ClinVar Miner

Submissions for variant NM_012452.3(TNFRSF13B):c.310T>C (p.Cys104Arg)

gnomAD frequency: 0.00403  dbSNP: rs34557412
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Total submissions: 36
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
UCLA Clinical Genomics Center, UCLA RCV000005623 SCV000255489 likely pathogenic Immunodeficiency, common variable, 2 2014-07-15 criteria provided, single submitter clinical testing
GeneDx RCV000403933 SCV000329550 pathogenic not provided 2022-01-10 criteria provided, single submitter clinical testing Reported previously in association with both autosomal dominant and autosomal recessive forms of CVID and immunoglobulin A deficiency; however, this variant is most commonly associated with autosomal recessive inheritance (Salzer et al., 2009; Barroeta Seijas et al., 2012; Speletas et al., 2013; Martinez-Gallo et al., 2013; Lucena et al., 2015); Published functional studies demonstrate C104R results in reduced surface expression and elimination of ligand binding, supporting a damaging effect (Lee et al., 2010; Fried et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25326637, 24051380, 17392797, 30269248, 17492055, 26727773, 22983507, 22697072, 20889194, 23956760, 23237420, 16007086, 19210517, 16007087, 18981294, 22884984, 25174870, 21850030, 27123465, 26100089, 27577878, 16630947, 29146883, 29867916, 29555771, 29921932, 29114388, 30665703, 31681265, 31618753, 32499645, 32581362, 21419480, 34573280, 34426522, 34210994, 30755392, 33425813, 33258288, 32441320, 32531373, 33726816)
Illumina Laboratory Services,Illumina RCV000302082 SCV000400917 likely benign Common Variable Immune Deficiency, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000005623 SCV000590895 risk factor Immunodeficiency, common variable, 2 2017-06-07 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000403933 SCV000605391 pathogenic not provided 2021-09-08 criteria provided, single submitter clinical testing The TNFRSF13B c.310T>C; p.Cys104Arg variant (rs34557412) has been reported in patients diagnosed with common variable immunodeficiency, and the association with the disease was found to be statistically significant (odds ratio 4.16 (1.98-8.74)) (Pan-Hammarstrom 2007). Additionally, functional studies show that this variant disrupts protein signaling (Martinez-Gallo 2013, Salzer 2005). However, this variant does not always segregate with disease in families (Poodt 2009, Koopmans 2013) and the variant is often observed in clinically asymptomatic first-degree relatives and healthy controls (Barroeta- Seijas, Matrtinez-Pomar 2009). This variant is reported in ClinVar (Variation ID: 5302), and is found in the general population with an overall allele frequency of 0.35% (983/282890 alleles, including 4 homozygotes) in the Genome Aggregation Database. Based on available information, this variant is considered to be a pathogenic CVID-associated variant with variable penetrance, that may act in co-existence with other genetic and/or environmental factors (Koopmans 2013). References: Barroeta Seijas AB et al. The impact of TACI mutations: from hypogammaglobulinemia in infancy to autoimmunity in adulthood. Int J Immunopathol Pharmacol. 2012 Apr-Jun;25(2):407-14. PMID: 22697072. Koopmans et al. Clinical variability of family members with the C104R mutation in transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI). J Clin Immunol. 2013 33(1):68-73. Martínez-Pomar N et al. Role of TNFRSF13B variants in patients with common variable immunodeficiency. Blood. 2009 Sep 24;114(13):2846-8. PMID: 19779048. Martinez-Gallo et al. TACI mutations and impaired B-cell function in subjects with CVID and healthy heterozygotes. J Allergy Clin Immunol. 2013 131(2):468-476. Pan-Hammarstrom et al. Reexamining the role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency. Nat Genet. 2007 39(4):429-30. Poodt AE et al. TACI mutations and disease susceptibility in patients with common variable immunodeficiency. Clin Exp Immunol. 2009 Apr;156(1):35-9. PMID: 19210517. 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. PMID: 16007087.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000403933 SCV000610665 likely benign not provided 2017-09-25 criteria provided, single submitter clinical testing
