ClinVar Miner

Submissions for variant NM_012452.2(TNFRSF13B):c.542C>A (p.Ala181Glu) (rs72553883)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255118 SCV000321966 pathogenic not provided 2018-08-10 criteria provided, single submitter clinical testing The A181E variant in the TNFRSF13B gene has been reported multiple times as a commonly occurring variant associated with CVID (Lee et al., 2009; Martinez-Gallo et al., 2013). Among affected individuals, the A181E variant has been identified in the heterozygous, homozygous, and compound heterozygous state, but is also seen in unaffected individuals, indicating variable expressivity and reduced penetrance (Martinez-Gallo et al., 2013). Functional studies indicate that the A181E variant introduces a negative charge in the transmembrane domain, which disrupts signaling and impairs B-cell function (Lee et al., 2009). The A181E variant is observed in 627/25,674 (2.4%) alleles from individuals of Finnish background, including multiple homozygous individuals, in large population cohorts (Lek et al., 2016). The A181E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. We interpret A181E as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000263268 SCV000400916 likely benign Common Variable Immune Deficiency, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000005625 SCV000597507 likely pathogenic Common variable immunodeficiency 2 2017-01-10 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000999848 SCV000605399 pathogenic not specified 2019-05-01 criteria provided, single submitter clinical testing The TNFRSF13B c.542C>A; p.Ala181Glu variant (rs72553883) is reported in the literature in multiple individuals diagnosed with common variable immunodeficiency (Castigli 2005, Salzer 2005, Martinez-Gallo 2013). This variant is also observed in clinically asymptomatic relatives and is found in the Finnish European population with an overall allele frequency of 2.4% (603/24990 alleles, including eight homozygotes) in the Genome Aggregation Database, suggesting it may act as a susceptibility or disease-associated variant, possibly with other genetic and/or environmental factors (Dong 2010). Still, case-control studies demonstrate the p.Ala181Glu variant is significantly enriched in affected individuals (OR >5, p< 0.05) (Pan-Hammarstrom 2007, Dong 2010, Freiberger 2012). Functional characterization of the p.Ala181Glu protein in mice (A144E) and human B-cells indicate disrupted NF-KB signaling and significantly impaired B-cell function (Lee 2009, Fried 2011). Based on available information, the variant is considered to be pathogenic. References: Castigli E et al. TACI is mutant in common variable immunodeficiency and IgA deficiency. Nat Genet. 2005 Aug;37(8):829-34. Dong X et al. (2010) Phenotypic and clinical heterogeneity associated with monoallelic TNFRSF13B-A181E mutations in common variable immunodeficiency. Hum Immunol. 71(5):505-11. Freiberger T et al. Sequence variants of the TNFRSF13B gene in Czech CVID and IgAD patients in the context of other populations. Hum Immunol. 2012 Nov;73(11):1147-54. Fried A et al. Functional analysis of transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) mutations associated with common variable immunodeficiency. J Allergy Clin Immunol. 2011 Jul;128(1):226-228.e1. Martinez-Gallo M et al. TACI mutations and impaired B-cell function in subjects with CVID and healthy heterozygotes. J Allergy Clin Immunol. 2013 Feb;131(2):468-76. Lee J et al. The murine equivalent of the A181E TACI mutation associated with common variable immunodeficiency severely impairs B-cell function. Blood. 2009 Sep 10;114(11):2254-62. Pan-Hammarstrom Q et al. Reexamining the role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency. Nat Genet. 2007 Apr;39(4):429-30. 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.
Invitae RCV000005625 SCV000649857 likely pathogenic Common variable immunodeficiency 2 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces alanine with glutamic acid at codon 181 of the TNFRSF13B protein (p.Ala181Glu). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and glutamic acid. This variant is present in population databases (rs72553883, ExAC 2.5%). This variant has been reported in many individuals affected with CVID as both homozygous, compound heterozygous with other TACI variants, and as a heterozygous variant, as well as unaffected control individuals (PMID: 23237420, 17392797, 20156508, 24051380, 16007086). In a case-control study of 844 individuals with CVID and 3924 controls, this variant was found to be a risk factor for development of CVID (OR 5.60, CI 2.99-10.51) (PMID: 17392797). A meta-analysis of 1,439 CVID patients and 3,558 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 families although it appears to have reduced penetrance (PMID: 16007087, 22884984, 23237420). ClinVar contains an entry for this variant (Variation ID: 5303). Experimental studies have shown that this missense change disrupts constitutive and ligand-induced NF B and NF-AT signaling, and leads to defective B-cell proliferation in response to stimulation (PMID: 21419480, 23237420, 19605846). Individuals who are heterozygous for p.Ala181Glu 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: 19605846). In summary, this variant is a rare missense change that has been seen to segregate in 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000255118 SCV000780566 uncertain significance not provided 2020-01-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001195839 SCV001366259 pathogenic CNS disorder 2020-01-29 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PM2,PP2,PP3. This variant was detected in heterozygous state.
Integrated Genetics/Laboratory Corporation of America RCV001199863 SCV001370599 likely pathogenic Common variable agammaglobulinemia 2020-05-01 criteria provided, single submitter clinical testing Variant summary: TNFRSF13B c.542C>A (p.Ala181Glu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0053 in 250818 control chromosomes in the gnomAD database, including 9 homozygotes. The observed variant frequency is approximately 1864 fold of the estimated maximal expected allele frequency for a pathogenic variant in TNFRSF13B causing Common Variable Immunodeficiency phenotype (2.9e-06), suggesting that the variant is benign. However, this variant has been reported in many individuals with Common Variable Immunodeficiency (CVID, examples: Dong_2010, Castigli_2005, Martinez-Gallo_2013, Salzer_2011, Pomar_2009). These data indicate that the variant is likely to be associated with disease. The variant has been reported in CVID patients as heterozygous, homozygous, and in compound heterozygosity with other pathogenic variants in TNFRSF13B. c.542C>A has been shown to segregate with disease in multiple families (example: Castigli_2005), but has also been observed in unaffected family members (example: Martinez-Gallo_2013), indicating reduced penetrance. Different clinical manifestations have been observed in individuals with the variant, even within the same family (example: Dong_2010). The variant was associated with CVID in a case-control study (OR=5.60, CI 2.99-10.51; Pan-Hammarstrom_2007) and a meta-analysis of cases and controls from the literature (Freiberger_2012). In-vitro functional studies indicated that the variant impaired downstream signaling (example-Fried_2011). In addition, a murine model equivalent to the A181E mutation was assessed as having impaired TACI signaling and function in-vivo (Lee_2009). Six ClinVar submitters (evaluation after 2014) cite the variant with conflicting assessments of pathogenic/likely pathogenic (n=4, ) uncertain significance (n=1), likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
OMIM RCV000005625 SCV000025807 pathogenic Common variable immunodeficiency 2 2009-09-10 no assertion criteria provided literature only
OMIM RCV000005626 SCV000025808 pathogenic Immunoglobulin A deficiency 2 2009-09-10 no assertion criteria provided literature only
GenomeConnect, ClinGen RCV000005625 SCV000840265 not provided Common variable immunodeficiency 2 no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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