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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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001574305Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jun 13, 2022) 		germlineclinical testing

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

SCV005375410ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen
reviewed by expert panel

(ClinGen SCID ACMG Specifications IL2RG V1.0.0)		Pathogenic
(Jun 12, 2024) 		germlinecuration

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot 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).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 26, 2024