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]

Variant: NM_000536.4(RAG2):c.362C>T (p.Thr121Ile)

CA5950586

960496 (ClinVar)

Gene: RAG2 (HGNC:5897)

Condition: recombinase activating gene 2 deficiency (MONDO:0000573)

Inheritance Mode: Autosomal recessive inheritance

UUID: ab08460b-4f62-4a4b-9fd7-5fd8c18a8f4e

Approved on: 2025-11-03

Published on: 2026-01-13

HGVS expressions

NM_000536.4(RAG2):c.362C>T (p.Thr121Ile)

NM_000536.4:c.362C>T

NC_000011.10:g.36593807G>A

CM000673.2:g.36593807G>A

NC_000011.9:g.36615357G>A

CM000673.1:g.36615357G>A

NC_000011.8:g.36571933G>A

NG_007573.1:g.9430C>T

NG_033154.1:g.4315G>A

ENST00000527033.6:c.362C>T

ENST00000529083.2:c.362C>T

ENST00000532616.2:c.362C>T

ENST00000311485.8:c.362C>T

ENST00000311485.7:c.362C>T

ENST00000524423.1:n.131+4295C>T

ENST00000529083.1:c.362C>T

ENST00000618712.4:c.362C>T

NM_000536.3:c.362C>T

NM_001243785.1:c.362C>T

NM_001243786.1:c.362C>T

NM_001243785.2:c.362C>T

NM_001243786.2:c.362C>T

Uncertain Significance

PM2_Supporting PM1_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 RAG2 Version 2.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Severe Combined Immunodeficiency Disease VCEP

The NM_000536.4(RAG2):c.362C>T variant is a missense variant predicted to cause substitution of Threonine by Isoleucine at amino acid 121 (p.Thr121Ile). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00002228 (1/44888 alleles) in the East Asian population, which is lower than the ClinGen SCID VCEP threshold of <0.0000588. No homozygotes have been observed in gnomAD v4.1.0 (PM2_Supporting). The variant is located in the core domain (amino acids 1-383), which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199) (PM1_Supporting). To our knowledge, this variant has not been reported in the literature in individuals affected with RAG2-related conditions. In summary, this variant is classified as variant of uncertain significance for autosomal recessive RAG2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_supporting, PM1_supporting (SCID VCEP specifications version 2.1.0, 10/01/2025).

PM2_Supporting

The highest population minor allele frequency in gnomAD v4.1.0 is 0.00002228 (1/44888 alleles) in the East Asian population, which is lower than the ClinGen SCID VCEP threshold of <0.0000588 and, no homozygotes have been observed in gnomAD v4.1.0 (PM2_Supporting).

PM1_Supporting

The variant is located in the core domain (amino acids 1-383), which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199); (PM1_Supporting).

Curation History

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