Submissions for variant NM_012452.3(TNFRSF13B):c.58C>T (p.Arg20Cys)

gnomAD frequency: 0.00012  dbSNP: rs200013015

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000700484	SCV000829241	uncertain significance	Immunodeficiency, common variable, 2	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 20 of the TNFRSF13B protein (p.Arg20Cys). This variant is present in population databases (rs200013015, gnomAD 0.03%). This missense change has been observed in individual(s) with systemic lupus erythematosus (SLE) and hyper-IgM syndrome or common variable immunodeficiency (PMID: 17464555, 20652909, 33859323, 34441032). ClinVar contains an entry for this variant (Variation ID: 577672). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Center for Personalized Medicine, Children's Hospital Los Angeles	RCV000735375	SCV000854529	uncertain significance	Seizure; Micrognathia; Cognitive impairment; Cafe-au-lait spot; Frontal bossing; High forehead; Abnormal basal ganglia morphology; Thoracic scoliosis; Abnormal basal ganglia MRI signal intensity		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001171924	SCV001334827	uncertain significance	not provided	2022-08-01	criteria provided, single submitter	clinical testing
New York Genome Center	RCV001836866	SCV002097834	uncertain significance	Immunodeficiency, common variable, 2; Immunoglobulin A deficiency 2	2021-07-23	criteria provided, single submitter	clinical testing	The inherited heterozygous c.58C>T (p.Arg20Cys) missense variant identified in the TNFRSF13B gene has been reported in a patient affected with hyper-IgM syndrome or common variable immunodeficiency [PMID: 20652909], and in another individual affected with systemic lupus erythematosus (but didn't co-segregate with the disease in that family [PMID: 17464555]. This variant has been reported in ClinVar database as a variant of uncertain significance [Variation ID: 577672]. The variant has 0.0001249 allele frequency in the gnomAD database (19 out of 152,114 heterozygous alleles, no homozygotes) indicating it is not a benign polymorphism in the populations represented in that database. The variant affects a weakly conserved reside and in silico tools provide conflicting interpretations about potential pathogenicity of this variant. Due to the lack of compelling evidence for its pathogenicity, the inherited heterozygous c.58C>T (p.Arg20Cys) missense variant identified in the TNFRSF13B gene of this individual is reported as a variant of uncertain significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV004596330	SCV005090288	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001171924	SCV005875417	uncertain significance	not provided	2024-05-23	criteria provided, single submitter	clinical testing	The TNFRSF13B c.58C>T; p.Arg20Cys variant (rs200013015) is reported in the literature in individuals affected with primary antibody deficiency, common variable immunodeficiency, or systemic lupus erythematosus, but did not segregate with disease in at least one family (Bisgin 2021, Kakkas 2021, Salzer 2007, Wang 2010). This variant is also reported in ClinVar (Variation ID: 577672), and is found in the general population with an overall allele frequency of 0.0081% (23/282658 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.294). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Bisgin A et al. The impact of rare and low-frequency genetic variants in common variable immunodeficiency (CVID). Sci Rep. 2021 Apr 15;11(1):8308. PMID: 33859323. Kakkas I et al. TACI Mutations in Primary Antibody Deficiencies: A Nationwide Study in Greece. Medicina (Kaunas). 2021 Aug 16;57(8):827. PMID: 34441032. Salzer U et al. Sequence analysis of TNFRSF13b, encoding TACI, in patients with systemic lupus erythematosus. J Clin Immunol. 2007 Jul;27(4):372-7. PMID: 17464555. Wang HY et al. A custom 148 gene-based resequencing chip and the SNP explorer software: new tools to study antibody deficiency. Hum Mutat. 2010 Sep;31(9):1080-8. PMID: 20652909.