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_000536.4(RAG2):c.115A>G (p.Arg39Gly)

CA122867

13136 (ClinVar)

Gene: RAG2

Condition: recombinase activating gene 2 deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 418ca304-b22e-4a9e-a014-7abfa82d833c

HGVS expressions

NM_000536.4:c.115A>G

NM_000536.4(RAG2):c.115A>G (p.Arg39Gly)

NC_000011.10:g.36594054T>C

CM000673.2:g.36594054T>C

NC_000011.9:g.36615604T>C

CM000673.1:g.36615604T>C

NC_000011.8:g.36572180T>C

NG_007573.1:g.9183A>G

NG_033154.1:g.4562T>C

ENST00000527033.6:c.115A>G

ENST00000529083.2:c.115A>G

ENST00000532616.2:c.115A>G

ENST00000311485.8:c.115A>G

ENST00000311485.7:c.115A>G

ENST00000524423.1:n.131+4048A>G

ENST00000527033.5:c.115A>G

ENST00000529083.1:c.115A>G

ENST00000618712.4:c.115A>G

NM_000536.3:c.115A>G

NM_001243785.1:c.115A>G

NM_001243786.1:c.115A>G

NM_001243785.2:c.115A>G

NM_001243786.2:c.115A>G

Pathogenic

PP4 PM2_Supporting PM3_Strong PS3_Moderate PP1_Moderate PM1_Supporting

Evidence Links 1

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 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Severe Combined Immunodeficiency Disease VCEP

NM_000536.4(RAG2):c.115A>G is a missense variant predicted to cause substitution of Arginine by Glycine at amino acid 39 (p.Arg39Gly).This missense variant is located in the core domain (amino acids 1-383) (PM1_supporting).The variant is absent in gnomAD v4 (PM2_supporting). Patient with SCID (0.5 pt.), genome sequencing conducted (0.5 pt.),T-B-NK+ lymphocyte subset profile (0.5 pt.) :Total :1.5 pts. PP4 met (PMID: 11313270). This variant was found to segregate in 2 affected siblings from one family (PP1_moderate) (PMID: 11313270).Two patients (PMID: 11313270) were found compound heterozygous for R39G and R229Q (pathogenic variant) ;total : 2pts. (PM3_strong).This variant showed <25 % of wild type activity in In vitro V(D)J recombination assay (PS3_moderate) (PMID: 11313270). In summary, this variant meets the criteria to be classified as a Pathogenic variant for autosomal recessive severe combined immunodeficiency due to RAG2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM1_supporting,PM2_supporting,PP4 met,PP1_moderate,PM3_strong,PS3_moderate(VCEP specifications version 1).

PP4

Patient with SCID (0.5 pt.), genome sequencing conducted (0.5 pt.),T-B-NK+ lymphocyte subset profile (0.5 pt.) :Total :1.5 pts. PP4 met (PMID: 11313270)

PM2_Supporting

The variant is absent in gnomAD v4 (PM2_supporting).

PM3_Strong

Two patients ( PMID: 11313270) were found compound heterozygous for R39G and R229Q (pathogenic variant) ;total : 2pts. (PM3_strong)

PS3_Moderate

This variant showed <25 % of wild type activity in In vitro V(D)J recombination assay (PS3_moderate) (PMID: 11313270).

This variant showed <25 % of wild type activity in In vitro V(D)J recombination assay (PS3_moderate) (PMID: 11313270). PubMed:11313270

PP1_Moderate

This variant was found to segregate in 2 affected siblings from one family (PP1_moderate) (PMID: 11313270).

PM1_Supporting

This missense variant is located in the core domain (amino acids 1-383) (PM1_supporting).

Approved on: 2024-02-26

Published on: 2024-02-26

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