ClinVar Miner

Submissions for variant NM_012452.2(TNFRSF13B):c.204dup (p.Leu69fs) (rs72553875)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,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 2018-09-21 criteria provided, single submitter clinical testing The c.204dupA variant in the TNFRSF13B gene has been 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 (Castigli et al., 2005; Salzer et al., 2009; Speletas et al., 2011; Pulvirenti et al., 2016). The c.204dupA variant causes a frameshift starting with codon Leucine 69, changes this amino acid to a Threonine residue, and creates a premature Stop codon at position 12 of the new reading frame, denoted p.Leu69ThrfsX12. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.204dupA variant is observed in 40/66450 (0.06%) alleles from individuals of non-Finnish European background in the ExAC dataset (Lek et al., 2016). We interpret c.204dupA as a pathogenic variant.
Invitae RCV000557905 SCV000649854 pathogenic Common variable immunodeficiency 2 2019-12-09 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. This variant is present in population databases (rs72553875, ExAC 0.06%). This variant has been reported to occur as a heterozygous variant or in combination with other TNFRSF13B variants in multiple individuals affected with common variable immunodeficiency or IgA deficiency (PMID: 16007086, 26100089, 18981294, 27123465, 17392798, 26046366, 22884984). ClinVar contains an entry for this variant (Variation ID: 322029). Loss-of-function variants in TNFRSF13B are known to be pathogenic (PMID: 16007087, 27123465). Experimental studies using patient cells carrying the c.204dupA variant report these cells display normal regulatory T cell function, normal establishment of peripheral B cell tolerance, and normal activation responses in naive B cells, but display impaired activation and antibody secretion in memory B cells (PMID: 26100089). For these reasons, this variant has been classified as Pathogenic.
Mendelics RCV000557905 SCV001140308 likely pathogenic Common variable immunodeficiency 2 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000520212 SCV001250127 pathogenic not provided 2019-09-01 criteria provided, single submitter clinical testing

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