The relationship between CD79B and Agammaglobulinemia 6, an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of December, 2020. CD79B encodes the Ig-beta protein of the B-cell antigen receptor. Agammaglobulinemia is characterized by absence of circulating B cells and low or absent serum immunoglobulin levels (PMID: 18978465). CD79B was first reported in relation to autosomal recessive Agammaglobulinemia 6 in 2007 (Dobbs et al, PMID: 17675462; Ferrari et al, PMID: 17709424). Variants reported in this gene thus far include missense and nonsense variants. Evidence supporting this gene-disease relationship includes case-level data and experimental data.
Summary of Case Level Data (6.25 points): There have been 3 patients from 3 publications and 1 unpublished proband, till date, reported with homozygous variants in CD79B (PMID: 17675462; 17709424, 24722855). The mechanism of disease is expected to be biallelic loss of function.
Summary of experimental data (6 points): This gene-disease association is supported by in-vitro functional assays and animal models. Igβ is expressed on B cells (PMID: 10383452), and together with Igα, it forms a hetetrodimer on the surface of B cells. The Igα/Igβ complex is involved in signal transduction that induces B-cell differentiation (PMID: 9354476). B cells lacking Igβ are arrested in the proB cell stage of development (PMID: 12165571). A targeted knock-out mouse model (PMID: 8602530) and a naturally occurring mouse model with a spontaneous nonsense mutation (PMID: 19727123) have been reported, which recapitulate the arrest of B-cell development at the early pre-B cell stage, as noted in patient cells.
In summary, the evidence to support the gene-disease relationship of CD79B and Agammaglobulinemia 6 is moderate. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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