ClinVar Miner

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

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Total submissions: 9
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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 RCV000255118 SCV000605399 pathogenic not provided 2018-02-06 criteria provided, single submitter clinical testing One copy of the c.542C>A, p.Ala181Glu variant in the TNFRSF13B (TACI) gene was detected by sequencing. This variant has been reported in patients diagnosed with common variable immunodeficiency (Castigli 2005, Salzer 2005, Martinez-Gallo 2013) and the association with the disease was found statistically significant (Pan-Hammarstrom 2007, Dong 2010, Freiberger 2012). Additionally, functional studies have confirmed that the c.542C>A variant affects tertiary protein structure, receptor association and NF kappa B signaling (Lee 2009, Fried 2011). However, this variant was also observed in clinically asymptomatic first degree relatives and in up to 0.9% of unrelated healthy controls in certain ethnic populations. Thus, the c.542C>A, p. Ala181Glu variant appears to act as a susceptibility or disease-associated variant, possibly in co-existence with other genetic and/or environmental factors (Dong 2010). This result is consistent with the diagnosis of common variable immunodeficiency (CVID); clinical manifestations show a wide range of onset and severity.
Invitae RCV000005625 SCV000649857 likely pathogenic Common variable immunodeficiency 2 2018-12-31 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 NFκB 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 2019-05-01 criteria provided, single submitter clinical testing
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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