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]

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Variant: NM_000206.3(IL2RG):c.677G>A (p.Arg226His)

CA358793

225196 (ClinVar)

Gene: IL2RG

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

Inheritance Mode: X-linked inheritance

Link to MONDO

UUID: df49371f-60da-48d8-9c4d-d677e3afed13

Approved on: 2024-03-08

Published on: 2024-03-08

HGVS expressions

NM_000206.3:c.677G>A

NM_000206.3(IL2RG):c.677G>A (p.Arg226His)

NC_000023.11:g.71109308C>T

CM000685.2:g.71109308C>T

NC_000023.10:g.70329158C>T

CM000685.1:g.70329158C>T

NC_000023.9:g.70245883C>T

NG_009088.1:g.7246G>A

NG_021141.1:g.2481G>A

ENST00000482750.6:c.677G>A

ENST00000696903.1:n.728G>A

ENST00000374202.7:c.677G>A

ENST00000642473.1:n.1041G>A

ENST00000644022.1:n.943G>A

ENST00000644708.1:n.1083G>A

ENST00000644911.1:n.1083G>A

ENST00000645266.1:c.677G>A

ENST00000645518.1:c.677G>A

ENST00000646106.1:c.677G>A

ENST00000646505.1:c.677G>A

ENST00000647492.1:c.677G>A

ENST00000276110.6:n.1270G>A

ENST00000374188.7:c.-40G>A

ENST00000374202.6:c.677G>A

ENST00000456850.6:c.107G>A

ENST00000464642.5:c.545G>A

ENST00000482750.5:c.90G>A

ENST00000512747.3:n.604G>A

NM_000206.2:c.677G>A

Pathogenic

PM5 PM1_Strong PS3_Supporting PM2_Supporting PS4 PP4_Moderate

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:c.677G>A variant in IL2RG is a missense variant predicted to cause substitution of arginine by histidine at amino acid 226 (p.Arg226His). The variant has been observed in at least 9 probands with SCID/Ommen Syndrome (PMIDs 7668284, 9058718, 17598841, 21184155) (PS4). Among these probands, one presented with symptoms reminiscent of Omenn syndrome. The proband exhibited a T-B-NK+ lymphocyte profile. CD132 was absent in every lymphocyte subpopulation, and the NK cells isolated from the patient did not respond to IL-2 stimulation (PMID 17598841) (PP4). The variant is absent from gnomAD v4.0 (PM2_Supporting). The variant affects CpG dinucleotides at c.677G, 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 addition, another missense variant c.676C>T, p.Arg226Cys (ClinVar Variation ID 225195) in the same codon has been classified as pathogenic for SCID by the ClinGen SCID VCEP (PM5). 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_Strong, PM5, PP4_Moderate, PM2_Supporting, PS3_Supporting. (VCEP specifications version 1.0)

PM5

Another missense variant c.676C>T, p.Arg226Cys (ClinVar Variation ID 225195) in the same codon has been classified as pathogenic for SCID by the ClinGen SCID VCEP.

PM1_Strong

This variant affects CpG dinucleotides at c.677G, which is defined as a mutational hotspot by the ClinGen SCID VCEP. (PM1_Strong)

PS3_Supporting

Surface expression of the IL-2 receptor gamma chain in patient B cells showed that the variant causes compromised surface localization of the protein, indicating that this variant impacts protein function (PMID 9058718)(PS3_Supporting).

PM2_Supporting

This variant is absent from gnomAD v4.0. (PM2_Supporting)

PS4

This variant has been reported in 8 probands meeting the PP4 criteria for SCID. 8pts for PP4 in total, PS4 default strength is met.

PP4_Moderate

One male proband (0.5pt) who was hemizygous for this variant presented with symptoms reminiscent of Omenn syndrome (0.5pt). The proband exhibited a T-B-NK+ lymphocyte profile (0pt). CD132 was absent in every lymphocyte subpopulation (1pt), and the NK cells isolated from the patient did not respond to IL-2 stimulation (1pt). The proband had a family history of immunodeficiency, however, neither a SCID gene panel nor exome/genome sequencing was conducted on the proband (0pt). 3pt in total for PP4, PP4_Moderate is met.

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