ClinVar

This variant is classified as a variant of unknown significance because its contribution to a primary immunodeficiency disorder has not been confirmed.

In a man and his 2 children with a primary immunodeficiency disorder characterized by recurrent infections, poor antibody responses, and decreased immunoglobulins, Wang et al. (2013) identified a heterozygous c.433C-T transition in exon 6 of the TNFSF12 gene, resulting in an arg145-to-cys (R145C) substitution in the conserved TNF homology domain of the full-length protein (residue 52 in the secreted protein). The variant, which was found by array-based resequencing of 148 candidate genes implicated in B-cell development, was not found in the dbSNP database or in 200 control samples. In vitro functional expression studies showed that the variant protein was unable to induce apoptosis in HT29 cells in the presence of gamma-interferon (IFNG; 147570). The secreted form of the variant protein formed abnormal high molecular weight aggregates, which could have resulted in the loss of apoptotic function. Although binding to the receptor (TNFRSF12A; 605914) was slightly increased, the variant protein failed to stimulate NFKB (see 164011) activation and induce cell death. Variant TNFSF12 also bound stronger to BAFF (TNFSF13B; 603969) compared to wildtype, and this interaction inhibited downstream BAFF signaling in B cells. Overall, the data suggested that this variant TNFSF12 may dominantly inhibit B-cell survival and proliferation as well as Ig class switching by forming ineffective oligomers with BAFF. All 3 patients had recurrent respiratory infections since infancy, although the frequency and severity of the infections decreased in adulthood in the father. Immunologic workup showed absence of antibody responses to T-cell-dependent and polysaccharide antigens as well as low levels of immunoglobulins. The father and 1 child had decreased numbers of B cells, and nearly all the B cells in all patients were IgM+ IgD+ naive B cells. There was also a slight increase in the percentage of CD4-, CD8- T cells (double-negative T cells) as well as an increase in CD8+ T cells.