: CTLA4, PIK3CD, and PIK3R1. Variants in these genes will be curated using the VCEP modified-ACMG criteria. Variants will be identified from ClinVar, various primary immunodeficiency databases, both public and private, and variants will be consolidated by gene, and then categorized, based on literature with functional, immunological and clinical phenotype data. The panel will curate variants based on several lines of evidence. Since many of the inborn errors of immunity genes can have a spectrum of clinical and immunological phenotypes, ranging from complete loss-of-function (LOF), gain-of-function (GOF), partial LOF (hypomorphic or leaky defects), haploinsufficiency and dominant negative, variants will be classified based on current knowledge as well as experimental data. Variants will be curated based on gene priority and relatively more common humoral defects first before tackling the ultra-rare antibody deficiencies.

Step 2 Approval:

• August 25, 2022 - VCEP received approval to pilot ACMG/AMP specifications for CTLA4
• July 12, 2023 - VCEP received approval to pilot ACMG/AMP specifications for PIK3CD