CD3G

Inheritance Pattern: AR

Disease ID:MONDO:0014276

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0014276

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0014276

Submitter: ClinGen

CD3G was first reported in relation to autosomal recessive, combined immunodeficiency due to CD3gamma deficiency in 1986 (Regueiro et al., PMID:2872416) and in 1992 (Arnaiz-Villena et al., PMID:1635567). Also known as immunodeficiency 17, CD3gamma deficiency is an autosomal recessive primary immunodeficiency characterized by partial T-cell lymphopenia, decreased amounts of the CD3 complex, and impaired proliferative responses to T-cell receptor (TCR)-dependent stimuli. This disease results in a variable clinical presentation that ranges from asymptomatic until adulthood, to high susceptibility to infections from early infancy with predominant autoimmune manifestations. The more severely affected patients may have evidence of autoimmune disease or enteropathy. At least 4 unique variants (missense, splice acceptor, nonsense, and frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data: 13.25 points. Variants in this gene have been reported in at least 11 probands in 8 publications (PMID: 2872416, PMID: 1635567, PMID: 17277165, PMID:31921117, PMID:24910257, PMID:23590417, PMID:29653965, and PMID:18482219). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Summary of Experimental Evidence: 2.5 points. This gene-disease association is supported by animal models, expression studies, and patient cell functional studies (PMID:1635567, PMID: 29653965, PMID: 19801521). Boding L et al. demonstrated that the age-associated decline of naive T cells is strongly accelerated in CD3gammaLLAA knock-in mice, homozygous for a double leucine to alanine mutation in the CD3gamma di-leucine-based motif. This resulted in premature T cell population senescence with a severe dominance of memory T cells and very few naive T cells, caused by the combination of reduced thymic output, decreased T cell apoptosis, and increased transition of naive T cells to memory T cells. Rowe JH et al. studied 6 patients with CD3G mutations to assess T-reg function and its ability to suppress proliferation of T-conv cells. T-reg cells in patients with CD3G defects had reduced diversity, increased clonality, and reduced suppressive function. In summary, there is definitive evidence to support the relationship between CD3G and autosomal recessive, combined immunodeficiency due to CD3gamma deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen SCID-CID GCEP on the meeting date July 15, 2021 (SOP Version 8).