Invitae RCV000005623 SCV000649856 likely pathogenic Immunodeficiency, common variable, 2 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 104 of the TNFRSF13B protein (p.Cys104Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is present in population databases (rs34557412, ExAC 0.5%). This variant has been reported in many individuals affected with common variable immunodeficiency (CVID) as homozygous, compound heterozygous with other TNFRSF13B variants, and as a heterozygous variant (PMID: 16007087, 17392797, 22697072, 27123465, 24051380, 19779048). This variant has also been seen as heterozygous in multiple unaffected relatives, but studies on B cells of these relatives show impaired function compared to unaffected individuals without TNFRSF13B variants (PMID: 23237420, 24051380). A meta-analysis of 1,423 CVID patients and 4,225 controls showed that this variant is significantly enriched in CVID patients (PMID: 22884984). In addition, this variant has been seen to segregate with disease in multiple families, although it appears to have reduced penetrance (PMID: 16007087, 19779048, 22983507, 22697072, 22884984, 23237420). The TNFRSF13B gene is also known as TACI in the literature. ClinVar contains an entry for this variant (Variation ID: 5302). Experimental studies have shown that this missense change disrupts ligand binding with APRIL, impairs B-cell proliferation in response to stimulation, and reduces the expression of TNFRSF13B on the surface of B-cells (PMID: 16007087, 21419480, 23237420). Individuals who are heterozygous for p.Cys104Arg have an increased number of autoreactive B-cells in the bone marrow (PMID: 24051380). In addition, mouse models with this variant also show reduced immunoglobulin production upon stimulation (PMID: 20889194, 21458042). In summary, this variant is a rare missense change that has been seen to segregate in multiple CVID families and disrupts protein function. This evidence indicates that the variant is pathogenic, but given the frequency of this variant in unaffected individuals, additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001526850 SCV000699342 pathogenic Common variable agammaglobulinemia 2020-03-31 criteria provided, single submitter clinical testing Variant summary: TNFRSF13B c.310T>C (p.Cys104Arg) results in a non-conservative amino acid change located in the TACI, cysteine-rich domain (IPR015384) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0035 in 251490 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is considerably higher than the estimated maximal expected allele frequency for a pathogenic variant in TNFRSF13B causing Common Variable Immunodeficiency (CVID) phenotype, strongly suggesting that the variant is benign. c.310T>C has been reported in the literature (in heterozygous, compound heterozygous or homozygous state) in multiple individuals affected with CVID. Specifically, in terms of individuals heterozygous for the variant, some are reported with CVID, some are reported with CVID-related symptoms and minor clinical manifestations while a lot of others are reported as healthy without any clinical symptoms (e.g. Abolhassani_2019, Alachkar_2006, Berglund_2006, Castigli_2005, Koopmans_2013, Kralickova_2019, Martinez-Pomar_2009, Poodt_2009, Salzer_2005, Salzer_2009, Speletas_2011, Zhang_2007). Many compound heterozygous and homozygous individuals are reported affected with CVID (e.g. Castigli_2005, de Valles-Ibanez_2018, Koopmans_2013, Maffucci_2016, Martinez-Pomar_2009, Salzer_2005, Salzer_2009, Zhang_2007). Interestingly, among 4 homozygous individuals reported as asymptomatic in two studies, 2 of them were observed with low immunoglobulin plasma levels and 1 with severe hypogammaglobulinemia (Koopmans_2013, Martinez-Pomar_2009). Altogether, these data indicate that the variant is likely to be associated with disease and reveal a continuum spectrum of disease severity, ranging from the absence of clinical symptoms, minor clinical manifestations and moderate to severe forms of CVID. Additional genetic or environmental factors are likely to play a role in disease manifestation. Multiple experimental studies suggest the variant causes significant defects to protein function. Specifically, protein expression and ligand binding were demonstrated to be significantly diminished (Bacchelli_2011, Salzer_2005). Mice heterozygous and homozygous for the equivalent murine mutation (C76R) exhibited significant B-cell dysfunction with splenomegaly, marginal zone B-cell expansion, diminished immunoglobulin production and serological responses to T cell-independent antigen, and abnormal immunoglobulin synthesis (Bacchelli_2011). A study by Martinez-Gallo et al (2013) showed that both, CVID affected individuals and their unaffected family members with the variant in heterozygous or homozygous form, had impaired B-cell TACI expression, reduced ligand binding, and markedly defective upregulation of AID mRNA. The authors concluded that B cells of relatives of subjects with CVID who have mutations in TNFRSF13B but normal immune globulin levels still have detectable in vitro B-cell defects. Eight ClinVar submitters (evaluation after 2014) cite the variant with conflicting interpretations [pathogenic/likely pathogenic (n=3); risk factor (n=1); uncertain significance (n=2); likely benign (n=2)]. Based upon comprehensive review of a large quantity of evidence spanning more than a decade, the variant was classified as a pathogenic risk factor for CVID.
