ClinVar

Description

TNFRSF13B NM_012452.2 exon 3 p.Leu69Thrfs*12 (c.204dupA):This variant has been reported in the literature in at least 5 individuals with Common Variable Immunodeficiency (CVID) or IgA deficiency (IgAD), segregating with disease in at least 4 affected family members. This variant has also been identified in 1 individual with tonsillar hypertrophy (Castigli 2005 PMID:16007086, Castigli 2007 PMID:17392798, Salzer 2009 PMID:18981294, Speletas 2011 PMID:21547394, Freiberger 2012 PMID:22884984, Speletas 2013 PMID:23956760, Pulvirenti 2016 PMID:27123465). This variant is present in 0.5% (58/10358) of Ashkenazi Jewish alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/17-16852292-G-GT?dataset=gnomad_r2_1). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as Pathogenic or Likely Pathogenic (Variation ID: 322029). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. In addition, functional studies have shown a deleterious effect of this variant suggesting no impact to protein expression, activation responses or central B-cell tolerance in naive B cells, but decreased expression on memory B cells with subsequent impaired activation and antibody secretion (Romberg 2015 PMID:26100089). This variant is a duplication of 1 nucleotide at position 204 and creates a premature stop codon 12 amino acids downstream from this location resulting in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Romberg 2015 PMID:26100089). In summary, this variant is classified as pathogenic.