NM_000206.3(IL2RG):c.184T>C (p.Cys62Arg) AND X-linked severe combined immunodeficiency

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jun 12, 2024
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001377072.8

Allele description [Variation Report for NM_000206.3(IL2RG):c.184T>C (p.Cys62Arg)]

NM_000206.3(IL2RG):c.184T>C (p.Cys62Arg)

Gene:

IL2RG:interleukin 2 receptor subunit gamma [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq13.1

Genomic location:

Preferred name:

NM_000206.3(IL2RG):c.184T>C (p.Cys62Arg)

Other names:

NM_000206.3(IL2RG):c.184T>C; p.Cys62Arg

HGVS:

NC_000023.11:g.71110982A>G
NG_009088.1:g.5572T>C
NG_021141.1:g.807T>C
NM_000206.3:c.184T>CMANE SELECT
NP_000197.1:p.Cys62Arg
LRG_150t1:c.184T>C
LRG_150:g.5572T>C
NC_000023.10:g.70330832A>G
NM_000206.2:c.184T>C

Protein change:

C62R

Links:

dbSNP: rs1602289649

NCBI 1000 Genomes Browser:

rs1602289649

Molecular consequence:

NM_000206.3:c.184T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: X-linked severe combined immunodeficiency (SCIDX1)
Synonyms:: IMMUNODEFICIENCY 4; X-Linked Combined Immunodeficiency Diseases; Severe combined immunodeficiency, X-linked, T cell-negative, B cell-positive, NK cell-negative; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010315; MedGen: C1279481; Orphanet: 276; OMIM: 300400

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Cupriavidus necator A5-1 K307DRAFT_scf7180000000046_quiver.4_C, whole genome sho...
Cupriavidus necator A5-1 K307DRAFT_scf7180000000046_quiver.4_C, whole genome shotgun sequence
gi|757644052|ref|NZ_JQLI01000004.1| WGS:NZ_JQLI01|K307DRAFT_scf7180000000046_quiver.4_C

Nucleotide
Adiantum wilsonii (1)
Taxonomy
Rattus norvegicus ubiquitin specific peptidase 11, mRNA (cDNA clone IMAGE:731423...
Rattus norvegicus ubiquitin specific peptidase 11, mRNA (cDNA clone IMAGE:7314230), partial cds
gi|114205509|gb|BC105613.1|

Nucleotide
Chromosome neighbors for GEO Profiles (Select 129803447) (20)
GEO Profiles
Early Parkinson's disease: peripheral blood
Early Parkinson's disease: peripheral blood
Accession: GDS5646

GEO DataSets

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001574305	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 13, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 27484032, 8605324, 25843602, 28492532
SCV005375410	ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen SCID ACMG Specifications IL2RG V1.0.0)	Pathogenic (Jun 12, 2024)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001574305

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 13, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV005375410

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen SCID ACMG Specifications IL2RG V1.0.0)

Pathogenic
(Jun 12, 2024)

germline

curation

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Rapid molecular diagnostics of severe primary immunodeficiency determined by using targeted next-generation sequencing.

Yu H, Zhang VW, Stray-Pedersen A, Hanson IC, Forbes LR, de la Morena MT, Chinn IK, Gorman E, Mendelsohn NJ, Pozos T, Wiszniewski W, Nicholas SK, Yates AB, Moore LE, Berge KE, Sorte H, Bayer DK, ALZahrani D, Geha RS, Feng Y, Wang G, Orange JS, et al.

J Allergy Clin Immunol. 2016 Oct;138(4):1142-1151.e2. doi: 10.1016/j.jaci.2016.05.035. Epub 2016 Jul 12. Erratum in: J Allergy Clin Immunol. 2017 Jan;139(1):378. doi: 10.1016/j.jaci.2016.11.002.

PubMed [citation]

PMID:: 27484032

gamma-c gene transfer into SCID X1 patients' B-cell lines restores normal high-affinity interleukin-2 receptor expression and function.

Hacein-Bey H, Cavazzana-Calvo M, Le Deist F, Dautry-Varsat A, Hivroz C, Rivière I, Danos O, Heard JM, Sugamura K, Fischer A, De Saint Basile G.

Blood. 1996 Apr 15;87(8):3108-16.

PubMed [citation]

PMID:: 8605324

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001574305.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This missense change has been observed in individual(s) with clinical features of severe combined immunodeficiency (PMID: 27484032; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 62 of the IL2RG protein (p.Cys62Arg). ClinVar contains an entry for this variant (Variation ID: 1066149). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys62 amino acid residue in IL2RG. Other variant(s) that disrupt this residue have been observed in individuals with IL2RG-related conditions (PMID: 8605324, 25843602), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen, SCV005375410.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

NM_000206.3(IL2RG):c.184T>C is a missense variant predicted to cause substitution of Cysteine by Arginine at amino acid 62 (p.Cys62Arg). This mutation affects conserved cysteine residue i.e. Cys62 (PM1_strong). The variant is absent in gnomAD v4 (PM2_supporting). Male patient (0.5 pt.) with SCID (0.5 pt.), genome sequencing conducted (1 pt.),T-B+NK- lymphocyte subset profile (0.5 pt.); total : 2.5 pts (PP4_Moderate) (Invitae).Another missense variant [NM_000206.3(IL2RG):c.186T>A (p.Cys62Ter)] in the same codon has been reported (classified as pathogenic by SCID VCEP) (PM5 met).The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (Invitae, PMID: 27484032) (PS4_supporting). In summary, this variant meets the criteria to be classified as a Pathogenic variant for X-linked severe combined immunodeficiency due to IL2RG deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM1_strong, PM2_supporting, PP4_Moderate,PM5 met,PS4_supporting (VCEP specifications version 1).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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