Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000210841 | SCV004809089 | pathogenic | X-linked severe combined immunodeficiency | 2024-03-08 | reviewed by expert panel | curation | The NM_000206.3:c.677G>A variant in IL2RG is a missense variant predicted to cause substitution of arginine by histidine at amino acid 226 (p.Arg226His). The variant has been observed in at least 9 probands with SCID/Ommen Syndrome (PMIDs 7668284, 9058718, 17598841, 21184155) (PS4). Among these probands, one presented with symptoms reminiscent of Omenn syndrome. The proband exhibited a T-B-NK+ lymphocyte profile. CD132 was absent in every lymphocyte subpopulation, and the NK cells isolated from the patient did not respond to IL-2 stimulation (PMID 17598841) (PP4). The variant is absent from gnomAD v4.0 (PM2_Supporting). The variant affects CpG dinucleotides at c.677G, which is defined as a mutational hotspot by the ClinGen SCID VCEP (PMID 7668284) (PM1_Strong). Surface expression of the IL-2 receptor gamma chain in patient B cells showed that the variant causes decreased surface localization of the protein, indicating that this variant impacts protein function (PMID 9058718)(PS3_Supporting). In addition, another missense variant c.676C>T, p.Arg226Cys (ClinVar Variation ID 225195) in the same codon has been classified as pathogenic for SCID by the ClinGen SCID VCEP (PM5). In summary, this variant meets the criteria to be classified as pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM1_Strong, PS4_Strong, PM5, PP4_Moderate, PM2_Supporting, PS3_Supporting. (VCEP specifications version 1.0) |
| Gene |
RCV000431556 | SCV000513279 | pathogenic | not provided | 2016-09-28 | criteria provided, single submitter | clinical testing | The R226H variant has been published previously in association with X-linked SCID (Pepper et al., 1995; Shibata et al., 2007). The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies have shown that R226H destabilizes the final protein (Randles et al., 2006). Missense variants in the same residue (R226C) and in nearby residues (R222C, R224W, S225R, F227C, L230P, C231R/S/Y) have been reported in the Human Gene Mutation Database in association with X-linked SCID (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we consider this variant to be pathogenic. |
| Labcorp Genetics |
RCV000210841 | SCV000637249 | pathogenic | X-linked severe combined immunodeficiency | 2023-10-06 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 226 of the IL2RG protein (p.Arg226His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked severe combined immunodeficiency (PMID: 11213805, 17598841, 21184155, 22039266). ClinVar contains an entry for this variant (Variation ID: 225196). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt IL2RG protein function. Experimental studies have shown that this missense change affects IL2RG function (PMID: 9058718, 11213805, 16760466). For these reasons, this variant has been classified as Pathogenic. |