ClinVar Miner

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

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Total submissions: 2
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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 2018-12-29 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.

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