Variant: NM_000536.4(RAG2):c.1357T>A (p.Trp453Arg)

CA380140542

496630 (ClinVar)

Gene: RAG2

Condition: recombinase activating gene 2 deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 2f9eb7c7-cf9e-45e0-8dc7-b900733055f4

Approved on: 2024-01-17

Published on: 2024-01-17

HGVS expressions

NM_000536.4:c.1357T>A
NM_000536.4(RAG2):c.1357T>A (p.Trp453Arg)
NC_000011.10:g.36592812A>T
CM000673.2:g.36592812A>T
NC_000011.9:g.36614362A>T
CM000673.1:g.36614362A>T
NC_000011.8:g.36570938A>T
NG_007573.1:g.10425T>A
NG_033154.1:g.3320A>T
ENST00000311485.8:c.1357T>A
ENST00000311485.7:c.1357T>A
ENST00000524423.1:n.131+5290T>A
ENST00000534663.1:c.*86-155A>T
ENST00000618712.4:c.1357T>A
NM_000536.3:c.1357T>A
NM_001243785.1:c.1357T>A
NM_001243786.1:c.1357T>A
NM_001243785.2:c.1357T>A
NM_001243786.2:c.1357T>A

Likely Pathogenic

• Met criteria codes: PP4 PM1 PM3_Supporting PS3_Moderate PM2_Supporting

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.1357T>A (NM_000536.4) variant in RAG2 is a missense variant predicted to cause substitution of Tryptophan by Arginine at amino acid 453 (p.Trp453Arg). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). It resides within a region, [amino acids 414 – 487, PHD domain], of RAG2 that is defined as a mutational hotspot/critical functional domain by the ClinGen SCID VCEP (PMID: 26996199) (PM1_Moderate). The results found by Tirosh et al., show a mean recombination activity (% of WT hRAG2): 0.6, SEM 0.1., which is below the threshold described by our VCEP (<25% of wild-type activity), so PS3 is met at a moderate level of evidence (PS3_moderate). One patient is homozygous for this variant (0.5 pt, reported in PMID: 12200379 and PMID: 29772310). One patient is heterozygous for G95R (Reported in PMID: 29772310 and PMID: 10891502). Despite the LP level of the G95R, we already applied points for this heterozygous occurrence evaluating that variant, so we will not apply here to avoid circularity - according to SVI Recommendation for in trans Criterion (PM3) - Version 1.0. (PM3_supporting). At least one patient in the literature present: T-/lowB-/low lymphocyte subset profile (0.5 pt) + Diagnostic criteria for Omenn syndrome (0.5 pt), total 1.0 pt, PP4 met (PMID: 10891502). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, PM1, PS3_moderate, PP4, PM2_supporting, and PM3_supporting, as specified by the ClinGen SCID VCEP (VCEP specifications version 1)

Met criteria codes

• PP4: Reported in 2 patients with Omenn syndrome, one homozygous and one heterozygous (but phase unknown) with p.G95R. PMID: 10891502, 12200379. At least one patient meets PP4 at regular strength (no modifications).
• PM1: Missense variant located in the PHD domain (amino acids 414-487), qualifies for PM1 (regular strength, no modifications) as per SCID VCEP specifications for RAG2.
• PM3_Supporting: Homozygous occurrence = 0.5p, which qualifies for PM3_Supporting. Also co-occurs phase unknown with p.G95R (classified as Likely Pathogenic by SCID VCEP) - since phase unknown, this is worth 0.25p. Total 0.75p, PM3 met at supporting strength.
• PS3_Moderate: At least one patient must meet PP4 criteria in order to apply PS3 (and we have 1 patient who meets PP4), so variant is eligible for PS3 criteria. V(D)J recombinase activity for this variant is < 25% of wild type, this meets PS3 criteria at moderate strength (PMID: 29772310, 18033247).
• PM2_Supporting: Absent from gnomAD v2.1.1.