Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_000206.3(IL2RG):c.664C>T (p.Arg222Cys)

CA120885

10027 (ClinVar)

Gene: IL2RG

Condition: T-B+ severe combined immunodeficiency due to gamma chain deficiency

Inheritance Mode: X-linked inheritance (recessive (HP:0001419))

Link to MONDO

UUID: 3f6af4f7-f617-4684-bd64-58811dc750eb

HGVS expressions

NM_000206.3:c.664C>T

NM_000206.3(IL2RG):c.664C>T (p.Arg222Cys)

NC_000023.11:g.71109321G>A

CM000685.2:g.71109321G>A

NC_000023.10:g.70329171G>A

CM000685.1:g.70329171G>A

NC_000023.9:g.70245896G>A

NG_009088.1:g.7233C>T

NG_021141.1:g.2468C>T

ENST00000374202.7:c.664C>T

ENST00000642473.1:n.1028C>T

ENST00000644022.1:n.930C>T

ENST00000644708.1:n.1070C>T

ENST00000644911.1:n.1070C>T

ENST00000645266.1:c.664C>T

ENST00000645518.1:c.664C>T

ENST00000646106.1:c.664C>T

ENST00000646505.1:c.664C>T

ENST00000647492.1:c.664C>T

ENST00000276110.6:n.1257C>T

ENST00000374188.7:c.-53C>T

ENST00000374202.6:c.664C>T

ENST00000456850.6:c.94C>T

ENST00000464642.5:c.532C>T

ENST00000482750.5:c.77C>T

ENST00000512747.3:n.591C>T

NM_000206.2:c.664C>T

Pathogenic

PP1_Strong PS4 PP4_Moderate PM2_Supporting

PS3 PP3

Evidence Links 0

Expert Panel

Severe Combined Immunodeficiency Disease VCEP

Criteria Specification Information

Criteria Specification: ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for IL2RG Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Severe Combined Immunodeficiency Disease VCEP

The NM_000206.3(IL2RG):c.664C>T (p.Arg222Cys) missense variant has been reported in several (atypical) SCID cases, including male (0.5pt) patient P1 (PMID: 29948574) in whom the variant was detected by WES (1pt) and there was a family history of SCID (first-degree male relatives from the maternal side with suspected primary immune deficiency, who were not available for this study; 0.5pt), additionally STAT5 phosphorylation after exposure to IL-2 was virtually absent in CD4 and CD8 T cells (1pt); together these are highly specific for SCID due to gamma chain deficiency (3pt; PP4_moderate). There are 5 genotype/phenotype positive individuals in the pedigree through 11 segregations of this variant (PMID: 29948574); P1 plus four second cousins are all hemizygous for this variant and affected with atypical SCID and an additional great uncle was also affected but not available for genotyping (5+ segregations; PP1_Strong). At least 15 additional male X-SCID patients have been reported (PMIDs: 25042067, 16227049, 10794431, 7557965) with this hemizygous variant (total 11pt; PS4) and this variant is absent from gnomADv2.1.1 (PM2_Supporting). 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, Pp1_Strong, PP4_Moderate and PM2_supporting. (VCEP specifications version 1).

PP1_Strong

There are 5 genotype/phenotype positive individuals in the pedigree through 11 segregations of this variant (PMID: 29948574). P1 plus four second cousins are all hemizygous for this variant and affected with atypical SCID. An additional great uncle was also affected but not available for genotyping. (5+ segregations; PP1_Strong).

PS4

At least 15 additional male X-SCID patients have been reported (PMIDs: 25042067, 16227049, 10794431, 7557965) with this hemizygous variant (total 11pt; PS4).

PP4_Moderate

For P1 (PMID: 29948574) male 0.5pt, WES 1pt, family history of SCID (first-degree male relatives from the maternal side with suspected primary immune deficiency, who were not available for this study) 0.5pt, STAT5 phosphorylation after exposure to IL-2 was virtually absent in CD4 and CD8 T cells 1pt (total 3pt; PP4_moderate)

PM2_Supporting

This variant is absent from gnomADv2.1.1 (PM2_Supporting).

PS3

cDNA for a normal IL-2Rb chain was cotransfected into COS cells with either a normal IL-2Rg cDNA or the mutated version derived from the patient. A clear difference between the contribution of the patient and normal IL-2Rg chains was evident. Although appreciably greater IL-2 binding was observed to the combined b and g (R222C) chains, than to b alone, it was significantly lower than IL-2 binding to the normal bg complex. In summary, these results indicate that although receptors containing the mutated gamma chain are capable of binding IL-2, their affinity is reduced. Additionally, when cotransfected with Jak3 and the level of Jak3 phosphorylation induced by low levels of IL-2 examined R222C was clearly less effective in modulating Jak3 activation. (PS3_NotMet) The SCID-VCEP has not approved functional studies in cell lines as evidence for assessing the pathogenicity of IL2RG.

PP3

REVEL score of 0.784 predicts a deleterious effect. Not considered for this gene.

Approved on: 2024-01-17

Published on: 2024-01-17

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.