ClinVar Genomic variation as it relates to human health

proposed classification - variant undergoing re-assessment, contact laboratory

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.

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.

This is a recurrent variant that has been reported as homozygous, compound heterozygous, and heterozygous change in individuals with common variable immunodeficiency (CVID) and in unaffected control individuals (PMID: 23237420, 17392797, 20156508, 24051380, 16007086, 16007087, 22884984). A study of 844 cases with CVID and 3924 controls found the p.Cys104Arg variant significantly enriched in cases versus controls (OR 5.60, CI 2.99-10.51, p=3.9 x 10-8) (PMID: 17392797). Further, a meta-analysis of 1,439 CVID patients and 3,558 controls confirmed enrichment of this variant in CVID cases versus controls (p < 10-5) (PMID: 22884984). In-vitro studies showed that the variant, which is located in the transmembrane (TM) domain of TACI, disrupts NF-kB/NF-AT signaling and leads to defective B-cell proliferation in response to stimulation (PMID: 21419480, 23237420, 19605846). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.35% (983/282890) and in the homozygote state in 4 individuals. The c.310T>C (p.Cys104Arg) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.310T>C (p.Cys104Arg) variant is classified as Likely Pathogenic.

PS3, PS4_moderate, PP3

PM2, PM5, PP3, PP5

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.

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.

PS3 PM1 PP3

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)

ACMG classification criteria: PS3 supporting, PM3 moderated, PP1 moderated, PP3 supporting

Criteria applied: PS4,PS3_MOD,PM1,PM5

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 104 of the TNFRSF13B protein (p.Cys104Arg). This variant is present in population databases (rs34557412, gnomAD 0.5%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with common variable immunodeficiency (CVID) (PMID: 16007087, 17392797, 19779048, 22697072, 24051380, 27123465). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5302). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TNFRSF13B protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects TNFRSF13B function (PMID: 16007087, 20889194, 21419480, 21458042, 23237420, 24051380). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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 2012, Martinez-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). 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. PMID: 22983507. 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. PMID: 23237420. 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. PMID: 17392797. 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.

ACMG Criteria: PS3, PS4, PM1, PM3, PM5, PP1, PP3, PP5; Variant was found in heterozygous state

TNFRSF13B: PP1:Strong, PM5, PS3:Moderate, PS4:Moderate

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]

The TNFRSF13B c.310T>C variant is predicted to result in the amino acid substitution p.Cys104Arg. This variant has previously been reported to be causative for both autosomal dominant and autosomal recessive forms of common variable immunodeficiency type 2, although autosomal recessive inheritance is more common (Salzer et al. 2005. PubMed ID: 16007087; Romberg et al. 2013. PubMed ID: 24051380). However, the c.310T>C variant has been shown to exhibit incomplete penetrance (Pan-Hammarström et al. 2007. PubMed ID: 17392797; Barroeta Seijas et al. 2012. PubMed ID: 22697072). Functional studies have shown the p.Cys104Arg variant impairs TACI ligand binding and B-cell function (Romberg et al. 2015. PubMed ID: 26100089; Lee et al. 2010. PubMed ID: 20889194). This variant is reported in 0.54% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.

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.

The TNFRSF13B c.310T>C (p.Cys104Arg) variant has been reported in >50 homozygous, heterozygous, and compound heterozygous individuals with common variable immune deficiency (CVID), as well as in multiple healthy individuals (Salzer_2009_PMID: 18981294; Barroeta Seijas_2012_PMID: 22697072; Martinez-Gallo_2013_PMID: 23237420; Lee_2010_PMID: 20889194; Pulvirenti_2016_PMID: 27123465; Freiberger_2012_PMID: 22884984). In addition, this variant segregated with disease in at least 13 members from 7 families; however, asymptomatic homozygous and heterozygous family members were also identified, suggesting incomplete penetrance (Salzer_2009_PMID: 18981294; Barroeta Seijas_2012_PMID: 22697072; Martinez-Gallo_2013_PMID: 23237420; Koopmans_2013_PMID: 22983507). The variant was identified in dbSNP (ID: rs34557412) and ClinVar (classified as pathogenic by GeneDx and two other submitters, as likely pathogenic by Invitae and three other submitters, as uncertain significance by Laboratory for Molecular Medicine and five other submitters, as likely benign by Illumina and one other submitter, and as 'risk factor' by University Hospital of Geneva). The variant was identified in control databases in 983 of 282890 chromosomes (4 homozygous) at a frequency of 0.00347, and was observed at the highest frequency in the European (non-Finnish) population in 697 of 129190 chromosomes (freq: 0.005395) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.C104 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein. Furthermore, multiple in vitro functional studies and murine models reveal that this variants leads to decreased protein surface expression, decreased antibody response, and impaired ligand binding ability compared to wildtype (Salzer_2009_PMID: 18981294; Martinez-Gallo_2013_PMID: 23237420; Lee_2010_PMID: 20889194; Bacchelli_2011_PMID: 21458042). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI) do not predict a deleterious effect on splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic - risk factor for common variable immunodeficiency.

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.