Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000554205 | SCV000637245 | likely pathogenic | X-linked severe combined immunodeficiency | 2016-07-11 | criteria provided, single submitter | clinical testing | A B-lymphoblastoid cell line generated from patient blood cells showed a reduction in their affinity for IL-2 compared with WT, suggesting that p.Cys115Tyr has a profound impact on protein function (PMID: 8299698). In summary, this is a rare missense variant that is absent from the general population, has been found in an affected individual that showed a decrease in the IL2 receptor function and alters a cysteine residue that is probably important for protein structure. Although all the evidence recorded indicates that this variant is deleterious, in the absence of segregation data it has been classified as Likely Pathogenic. The cysteine replaced is conserved in all of the members of the cytokine I receptor family and is thought to provide strong spatial constraints for tertiary folding through disulfide bonding (PMID: 2169613, 9058718). In addition, variants within exons 2,3 of the IL2RG gene that substitute or generate cysteine residues are overrepresented among patients with SCID (PMID: 8961626). This variant has been reported in an individual affected with severe combined immunodeficiency (SCID) (PMID: 8299698). This variant has also been observed in an individual with T-B+NK- SCID, a finding that is highly specific for IL2RG-related SCID (Invitae). This variant is also known as Cys93Tyr in the literature. This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tyrosine at codon 115 of the IL2RG protein (p.Cys115Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. |