CD247 was first reported in relation to autosomal recessive immunodeficiency 25 in 2006 (Rieux-Laucat et al., PMID: 16672702). Immunodeficiency 25 is a T-B+NK+ severe combined immunodeficiency (SCID). Three variants (nonsense, initiator codon, and extension) that have been reported in 3 probands in 3 publications (PMIDs: 16672702, 27555457, 17170122) are included in this curation. Affected individuals typically present in infancy with severe, recurrent infections; low T cell counts; and impaired T cell proliferation. The production of autoantibodies has been described (PMID: 16672702); however, evidence for symptomatic autoimmunity is currently lacking. Multiple probands have been identified with somatic reversion in which spontaneously arising somatic mutations recover protein expression (PMID: 16672702, 27555457). Heterozygous carriers are reported as unaffected (PMID: 27555457). The mechanism of pathogenicity appears to be loss of function.
This gene-disease association is supported by expression studies, protein interactions, functional assays, and animal models (PMIDs: 18853439, 31461748, 1717999, 27555457, 8223444, 8223445). CD247 is expressed in lymphoid tissues and encodes the zeta chain of the T-cell receptor (TCR) complex (PMID: 18853439). The TCR is made up of multiple other CD3 chains including gamma (CD3G gene) and epsilon (CD3E gene) (PMID: 31461748). Extracellular stimulation of the TCR phosphorylates the intracellular zeta chain, and the phosphorylated zeta chain binds a zeta chain associated protein kinase 70 (ZAP70 gene) to initiate downstream signaling (PMID: 1717999). We have previously established that these three genes; CD3E, CD3G, and ZAP70; are definitively associated with severe combined immunodeficiency. Impaired TCR-induced signaling including impaired ZAP70 phosphorylation has also been observed in human T cells that have a CD247 homozygous loss of function variant (PMID: 27555457). CD247 knockout mice have T cell lymphocytopenia and reduced T cell proliferation consistent with SCID (PMID: 8223444, 8223445).
In summary, CD247 is definitively associated with autosomal recessive immunodeficiency 25. 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 February 17, 2022 (SOP Version 8).
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