Submission Details

The relationship between CTNNBL1 and Common Variable Immunodeficiency (CVID), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of May, 2022. Note, at the time of curation, OMIM did not indicate an associated disease entity for this gene. CTNNBL1 encodes a protein that activates pre-mRNA splicing and is an integral part of the spliceosome. The encoded protein is also a nuclear localization sequence binding protein, and binds to activation-induced deaminase and is important for antibody diversification (RefSeq, Jul 2013). The phenotype associated with common variable immunodeficiency due to CTNNBL1 variants is characterized by hypogammaglobulinemia and recurrent infections (Kuhny et al, 2020; PMID: 32484799). CTNNBL1 was first reported in relation to autosomal recessive CVID in 2020 (Kuhny et al, 2020; PMID: 32484799). To date, this is the only patient that has been reported with biallelic loss-of-function variants in CTNNBL1 and a positive disease association. There is limited evidence supporting this gene-disease relationship including case-level data and experimental data.

Summary of Case Level Data (1 point): There has been 1 patient from 1 publication, till date, reported with a homozygous variant in CTNNBL1 (PMID: 32484799). The mechanism of disease is expected to be biallelic loss of function. While functional studies in patient cells and in-vitro cultures of mutant-transfected cells suggest that the variant impairs activation-induced cytidine deaminase (AID) binding and therefore impaired somatic hypermutation (SHM) and class-switch recombination (CSR), which may be the disease mechanism, other studies suggest that CSR may not be impacted by loss of CTNNBL1 (PMID: 20585033).

Summary of experimental data (2.5 points): This gene-disease relationship is supported by protein interaction, mouse model and rescue evidence. CTNNBL1 is shown to interact with AID by coimmunoprecipitation and mammalian two-hybrid experiments (PMID: 18722174). Germline homozygous CTNNBL1 knock-out in mice is embryonic lethal, while B-cell specific CTNNBL1 deficiency results in reduced class switch recombination (PMID: 23343763), which is also observed in the human patient (PMID: 32484799). Introduction of wild-type CTNNBL1 in Ramos B cells that carried the Met466Val missense variant showed rescue of the hyper-IgM phenotype (PMID: 32484799).

In summary, the level of evidence to support the gene-disease relationship of CTNNBL1 and autosomal recessive common variable immunodeficiency is limited. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.