ClinVar

Description

Variant summary: TNFRSF13B c.310T>C (p.Cys104Arg) results in a non-conservative amino acid change located in the TACI, cysteine-rich domain (IPR015384) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0035 in 251490 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is considerably higher than the estimated maximal expected allele frequency for a pathogenic variant in TNFRSF13B causing Common Variable Immunodeficiency (CVID) phenotype, strongly suggesting that the variant is benign. c.310T>C has been reported in the literature (in heterozygous, compound heterozygous or homozygous state) in multiple individuals affected with CVID. Specifically, in terms of individuals heterozygous for the variant, some are reported with CVID, some are reported with CVID-related symptoms and minor clinical manifestations while a lot of others are reported as healthy without any clinical symptoms (e.g. Abolhassani_2019, Alachkar_2006, Berglund_2006, Castigli_2005, Koopmans_2013, Kralickova_2019, Martinez-Pomar_2009, Poodt_2009, Salzer_2005, Salzer_2009, Speletas_2011, Zhang_2007). Many compound heterozygous and homozygous individuals are reported affected with CVID (e.g. Castigli_2005, de Valles-Ibanez_2018, Koopmans_2013, Maffucci_2016, Martinez-Pomar_2009, Salzer_2005, Salzer_2009, Zhang_2007). Interestingly, among 4 homozygous individuals reported as asymptomatic in two studies, 2 of them were observed with low immunoglobulin plasma levels and 1 with severe hypogammaglobulinemia (Koopmans_2013, Martinez-Pomar_2009). Altogether, these data indicate that the variant is likely to be associated with disease and reveal a continuum spectrum of disease severity, ranging from the absence of clinical symptoms, minor clinical manifestations and moderate to severe forms of CVID. Additional genetic or environmental factors are likely to play a role in disease manifestation. Multiple experimental studies suggest the variant causes significant defects to protein function. Specifically, protein expression and ligand binding were demonstrated to be significantly diminished (Bacchelli_2011, Salzer_2005). Mice heterozygous and homozygous for the equivalent murine mutation (C76R) exhibited significant B-cell dysfunction with splenomegaly, marginal zone B-cell expansion, diminished immunoglobulin production and serological responses to T cell-independent antigen, and abnormal immunoglobulin synthesis (Bacchelli_2011). A study by Martinez-Gallo et al (2013) showed that both, CVID affected individuals and their unaffected family members with the variant in heterozygous or homozygous form, had impaired B-cell TACI expression, reduced ligand binding, and markedly defective upregulation of AID mRNA. The authors concluded that B cells of relatives of subjects with CVID who have mutations in TNFRSF13B but normal immune globulin levels still have detectable in vitro B-cell defects. Eight ClinVar submitters (evaluation after 2014) cite the variant with conflicting interpretations [pathogenic/likely pathogenic (n=3); risk factor (n=1); uncertain significance (n=2); likely benign (n=2)]. Based upon comprehensive review of a large quantity of evidence spanning more than a decade, the variant was classified as a pathogenic risk factor for CVID.