Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000586219 | SCV005375413 | pathogenic | X-linked severe combined immunodeficiency | 2024-06-13 | reviewed by expert panel | curation | The c.982C>T (p.Arg328Ter) variant in IL2RG is a nonsense variant located in the last exon (8/8). Although it is not predicted to cause nonsense-mediated decay, as it is located in a critical region for protein function, PVS1 is still applied at default strength (PVS1). This variant is absent from gnomAD v4 (PM2_Supporting). At least one proband in the literature presents: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5 pts) + SCID gene panel or exome (1pt) + XY male sex (0.5 pts), total is 2 points, PP4_Moderate (PMID: 31799703). In summary, this variant meets the criteria to be classified as Pathogenic for X-linked T-B+ severe combined immunodeficiency due to gamma chain deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1, PM2_Supporting, and PP4_Moderate (VCEP specifications version 1). |
| Laboratory of Hereditary Immune Disorders, |
RCV001090163 | SCV006087552 | pathogenic | Combined immunodeficiency, X-linked | 2023-12-02 | criteria provided, single submitter | clinical testing | The nonsense variant NM_000206.3(IL2RG):c.982C>T, p.(Arg328*) was identified in a hemizygous state in a proband diagnosed with SCID in Russian pilot NBS project covering more than 200,000 newborns. It occurred de novo. This variant has been previously reported in the literature multiple times (PMIDs: 28747913, 31799703, 30622570) and is not listed in gnomAD v2.1.1. The affected amino acid position is evolutionarily conserved, and multiple in silico prediction tools support a deleterious effect. Furthermore, functional studies have demonstrated a damaging impact on gene function (PMID: 31799703). Taken together, the variant meets the following ACMG/AMP criteria and can be classified as pathogenic with PM2, PP3, PVS1, PS2, PS3, PP5, PP4 criteria. |
| Labcorp Genetics |
RCV000586219 | SCV002135270 | pathogenic | X-linked severe combined immunodeficiency | 2025-06-10 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg328*) in the IL2RG gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 42 amino acid(s) of the IL2RG protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with severe combined immunodeficiency (SCID), atypical SCID, or other immunodeficiency phenotypes (PMID: 28747913, 30622570, 30778380, 31799703, 32499645). ClinVar contains an entry for this variant (Variation ID: 418656). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects IL2RG function (PMID: 31799703). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the C-terminus of the IL2RG protein. Other variant(s) that disrupt this region (p.Leu329Argfs*3) have been observed in individuals with IL2RG-related conditions (PMID: 10794430). This suggests that this may be a clinically significant region of the protein. For these reasons, this variant has been classified as Pathogenic. |
| Foundation for Research in Genetics and Endocrinology, |
RCV001090163 | SCV001190359 | pathogenic | Combined immunodeficiency, X-linked | 2020-03-06 | criteria provided, single submitter | clinical testing | A hemizygous nonsense variation in exon 8 of the IL2RG gene that results in a stop codon and premature truncation of the protein at codon 328 was detected. The observed variant c.982C>T (p.Arg328Ter) has previously been reported in a patient affected with severe combined immunodeficiency (Luk ADW. et al., 2017). The variant has not been reported in the 1000 genomes and ExAC databases. The in silico prediction of the variant is damaging by MutationTaster2. The reference codon is conserved across mammals. In summary, the variant meets our criteria to be classified as pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000586219 | SCV000695978 | likely pathogenic | X-linked severe combined immunodeficiency | 2016-08-19 | criteria provided, single submitter | clinical testing | Variant summary: The IL2RG c.982C>T (p.Arg328X) variant results in a premature termination codon, predicted to cause a truncated or absent IL2RG protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant is absent in 80559 control chromosomes. This variant has been reported in two brothers with a late-onset and atypical presentation of the disease via a conference abstract. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic until more information becomes available. |
| Gene |
RCV000483975 | SCV000565878 | pathogenic | not provided | 2025-02-14 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect on protein function, with impaired binding of JAK3 to the common gamma chain (PMID: 31799703); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation as the last 42 amino acids are lost; This variant is associated with the following publications: (PMID: 25618583, 28747913, 34134972, 32581362, 32888943, 32499645, 35503492, 35753512, 35874699, 32531373, 30778380, 30622570, 31799703) |
| Gene |
RCV000586219 | SCV001775478 | not provided | X-linked severe combined immunodeficiency | no classification provided | literature only | Observed in 2 brothers with atypical X-SCID |