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.821T>C (p.Ile274Thr)

CA10443808

532191 (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: 00b3e43d-5cb4-41ac-8205-01d1a33a0815

Approved on: 2024-01-17

Published on: 2024-01-17

HGVS expressions

NM_000206.3:c.821T>C

NM_000206.3(IL2RG):c.821T>C (p.Ile274Thr)

NC_000023.11:g.71108632A>G

CM000685.2:g.71108632A>G

NC_000023.10:g.70328482A>G

CM000685.1:g.70328482A>G

NC_000023.9:g.70245207A>G

NG_009088.1:g.7922T>C

NG_021141.1:g.3157T>C

ENST00000374202.7:c.821T>C

ENST00000642473.1:n.1185T>C

ENST00000644022.1:n.1087T>C

ENST00000644708.1:n.1164-286T>C

ENST00000644911.1:n.1227T>C

ENST00000645266.1:c.821T>C

ENST00000645518.1:c.821T>C

ENST00000646106.1:c.821T>C

ENST00000646505.1:c.821T>C

ENST00000647492.1:c.821T>C

ENST00000276110.6:n.1414T>C

ENST00000374188.7:c.42-286T>C

ENST00000374202.6:c.821T>C

ENST00000456850.6:c.251T>C

ENST00000482750.5:c.171-286T>C

ENST00000512747.3:n.748T>C

NM_000206.2:c.821T>C

Uncertain Significance

PM2_Supporting PM1_Strong

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.821T>C (p.Ile274Thr) is a missense variant that has been reported in ClinVar, without patient information, however it has not been reported in the literature to our knowledge. This variant introduces a polar residue within the transmembrane region (amino acids 263-283) of IL2RG, which is defined as a critical functional domain by the ClinGen SCID VCEP (PM1_Strong). The filtering allele frequency (the upper threshold of the 95% CI of 2/70896) of the c.821T>C variant in IL2RG is 0.000004680 for European (non- Finnish) chromosomes by gnomAD v2.1.1, which is lower than the ClinGen SCID VCEP threshold (<0.000124; PM2_Supporting). In summary, this variant is classified as uncertain significance due to insufficient information. Criteria applied: PM1_strong and PM2_supporting (VCEP specifications version 1).

PM2_Supporting

The filtering allele frequency (the upper threshold of the 95% CI of 2/70896) of the c.821T>C variant in IL2RG is 0.000004680 for European (non- Finnish) chromosomes by gnomAD v2.1.1, which is lower than the ClinGen SCID VCEP threshold (<0.000124) for PM2_Supporting, meeting this criterion (PM2_Supporting).

PM1_Strong

This variant introduces a polar residue within the transmembrane region (amino acids 263-283) of IL2RG, which is defined as a critical functional domain by the ClinGen SCID VCEP (PM1_Strong).

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