Center for Personalized Medicine, Children's Hospital Los Angeles RCV000735370 SCV000854523 uncertain significance Clubfoot; Skeletal dysplasia; Micrognathia; Hemivertebrae; Preaxial foot polydactyly; Respiratory failure; Short femur; Vertebral segmentation defect; Pseudoarthrosis; Chronic lung disease; Abnormal pulmonary interstitial morphology; Coat hanger sign of ribs; Vertebral hypoplasia; Absent epiphyses; Cleft palate; Patent ductus arteriosus criteria provided, single submitter clinical testing
Blueprint Genetics RCV000403933 SCV000927312 uncertain significance not provided 2017-06-26 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000507544 SCV000966775 uncertain significance not specified 2018-07-27 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
CeGaT Center for Human Genetics Tuebingen RCV000403933 SCV001250126 pathogenic not provided 2022-08-01 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000005623 SCV001448757 likely pathogenic Immunodeficiency, common variable, 2 2019-09-06 criteria provided, single submitter clinical testing
Baylor Genetics RCV000005623 SCV001530692 uncertain significance Immunodeficiency, common variable, 2 2018-06-18 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories,Mayo Clinic RCV000403933 SCV001712902 pathogenic not provided 2020-09-29 criteria provided, single submitter clinical testing PS3, PS4_moderate, PP3
Suma Genomics RCV000005623 SCV001837633 uncertain significance Immunodeficiency, common variable, 2 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000005623 SCV001934352 pathogenic Immunodeficiency, common variable, 2 2020-12-03 criteria provided, single submitter clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV000005623 SCV001976896 likely pathogenic Immunodeficiency, common variable, 2 2021-10-06 criteria provided, single submitter clinical testing PM2, PM5, PP3, PP5
3billion RCV000005623 SCV002058245 pathogenic Immunodeficiency, common variable, 2 2022-01-03 criteria provided, single submitter clinical testing Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000005302, PS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 21419480, 20889194, PS3_S). A different missense change at the same codon (p.Cys104Tyr) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000645207, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.919, 3CNET: 0.974, PP3_P). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genetic Services Laboratory,University of Chicago RCV000403933 SCV002070496 likely pathogenic not provided 2020-04-20 criteria provided, single submitter clinical testing DNA sequence analysis of the TNFRSF13B gene demonstrated a sequence change, c.310T>C, in exon 3 that results in an amino acid change, p.Cys104Arg. This sequence change has been described in the gnomAD database with a relatively high population frequency of 0.54% in European populations (dbSNP rs34557412). The p.Cys104Arg change affects a highly conserved amino acid residue located in a domain of the TNFRSF13B protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Cys104Arg substitution. The p.Cys104Arg change has been reported in the homozygous, compound heterozygous, and heterozygous states in many individuals affected with common variable immunodeficiency (CVID) (PMID: 16007087, 17392797, 22697072, 27123465, 24051380, 19779048). Individuals who are heterozygous for this sequence change have been reported with an increased number of autoreactive B-cells in the bone marrow (PMID: 24051380). This sequence has also been seen in the heterozygous state in multiple unaffected individuals, however functional studies on B cells of these individuals show impaired function compared to unaffected individuals without variants in TNFRSF13B (PMID: 23237420, 24051380). The p.Cys104Arg change has been reported to segregate with disease in several families; however, it appears to have reduced penetrance (PMID: 16007087, 19779048, 22983507, 22697072, 22884984, 23237420). Functional studies have demonstrated that this sequence change affects ligand binding and reduces protein expression (PMID: 16007087, 21419480, 23237420). This sequence change is predicted to confer an increased risk for the development of CVID and is may confer an increased risk for lymphoma. We interpret this change as likely pathogenic.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV002054418 SCV002495994 likely pathogenic Immunodeficiency, common variable, 2; Immunoglobulin A deficiency 2 2020-11-25 criteria provided, single submitter clinical testing TNFRSF13B:NM_012452.2:c.310T>C:p.Cys104Arg: This variant has been reported in the literature in numerous individuals with Combined Variable Immune Deficiency (CVID) in the heterozygous, homozygous and compound heterozygous state and is listed as the most common variant reported in association with this condition (Selected Publications: Salzer 2005 PMID:16007087, Berglund 2006 PMID:16630947, Pan-Hammarstrom 2007 PMID:17392797, Barroeta-Seijas 2012 PMID:22697072, Koopmans 2013 PMID:22983507, Martinez-Galllo 2013 PMID:23237420, Rudilla 2019 PMID:31681265). This variant has been identified to segregate with disease in multiple different family members, also in the heterozygous, compound heterozygous and homozygous state. However, this variant has been identified in multiple individuals who do not present with disease (including in the homozygous state) even within the same family, suggesting that this variant has significant reduced penetrance (Koopmans 2013 PMID:22983507, Martinez-Galllo 2013 PMID:23237420). This variant is present in 0.7% (109/15278) of Latino alleles, including 1 homozygote and is present at similar frequencies across different ethnicities in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/17-16948873-A-G?dataset=gnomad_r3). This variant is present in ClinVar, with classifications ranging from Variant of Uncertain Significance (Uncertain significance) to Pathogenic (Variation ID:5302). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Numerous functional studies including mouse models have demonstrated the impact of this variant by reducing expression on the surface of B-cells, impairing bindings with BAFF and APRIL and defective antibody production (Salzer 2005 PMID:16007087, Lee 2010 PMID:20889194, Fried 2011 PMID:21419480, Martinez-Galllo 2013 PMID:23237420). In summary, this variant is classified as likely pathogenic based on extensive studies, but may be best considered in the context of a non-mendelian risk allele.
