Submissions for variant NM_012452.3(TNFRSF13B):c.204dup (p.Leu69fs)

gnomAD frequency: 0.00031  dbSNP: rs72553875

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000380683	SCV000400921	uncertain significance	Common Variable Immune Deficiency, Dominant	2016-06-14	criteria provided, single submitter	clinical testing	The c.204dupA (p.Leu69ThrfsTer12) variant is a frameshift variant and is predicted to result in a premature termination of the protein. The p.Leu69ThrfsTer12 variant has been reported in at least five studies in individuals with either CVID or IgA deficiency (Castigli et al. 2005; Salzer et al. 2009; Speletas et al. 2011; Freiberger et al. 2012; Pulvirenti et al. 2016) and found in a compound heterozygous state with a missense variant in three patients with CVID and in a heterozygous state in six individuals with IgA deficiency. One multigenerational family study showed this variant segregating with disease in individuals with IgA deficiency or CVID, suggesting clinical heterogeneity with a potential spectrum of disease (Castigli et al. 2005). The p.Leu69ThrfsTer12 variant was absent from at least 1250 controls, but is reported at a frequency of 0.00109 in the European American population of the Exome Sequencing Project. Functional studies show that the p.Leu69ThrfsTer12 variant results in a severely impaired secretion of IgG and IgA in B cells in response to the TACI ligand, APRIL (Castigli et al. 2005). Castigli et al. (2005) also showed there was no detectable protein product on the surface of 293 cells carrying the p.Leu69ThrfsTer12 variant. However, Salzer et al. (2009) showed a single EBV-transformed cell line carrying a heterozygous p.Leu69ThrfsTer12 variant displayed no significant differences in TACI expression or ligand binding capacity compared with controls. Based on the potential impact of frameshift variants and the supporting evidence, the p.Leu69ThrfsTer12 variant is classified as a variant of unknown significance but suspicious for pathogenicity for common variable immune deficiency.
GeneDx	RCV000520212	SCV000617814	pathogenic	not provided	2024-11-26	criteria provided, single submitter	clinical testing	Reported in association with both autosomal dominant and autosomal recessive forms of CVID and immunoglobulin A deficiency; however, most commonly associated with autosomal recessive inheritance (PMID: 16007086, 18981294, 21547394, 27123465); Frameshift 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: 26100089, 27266541, 26046366, 23956760, 18981294, 22884984, 21547394, 30090215, 16007086, 27123465)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000557905	SCV000649854	pathogenic	Immunodeficiency, common variable, 2	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu69Thrfs*12) 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 (rs72553875, gnomAD 0.6%). This premature translational stop signal has been observed in individuals with common variable immunodeficiency or IgA deficiency (PMID: 16007086, 17392798, 18981294, 22884984, 26046366, 26100089, 27123465). ClinVar contains an entry for this variant (Variation ID: 322029). For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV000557905	SCV001140308	likely pathogenic	Immunodeficiency, common variable, 2	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000520212	SCV001250127	pathogenic	not provided	2020-12-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000520212	SCV002022362	pathogenic	not provided	2021-11-16	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224262	SCV003920575	pathogenic	Immunodeficiency, common variable, 2; Immunoglobulin A deficiency 2	2021-12-08	criteria provided, single submitter	clinical testing	TNFRSF13B NM_012452.2 exon 3 p.Leu69Thrfs*12 (c.204dupA):This variant has been reported in the literature in at least 5 individuals with Common Variable Immunodeficiency (CVID) or IgA deficiency (IgAD), segregating with disease in at least 4 affected family members. This variant has also been identified in 1 individual with tonsillar hypertrophy (Castigli 2005 PMID:16007086, Castigli 2007 PMID:17392798, Salzer 2009 PMID:18981294, Speletas 2011 PMID:21547394, Freiberger 2012 PMID:22884984, Speletas 2013 PMID:23956760, Pulvirenti 2016 PMID:27123465). This variant is present in 0.5% (58/10358) of Ashkenazi Jewish alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/17-16852292-G-GT?dataset=gnomad_r2_1). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as Pathogenic or Likely Pathogenic (Variation ID: 322029). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. In addition, functional studies have shown a deleterious effect of this variant suggesting no impact to protein expression, activation responses or central B-cell tolerance in naive B cells, but decreased expression on memory B cells with subsequent impaired activation and antibody secretion (Romberg 2015 PMID:26100089). This variant is a duplication of 1 nucleotide at position 204 and creates a premature stop codon 12 amino acids downstream from this location resulting in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Romberg 2015 PMID:26100089). In summary, this variant is classified as pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000557905	SCV004013327	pathogenic	Immunodeficiency, common variable, 2	2023-06-26	criteria provided, single submitter	clinical testing	PVS1, PS3
3billion	RCV000557905	SCV004013646	pathogenic	Immunodeficiency, common variable, 2	2023-08-22	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 36067766). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000977756 /PMID: 36067766 /3billion dataset). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 36067766, 36067766). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
PreventionGenetics, part of Exact Sciences	RCV003422282	SCV004116505	likely pathogenic	TNFRSF13B-related disorder	2023-03-06	criteria provided, single submitter	clinical testing	The TNFRSF13B c.204dupA variant is predicted to result in a frameshift and premature protein termination (p.Leu69Thrfs*12). This variant has been reported in either the heterozygous or compound heterozygous state in several individuals with either common variable immunodeficiency (CVID) or IgA deficiency (IgAD) (Castigli et al. 2005. PubMed ID: 16007086; Salzer et al. 2009. PubMed ID: 18981294; Speletas et al. 2011. PubMed ID: 21547394; Pulvirenti et al. 2016. PubMed ID: 27123465). At least one patient with this variant developed non-Hodgkin lymphoma as well as CVID (Pulvirenti et al. 2016. PubMed ID: 27123465). This variant is reported in 0.56% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-16852292-G-GT). Frameshift variants in TNFRSF13B are expected to be pathogenic. This variant is interpreted as likely pathogenic.
Genomic Medicine Lab, University of California San Francisco	RCV003995848	SCV004847103	pathogenic	Hyper-IgM syndrome type 2	2023-08-06	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000557905	SCV005918274	pathogenic	Immunodeficiency, common variable, 2	2020-11-02	criteria provided, single submitter	research
OMIM	RCV000557905	SCV000025810	pathogenic	Immunodeficiency, common variable, 2	2005-08-01	no assertion criteria provided	literature only
OMIM	RCV002460349	SCV000025811	pathogenic	Immunoglobulin A deficiency 2	2005-08-01	no assertion criteria provided	literature only
Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska"	RCV002283475	SCV002573436	likely pathogenic	Immunodeficiency, common variable, 1	2022-05-01	no assertion criteria provided	clinical testing