Variant: NM_000536.4(RAG2):c.1338C>G (p.Cys446Trp)

CA380140584

496629 (ClinVar)

Gene: RAG2

Condition: recombinase activating gene 2 deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: b978e817-e1af-49b1-b708-4d6bf5d38b07

Approved on: 2024-01-23

Published on: 2024-01-23

HGVS expressions

NM_000536.4:c.1338C>G
NM_000536.4(RAG2):c.1338C>G (p.Cys446Trp)
NC_000011.10:g.36592831G>C
CM000673.2:g.36592831G>C
NC_000011.9:g.36614381G>C
CM000673.1:g.36614381G>C
NC_000011.8:g.36570957G>C
NG_007573.1:g.10406C>G
NG_033154.1:g.3339G>C
ENST00000311485.8:c.1338C>G
ENST00000311485.7:c.1338C>G
ENST00000524423.1:n.131+5271C>G
ENST00000534663.1:c.*86-136G>C
ENST00000618712.4:c.1338C>G
NM_000536.3:c.1338C>G
NM_001243785.1:c.1338C>G
NM_001243786.1:c.1338C>G
NM_001243785.2:c.1338C>G
NM_001243786.2:c.1338C>G

Likely Pathogenic

• Met criteria codes: PM2_Supporting PM3_Supporting PP4 PM1 PS3_Moderate

• Not Met criteria codes: PM5

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

Evidence submitted by expert panel

Severe Combined Immunodeficiency Disease VCEP

The c.1338C>G (NM_000536.4) variant in RAG2 is a missense variant predicted to cause substitution of Cysteine by Tryptophan at amino acid 446 (p.Cys446Trp). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is located in the PHD domain, amino acids 414-487 of RAG2, which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199); PM1_Moderate. The recombination activity assay showed activity of this variant compared to wildtype RAG2 is 2.9% (SEM 0.1), which is lower than the SCID VCEP threshold (<25%) for PS3_Moderate, meeting this criterion (PS3_Moderate, PMID 29772310). Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met 0.5 pts + T-B-NK+ lymphocyte subset profile 0.5 pts, PP4 is met (PMID: 20234091). A second report describes one homozygous patient, 0.5 pts, PM3_Supporting (PMID: 31973905). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive recombinase activating gene 2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM2_Supporting, PM1_Moderate, PS3_Moderate, PM3_Supporting, and PP4 (VCEP specifications version 1.0).

Met criteria codes

• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
• PM3_Supporting: PMID: 31973905 reports one homozygous patient, 0.5 pts, PM3_Supporting.
• PP4: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met 0.5 pts + T-B-NK+ lymphocyte subset profile 0.5 pts, PP4 is met (PMID: 20234091). Another patient is reported in PMID: 29772310, however, the patient's complete genetic and clinical information is not available. I would say we have enough information to apply PP4 at least at a supporting level of evidence.
• PM1: This variant is located in the PHD domain, amino acids 414-487 of RAG2, which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199); PM1_Moderate.
• PS3_Moderate: The recombination activity assay showed activity of this variant compared to wildtype RAG2 is 2.9% (SEM 0.1), which is lower than the SCID VCEP threshold (<25%) for PS3_Moderate, meeting this criterion (PS3_Moderate, PMID 29772310).

Not Met criteria codes

• PM5: Another missense variant [NM_000536.4(RAG2):c.1336T>A (p.Cys446Ser)] in the same codon has been reported; Classified in ClinVar as VUS; It has not yet been evaluated according to the SCID VCEP specifications. PM5 is not met at this time. (PM5 not met).