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FCGR3B and Systemic Lupus Erythematosus

Copy number variation at the FCGR3B locus has been implicated in susceptibility to Systemic lupus erythematosus. A case–control study in an admixed Brazilian cohort showed that heterozygous deletions of FCGR3B confer a 3.6-fold increased risk of SLE when present alone and a 5.9-fold risk in combination with ADAM3A deletions, while duplications appeared protective (PMID:30485348). In contrast, analysis of FcγRIIIb single-nucleotide polymorphisms in 157 Brazilian patients and 160 controls demonstrated no overall association between FCGR3B haplotypes and SLE susceptibility, although the FCGR3B*02*02 genotype was linked to arthritis and malar rash manifestations (PMID:24896836).

In vitro functional studies align with a pathogenic mechanism involving impaired immune complex clearance. Mutation of the N163 glycosylation site (p.Asn163Gln) enhances IgG binding affinity, indicating that N163 glycosylation modulates FcγRIIIb-ligand interactions (PMID:14632661). Complementary neutrophil haplotype assays revealed that specific FcγRIIIb variants significantly alter IgG-induced respiratory burst activity, supporting a hypomorphic effect on immune complex handling (PMID:24554771). Despite these mechanistic insights, the absence of familial segregation data and divergent SNP association results limit the current evidence to a Limited classification. Key Take-home: FCGR3B copy number deletions modulate receptor function and neutrophil activity in SLE, but further segregation and replication studies are needed to establish clinical validity.

References

  • PloS one • 2018 • Copy number variation in the susceptibility to systemic lupus erythematosus. PMID:30485348
  • Autoimmunity • 2014 • FcγRIIa and FcγRIIIb polymorphisms and associations with clinical manifestations in systemic lupus erythematosus patient PMID:24896836
  • Immunology • 2003 • Glycosylation of FcgammaRIII in N163 as mechanism of regulating receptor affinity. PMID:14632661
  • Journal of immunology • 2014 • Haplotypes of FcγRIIa and FcγRIIIb polymorphic variants influence IgG-mediated responses in neutrophil PMID:24554771

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Single CNV-based case–control study showing FCGR3B deletion increases SLE risk (3.6-fold) ([PMID:30485348]) and negative SNP association in a separate cohort ([PMID:24896836]); no segregation evidence.

Genetic Evidence

Limited

Association driven primarily by FCGR3B copy number variation with OR=3.6 for single deletion ([PMID:30485348]); absence of familial segregation or multiple unrelated probands.

Functional Evidence

Moderate

In vitro assays demonstrate N163 glycosylation site mutation alters IgG binding affinity ([PMID:14632661]) and neutrophil FcγRIIIb variants modulate respiratory burst activity ([PMID:24554771]).