CTNNBL1

Inheritance Pattern: AR

Disease ID:MONDO:0015517

Submitter: ClinGen

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.

Inheritance Pattern: Unknown

Disease ID:MONDO:0030798

Submitter: Labcorp Genetics (formerly Invitae)