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CR2 – Common Variable Immunodeficiency

Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by impaired immunoglobulin production and recurrent infections. Complement receptor 2 (CR2) is included in multigene CVID sequencing panels but no pathogenic CR2 variants have been identified in 103 patients by NGS (PMID:33859323), and familial segregation of CR2 defects in CVID remains unreported. Expression profiling in 57 CVID patients revealed downregulation of CD21 on B cells in memory-deficient groups, correlating with splenomegaly (59% in MB0, 42% in MB1) and autoimmunity across all subgroups (PMID:14601647).

Extensive in vitro mutagenesis and structural studies confirm essential CR2 domains for C3dg binding and EBV gp350 interaction, demonstrating its key role in B-cell activation (PMID:11034390; PMID:7868901). Human CD21 deficiency due to biallelic CR2 mutations leads to hypogammaglobulinemia and reduced memory B cells, underscoring a recessive mechanism (PMID:22035880). Taken together, direct genetic evidence linking CR2 to CVID is limited, but concordant functional data support its clinical relevance in B-cell co-stimulation and complement-mediated immunity. Key take-home: CR2 testing may inform mechanistic subtyping in CVID, but further genetic studies are needed to establish causality.

References

  • Journal of clinical immunology • 2003 • Common variable immunodeficiency patient classification based on impaired B cell memory differentiation correlates with clinical aspects. PMID:14601647
  • Scientific reports • 2021 • The impact of rare and low-frequency genetic variants in common variable immunodeficiency (CVID). PMID:33859323
  • Journal of immunology (Baltimore, Md. : 1950) • 1995 • Mutation of residues in the C3dg region of human complement component C3 corresponding to a proposed binding site for complement receptor type 2 (CR2, CD21) does not abolish binding of iC3b or C3dg to CR2. PMID:7868901
  • Journal of immunology (Baltimore, Md. : 1950) • 2000 • Structure-guided identification of C3d residues essential for its binding to complement receptor 2 (CD21). PMID:11034390
  • The Journal of allergy and clinical immunology • 2012 • Genetic CD21 deficiency is associated with hypogammaglobulinemia. PMID:22035880

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

No pathogenic CR2 variants reported in CVID cohorts; absence of familial segregation

Genetic Evidence

Limited

CR2 included in large NGS panel (103 patients) with zero pathogenic or likely pathogenic variants identified (PMID:33859323); no segregation data

Functional Evidence

Moderate

Multiple mutagenesis and structural assays demonstrate critical CR2 domains for C3dg and EBV gp350 binding, and human CD21 deficiency causes hypogammaglobulinemia (PMID:11034390; PMID:22035880)