ClinVar

Description

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.