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.670C>T (p.Arg224Trp)

CA358778

225194 (ClinVar)

Gene: IL2RG

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

Inheritance Mode: X-linked inheritance

Link to MONDO

UUID: 20eae169-0d74-4c7c-ab5c-ece464898a11

Approved on: 2024-03-08

Published on: 2024-03-08

HGVS expressions

NM_000206.3:c.670C>T

NM_000206.3(IL2RG):c.670C>T (p.Arg224Trp)

NC_000023.11:g.71109315G>A

CM000685.2:g.71109315G>A

NC_000023.10:g.70329165G>A

CM000685.1:g.70329165G>A

NC_000023.9:g.70245890G>A

NG_009088.1:g.7239C>T

NG_021141.1:g.2474C>T

ENST00000482750.6:c.670C>T

ENST00000696903.1:n.721C>T

ENST00000374202.7:c.670C>T

ENST00000642473.1:n.1034C>T

ENST00000644022.1:n.936C>T

ENST00000644708.1:n.1076C>T

ENST00000644911.1:n.1076C>T

ENST00000645266.1:c.670C>T

ENST00000645518.1:c.670C>T

ENST00000646106.1:c.670C>T

ENST00000646505.1:c.670C>T

ENST00000647492.1:c.670C>T

ENST00000276110.6:n.1263C>T

ENST00000374188.7:c.-47C>T

ENST00000374202.6:c.670C>T

ENST00000456850.6:c.100C>T

ENST00000464642.5:c.538C>T

ENST00000482750.5:c.83C>T

ENST00000512747.3:n.597C>T

NM_000206.2:c.670C>T

Pathogenic

PM1_Strong PS4 PP4 PM2_Supporting PS3_Supporting

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.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)

PM1_Strong

This variant affects CpG dinucleotides at c.670C, which is defined as a mutational hotspot by the ClinGen SCID VCEP. (PM1_Strong)

PS4

This variant has been reported in 9 probands meeting the PP4 criteria for SCID. 10pts for PP4 in total, PS4 default strength is met.

PP4

Two male siblings (0.5pt) from one family were hemizygous for this variant and were diagnosed with SCID (0.5pt). Both probands presented a T-B+NK- lymphocyte profile. 1.5pt for PP4, PP4 is met.

PM2_Supporting

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

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).

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