TNFRSF13C

Inheritance Pattern: AR

Disease ID:MONDO:0013284

Submitter: PanelApp Australia

Inheritance Pattern: Unknown

Disease ID:MONDO:0013284

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0013284

Submitter: ClinGen

Homozygous or compound heterozygous mutations in TNFRSF13C (also known as BAFF-R) cause immunodeficiency, common variable, 4 (CVID4). It was first reported clinically in two siblings with adult-onset CVID4 and a homozygous deletion in TNFRSF13C (Warnatz, K., 2009). TNFRSF13C encodes tumor necrosis factor receptor superfamily member 13C, which is a B-cell receptor specific for TNFSF13B. It is important for B cell survival. At least three unique variants in TNFRSF13C have been described since 2009 to confer CVID4; these variants are two missense (c.475C>T and c.62C>G) and one deletion (c.265_288del). Robust experimental data, including one particularly convincing paper (Thompson et al, 2001) which reports on expression, protein interaction, and model systems data, support the importance of BAFF-R in vitro and in vivo for immune system health. Additional experimental data regarding the function of TNFRSF13C in B cell survival (Kayagaki et al., 2002) and further mouse models (Saski et al., 2004 and Shul-ga-Morskaya et al., 2004) were also included. The maximum score was reached for experimental data. However, case data is less convincing and there are only a few cases to date of clinical autosomal recessive CVID4 by pathogenic variants in TNFRSF13C. There is one particular variant (c. 62c>G; p.Pro21Arg) that has been recurrently identified, including in one study (unpublished by Mouillot G et al.) where 485 patients with hypogammaglobulinemia were sequenced for mutations in TNFRSF13C. Seventy patients were found to have at least one mutation in TNFRSF13C, composed of 6 that were P21R homozygous, and 7 were compound heterozygotes with one variant being P21R. This variant is sometimes referred to as a “risk factor” and not described as causing sever disease, which was further iterated when Speletas M et al (unpublished) reported that P21R homozygosity results in mild immunodeficiency. However, Kutukculer et al identified an individual with compound heterozygous variants P21R and c.475C>T (which also has conflicting reports of pathogenicity) who had a severe presentation of CVID4. In summary, only the case of the homozygous c.265_288del variant is considered informative at this time, as such there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.