Submissions for variant NM_012452.3(TNFRSF13B):c.431C>G (p.Ser144Ter)

dbSNP: rs104894650

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255478	SCV000322127	pathogenic	not provided	2023-05-30	criteria provided, single submitter	clinical testing	Identified with two other TNFRSF13B variants in a patient with common variable immunodeficiency disorder, however, it is unclear if parental segregation studies were done to confirm the phase of these variants (Pulvirenti et al., 2016); Identified in the heterozygous state in an individual with autoimmunity/lymphoproliferation and severe hypogammaglobulinemia, however this variant was also detected in the heterozygous state in this individual's unaffected mother and sibling. This patient also harbored a heterozygous variant in the CASP9 gene (Clemente et al., 2015); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31589614, 28249164, 33859323, 25569260, 27123465)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000702330	SCV000831182	pathogenic	Immunodeficiency, common variable, 2	2025-02-03	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. Loss-of-function variants in TNFRSF13B are known to be pathogenic (PMID: 16007087, 27123465). This variant is present in population databases (rs104894650, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with autoimmune lymphoproliferative syndrome and common variable immunodeficiency (PMID: 25569260, 27123465). ClinVar contains an entry for this variant (Variation ID: 265340). 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 Center for Human Genetics Tuebingen	RCV000255478	SCV001250125	pathogenic	not provided	2025-03-01	criteria provided, single submitter	clinical testing	TNFRSF13B: PVS1, PM3, PM2:Supporting
Baylor Genetics	RCV000702330	SCV005049847	pathogenic	Immunodeficiency, common variable, 2	2024-01-10	criteria provided, single submitter	clinical testing
Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska"	RCV000702330	SCV002573408	pathogenic	Immunodeficiency, common variable, 2		no assertion criteria provided	clinical testing
Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska"	RCV002283472	SCV002573413	pathogenic	Immunodeficiency, common variable, 1	2022-05-01	no assertion criteria provided	clinical testing