X-71109315-G-A

Position:

• chrX-71109315-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1_Strong PS3_Supporting PP4 PM2_Supporting PS4

This summary comes from the ClinGen Evidence Repository: The NM_000206.3:c.670C>T variant in IL2RG is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 224 (p.Arg226Trp). The variant has been observed in at least 10 male probands with SCID (PMIDs 28747913, 21184155, 10792291, 9633906, 9058718, 9049783) (PS4). Among these probands, one proband hemizygous for this variant was diagnosed with SCID and presented a T-B+NK- lymphocyte profile (PMID 9049783) (PP4). The variant is absent from gnomAD v4.0 (PM2_Supporting). The variant affects CpG dinucleotides at c.670C, 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 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, PP4_Supporting, PM2_Supporting, PS3_Supporting. (VCEP specifications version 1.0) LINK:https://erepo.genome.network/evrepo/ui/classification/CA358778/MONDO:0010315/129

• Frequency: Genomes: not found (cov: 23)
• Consequence: IL2RG NM_000206.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 2.90

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IL2RG	NM_000206.3	c.670C>T	p.Arg224Trp	missense_variant	5/8	ENST00000374202.7
IL2RG	XM_047442089.1	c.670C>T	p.Arg224Trp	missense_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IL2RG	ENST00000374202.7	c.670C>T	p.Arg224Trp	missense_variant	5/8	1	NM_000206.3	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

X-linked severe combined immunodeficiency Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	Mar 08, 2024	The NM_000206.3:c.670C>T variant in IL2RG is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 224 (p.Arg226Trp). The variant has been observed in at least 10 male probands with SCID (PMIDs 28747913, 21184155, 10792291, 9633906, 9058718, 9049783) (PS4). Among these probands, one proband hemizygous for this variant was diagnosed with SCID and presented a T-B+NK- lymphocyte profile (PMID 9049783) (PP4). The variant is absent from gnomAD v4.0 (PM2_Supporting). The variant affects CpG dinucleotides at c.670C, 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 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, PP4_Supporting, PM2_Supporting, PS3_Supporting. (VCEP specifications version 1.0) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 06, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 224 of the IL2RG protein (p.Arg224Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with X-linked severe combined immunodeficiency (PMID: 9049783, 9058718, 9633906, 10792291, 21184155, 28747913). This variant is also known as c.684C>T. ClinVar contains an entry for this variant (Variation ID: 225194). 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. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 02, 2022	Published functional studies demonstrate a damaging effect; variant leads to a complete absence of the IL2RG protein on B cell surfaces (Puck et al., 1997); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 10444186, 9633906, 9049783, 10792291, 9058718, 32888943, 9399950, 34134972, 33628209) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 20, 2022	- -

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

Jan 24, 2019

This variant has been previously reported as a hemizygous change in patients with X-linked severe combined immunodeficiency (SCID) (PMID: 9058718, 9049783), and reported as pathogenic by a clinical laboratory in the ClinVar database. Functional studies using B-cell lines harboring this variant in the hemizygous state from patients with SCID demonstrated that while IL2RG mRNA can be detected, its protein product cannot be detected by immunofluorescence at the cell surface (PMID: 9058718). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.670C>T (p.Arg224Trp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.670C>T (p.Arg224Trp) variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.67
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;.;.
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.6	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-7.6	D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.79
MutPred		0.92		Loss of methylation at R226 (P = 0.0235);.;.;
MVP		1.0
MPC		1.6
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.95
gMVP		0.97

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: rs869320658; hg19: chrX-70329165; COSMIC: COSV52148736; COSMIC: COSV52148736;