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.269+1G>T

CA413496954

1028611 (ClinVar)

Gene: IL2RG

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

Inheritance Mode: X-linked inheritance

Link to MONDO

UUID: 4a93af6a-aeb4-4a7a-95c5-5c4df2173033

Approved on: 2024-01-30

Published on: 2024-01-30

HGVS expressions

NM_000206.3:c.269+1G>T

NM_000206.3(IL2RG):c.269+1G>T

NC_000023.11:g.71110896C>A

CM000685.2:g.71110896C>A

NC_000023.10:g.70330746C>A

CM000685.1:g.70330746C>A

NC_000023.9:g.70247471C>A

NG_009088.1:g.5658G>T

NG_021141.1:g.893G>T

ENST00000374202.7:c.269+1G>T

ENST00000642473.1:n.633+1G>T

ENST00000644022.1:n.675+1G>T

ENST00000644708.1:n.675+1G>T

ENST00000644911.1:n.675+1G>T

ENST00000645266.1:c.269+1G>T

ENST00000645518.1:c.269+1G>T

ENST00000646106.1:c.269+1G>T

ENST00000646505.1:c.269+1G>T

ENST00000647492.1:c.269+1G>T

ENST00000276110.6:n.654+1G>T

ENST00000374188.7:c.-448+1G>T

ENST00000374202.6:c.269+1G>T

ENST00000456850.6:c.24+529G>T

ENST00000464642.5:c.137+1G>T

ENST00000473378.1:c.206+1G>T

ENST00000487883.1:c.233+1G>T

ENST00000512747.3:n.336+1G>T

NM_000206.2:c.269+1G>T

Pathogenic

PVS1 PP4_Moderate PM2_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 c.269+1G>T (NM_000206.3) variant in IL2RG occurs within the canonical donor splice site (+1) of intron 2. The variant is predicted by SpliceAI to affect splicing. It is expected to cause skipping of a biologically relevant exon 2 resulting in a frameshift (p.Asp39Glyfs*57) leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). 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) PMID: 33628209. 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: PVS1,PM2_supporting,PP4_Moderate (VCEP specifications version 1).

PVS1

PP4_Moderate

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) PMID: 33628209.

PM2_Supporting

The variant is absent in gnomAD v4 (PM2_supporting).

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