rs869320659

Positions:

• chrX-71109309-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PP4 PM2_Supporting PS4 PM1_Strong PS3_Supporting PM6

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: Genomes: not found (cov: 23)
• Consequence: IL2RG NM_000206.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 3.56

Genes affected

IL2RG (HGNC:6010): (interleukin 2 receptor subunit gamma) The protein encoded by this gene is an important signaling component of many interleukin receptors, including those of interleukin -2, -4, -7 and -21, and is thus referred to as the common gamma chain. Mutations in this gene cause X-linked severe combined immunodeficiency (XSCID), as well as X-linked combined immunodeficiency (XCID), a less severe immunodeficiency disorder. [provided by RefSeq, Mar 2010]

ENSG00000285171 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IL2RG	NM_000206.3	c.676C>T	p.Arg226Cys	missense_variant	5/8	ENST00000374202.7	NP_000197.1
IL2RG	XM_047442089.1	c.676C>T	p.Arg226Cys	missense_variant	5/7		XP_047298045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IL2RG	ENST00000374202.7	c.676C>T	p.Arg226Cys	missense_variant	5/8	1	NM_000206.3	ENSP00000363318.3
ENSG00000285171	ENST00000646505.1	n.676C>T		non_coding_transcript_exon_variant	5/12			ENSP00000496673.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

X-linked severe combined immunodeficiency Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Jun 22, 2023	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. -
Pathogenic, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Nov 14, 2023	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). -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Mar 12, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 16, 2023	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. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 225195). 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. -

X-linked severe combined immunodeficiency;CN030319:Combined immunodeficiency, X-linked Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PM5+PS3_Supporting+PS4+PM6_Supporting+PP4 -

Combined immunodeficiency, X-linked Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Nov 21, 2018

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

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 15, 2023

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.64
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D;.;.
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.4	M;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-6.1	D;D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.60
MutPred		0.91		Loss of MoRF binding (P = 0.0065);.;.;
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs869320659; hg19: chrX-70329159;