Submission Details

IL7R was first reported in relation to autosomal recessive severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-positive, NK cell-positive in 1998 (PMID: 9843216). IL7R encodes a receptor for interleukin-7, a glycoprotein which is involved in lymphopoiesis regulation and is essential for the development of T cells. Nine variants (missense, splicing, nonsense, and frameshift) that have been reported in six probands in six publications (PMID: 11023514, 9843216, 19890784, 30778343, 15615257, 26123418) are included in this curation. Variants in this gene segregated with disease in two additional family members. Heterozygous parents and other relatives were unaffected in all reported families. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease association is also supported by expression studies showing that IL7R is expressed in murine B and T cell lineages (PMID: 8415665) and IL7R expression is severely decreased to absent in patients with T-B+NK+ SCID (PMID: 9843216). In addition, IL7R interacts with JAK3, which is also associated with a SCID phenotype (PMID: 17554063) and IL7R null mice have a phenotype consistent with T cell lymphopenia (PMID: 8692964, 7964471). T and B cell deficiency is rescued in IL7Ra deficient mice through introduction of IL7Ra by retroviral transfection (PMID: 16208423). In summary, IL7R is definitively associated with autosomal recessive severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-positive, NK cell-positive. 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 2/18/2021 (SOP Version 8).