AiLife Diagnostics, AiLife Diagnostics RCV000403933 SCV002503376 pathogenic not provided 2022-03-09 criteria provided, single submitter clinical testing
Mendelics RCV000005623 SCV002519879 pathogenic Immunodeficiency, common variable, 2 2022-05-04 criteria provided, single submitter clinical testing
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center RCV000005623 SCV002568305 likely pathogenic Immunodeficiency, common variable, 2 2022-04-26 criteria provided, single submitter clinical testing PS3 PM1 PP3
OMIM RCV000005623 SCV000025805 pathogenic Immunodeficiency, common variable, 2 2007-06-01 no assertion criteria provided literature only
OMIM RCV000005624 SCV000025806 pathogenic Immunoglobulin A deficiency 2 2007-06-01 no assertion criteria provided literature only
Clinical Genomics Program, Stanford Medicine RCV000005623 SCV001427230 uncertain significance Immunodeficiency, common variable, 2 2020-03-24 no assertion criteria provided clinical testing The p.Cys104Arg variant in the TNFRSF13B gene has been previously reported in the heterozygous, compound heterozygous, or homozygous state in many individuals with common variable immunodeficiency (CVID; Castigli et al., 2005; de Valles-Ibáñez et al., 2018; Martinez-Polmar et al., 2009; Salzer et al., 2005). The p.Cys104Arg variant has also been identified in 697/129,190 European chromosomes, including 3 homozygotes, by the Genome Aggregation Database (http://gnomad.broadinstitute.org/), indicating it may be a common, reduced penetrance allele. The p.Cys104Arg variant is relatively common in the general population, and case-control studies provide conflicting evidence for an association with antibody deficiency (Castigli 2005; de VallesIbanez 2018; Pan-Hammarström et al, 2007; Pulvirenti et al., 2016; Salzer et al., 2009). Functional studies have shown that this variant impairs ligand binding, B cell proliferation, and antibody responses (Castigli et al., 2005; Fried et al., 2011; Lee et al., 2010; Salzer et al., 2005). Computational tools predict that the p.Cys104Arg variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Cys104Arg variant is uncertain; however, there is suspicion that this variant could be associated with common variable immunodeficiency due to functional studies and the predicted impact to the protein. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PS3_moderate; PP3]
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn RCV001374734 SCV001571337 likely pathogenic Severe SARS-CoV-2 infection, susceptibility to 2021-03-03 no assertion criteria provided clinical testing This variant was observed in homozygous state in a child with a lethal course of covid-19. The child was also homozygous for a splice site variant in TBK1, that is associated to autoinflammatory disorder. Probably a combination of the deleterious homozygous missense mutation in TNFRSF13B and the homozygous splice site mutation in TBK1 in the presence of an autoinflammatory disease and its treatment regimen - might have promoted the severe disease course observed in the present case either alone or in concert.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000403933 SCV001742791 likely pathogenic not provided no assertion criteria provided clinical testing
GenomeConnect - Invitae Patient Insights Network RCV001535526 SCV001749491 not provided Immunodeficiency, common variable, 1; Immunodeficiency, common variable, 2 no assertion provided phenotyping only Variant interpreted as Likely pathogenic and reported on 04-25-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000403933 SCV001931341 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000403933 SCV001954885 likely pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000403933 SCV001969656 likely pathogenic not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000403933 SCV001977672 likely pathogenic not provided no assertion criteria provided clinical testing
PerkinElmer Genomics RCV000403933 SCV002020242 likely pathogenic not provided 2021-06-17 no assertion criteria provided clinical testing
Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID,University Hospital "Alexandrovska" RCV002283439 SCV002573414 likely pathogenic Immunodeficiency, common variable, 1 2022-05-01 no assertion criteria provided clinical testing

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