ClinVar

Description

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)