rs869320659
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PP4PM2_SupportingPS4PM1_StrongPS3_SupportingPM6
This summary comes from the ClinGen Evidence Repository: The NM_000206.3(IL2RG):c.676C>T (p.Arg226Cys) missense variant resides within a CpG dinucleotide region, cDNA 676-677 encoding amino acid R226, of IL2RG that is defined as a mutational hotspot (PMID:7668284; PM1_Strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The male (0.5pt) patient of PMID:14966353 has a T-B+NK- lymphocyte subset profile (0.5pt) [CD3: 2.5%; CD19: 95.4%; CD16/CD56: 0.5%] which is specific for SCID due to gamma chain deficiency (1pt; PP4). In a second case, the R226C variant arose de novo as a somatic mutation early in embryogenesis in the mother of the patient, 1 pt, PM6_Moderate (PMID:23683512).At least eight additional male X-SCID patients have been reported (PMIDs: 9058718, 11129345, 22936741, 7668284) with this hemizygous variant (total 4.5pt; PS4). PMID:7632950 Examined the mutant 7 chain distribution by confocal microscopy in transiently transfected COS-7 cells, comparing it with the wild-type 7 chain distribution. The mutant 7 chain could not be detected by an antihuman IL-2 receptor 7 chain monoclonal antibody, TUGh4, on the cell surface of the transfected COS-7 cells. This result was in sharp contrast to that obtained with the wild-type γ chain, which was clearly stained by TUGh4 on the transfected cells. PS3_Supporting is met.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. Criteria applied: PS4, PM1_Strong, PM6_Moderate, PM2_Supporting, PS3_Supporting, and PP4. (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA358784/MONDO:0010315/129
Frequency
Consequence
NM_000206.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| IL2RG | ENST00000374202.7 | c.676C>T | p.Arg226Cys | missense_variant | Exon 5 of 8 | 1 | NM_000206.3 | ENSP00000363318.3 | ||
| ENSG00000285171 | ENST00000646505.1 | n.676C>T | non_coding_transcript_exon_variant | Exon 5 of 12 | ENSP00000496673.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 30
GnomAD4 genome
ClinVar
Submissions by phenotype
X-linked severe combined immunodeficiency Pathogenic:4
The observed missense variant c.676C>T(p.Arg226Cys) in IL2RG gene has been reported previously in individual(s) with SCID. A different missense variant [c.677G>A; p.Arg226His] at the same position has been previously reported as pathogenic (Recher M, et al, 2011; Dong W, et al., 2023). Functional characterization of the variant indicate that the p.Arg226Cys substitution (referred to as p.Arg204Cys in the literature) results in the lack of cell surface expression of the IL2 receptor gamma chain (Kumaki S, et al., 1995). This variant is absent in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic. The amino acid Arg at position 226 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Possibly damaging, SIFT – Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
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This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 226 of the IL2RG protein (p.Arg226Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with SCID (PMID: 7668284, 9058718, 14966353, 22039266, 23683512). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 225195). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
The NM_000206.3(IL2RG):c.676C>T (p.Arg226Cys) missense variant resides within a CpG dinucleotide region, cDNA 676-677 encoding amino acid R226, of IL2RG that is defined as a mutational hotspot (PMID: 7668284; PM1_Strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The male (0.5pt) patient of PMID: 14966353 has a T-B+NK- lymphocyte subset profile (0.5pt) [CD3: 2.5%; CD19: 95.4%; CD16/CD56: 0.5%] which is specific for SCID due to gamma chain deficiency (1pt; PP4). In a second case, the R226C variant arose de novo as a somatic mutation early in embryogenesis in the mother of the patient, 1 pt, PM6_Moderate (PMID: 23683512). At least eight additional male X-SCID patients have been reported (PMIDs: 9058718, 11129345, 22936741, 7668284) with this hemizygous variant (total 4.5pt; PS4). PMID: 7632950 Examined the mutant 7 chain distribution by confocal microscopy in transiently transfected COS-7 cells, comparing it with the wild-type 7 chain distribution. The mutant 7 chain could not be detected by an antihuman IL-2 receptor 7 chain monoclonal antibody, TUGh4, on the cell surface of the transfected COS-7 cells. This result was in sharp contrast to that obtained with the wild-type γ chain, which was clearly stained by TUGh4 on the transfected cells. PS3_Supporting is met. 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. Criteria applied: PS4, PM1_Strong, PM6_Moderate, PM2_Supporting, PS3_Supporting, and PP4. (VCEP specifications version 1). -
X-linked severe combined immunodeficiency;CN030319:Combined immunodeficiency, X-linked Pathogenic:2
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PM2_Supporting+PM5+PS3_Supporting+PS4+PM6_Supporting+PP4 -
Combined immunodeficiency, X-linked Pathogenic:1
The c.676C>T, p.Arg226Cys has previously been reported in the literature as pathogenic (PMID: 7668284, 23683512) and by clinical laboratories in ClinVar as associated with X-linked SCID. Missense variants at the same codon (R226H) have also been identified in patients with SCID (PMID: 7668284). Functional characterization of the variant indicate that the p.Arg226Cys substitution (referred to as p.Arg204Cys in the literature) results in the lack of cell surface expression of the IL2 receptor gamma chain (PMID: 7632950). There are no reports of the variant in the population allele frequency database, gnomAD, thus the variant is presumed rare. The variant results in a non-conservative amino acid change at a conserved residue, and in silico protein models predict a damaging effect on protein function. Based on the combined evidence, this variant is classified as pathogenic. -
not provided Pathogenic:1
Published functional studies demonstrate variant impairs expression of the IL2RG protein (Kumaki et al., 1995); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 8299698, 8956936, 10444186, 32265911, 30778343, 7668284, 7632950, 9058718, 9921912, 11213805, 22832027, 28780374, 23683512, 30273710, 14966353, 32888943, 36007526, 35874699, 9399950) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at