ClinVar Miner

Submissions for variant NM_012452.2(TNFRSF13B):c.431C>G (p.Ser144Ter) (rs104894650)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255478 SCV000322127 pathogenic not provided 2017-07-18 criteria provided, single submitter clinical testing The S144X pathogenic variant in the TNFRSF13B gene has been reported previously in the homozygous state in two siblings with common variable immunodeficiency. The variant was absent in their unaffected sibling (Salzer et al., 2005). Functional studies using B cells from the probands demonstrated a loss of TACI function, profound B cell defects, and elevated autoreactive B cell frequencies (Salzer et al., 2005; Romberg et al., 2013). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The S144X variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret S144X as a pathogenic variant.
Invitae RCV000702330 SCV000831182 pathogenic Common variable immunodeficiency 2 2019-12-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser144*) in the TNFRSF13B gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs104894650, ExAC 0.004%). This variant has been reported in an individual affected with autoimmune lymphoproliferative syndrome and common variable immunodeficiency (PMID: 25569260), and has been observed in combination with another TNFRSF13B variant in an individual affected with common variable immunodeficiency (PMID: 27123465). ClinVar contains an entry for this variant (Variation ID: 265340). Experimental studies on a different variant (c.431C>A) giving rise to the same truncating effect observed here (p.Ser144*) have shown that this nonsense change causes defective central and peripheral B cell tolerance (PMID: 24051380). Loss-of-function variants in TNFRSF13B are known to be pathogenic (PMID: 16007087, 27123465). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002619 SCV001160601 pathogenic not specified 2019-06-18 criteria provided, single submitter clinical testing The TNFRSF13B c.431C>G; p.Ser144Ter variant (rs104894650) is reported in the literature in the compound heterozygous state in individuals affected with primary antibody deficiency syndromes (Brignier 2015, Pulvirenti 2016), and reported in the heterozygous state in unaffected relatives (Clemente 2015). This variant is reported as pathogenic in ClinVar (Variation ID: 265340), and is found in the general population with an overall allele frequency of 0.0056% (14/251478 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, another nonsense variant at this nucleotide (c.431C>A; p.Ser144Ter) has been reported in the homozygous state in two siblings with common variable immunodeficiency (Salzer 2005). Functional studies of cells from these patients demonstrate a lack of mRNA and protein expression leading to severe B cell defects (Romberg 2013, Salzer 2005). Based on available information, this variant is considered to be pathogenic. References: Brignier AC et al. Early-onset hypogammaglobulinemia: A survey of 44 patients. J Allergy Clin Immunol. 2015 Oct;136(4):1097-9.e2. Clemente N et al. A mutation in caspase-9 decreases the expression of BAFFR and ICOS in patients with immunodeficiency and lymphoproliferation. Genes Immun. 2015 Mar;16(2):151-61. Pulvirenti F et al. Clinical Associations of Biallelic and Monoallelic TNFRSF13B Variants in Italian Primary Antibody Deficiency Syndromes. J Immunol Res. 2016;2016:8390356. Romberg N et al. CVID-associated TACI mutations affect autoreactive B cell selection and activation. J Clin Invest. 2013 Oct;123(10):4283-93. Salzer U et al. Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet. 2005 Aug;37(8):820-8.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000255478 SCV001250125 pathogenic not provided 2018-06-01 criteria provided, single submitter clinical testing

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