Submissions for variant NM_000536.4(RAG2):c.1357T>A (p.Trp453Arg)

dbSNP: rs1564995627

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV003403379	SCV004102754	likely pathogenic	Recombinase activating gene 2 deficiency	2023-11-14	reviewed by expert panel	curation	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)
Pediatric Immunology Service, The Chaim Sheba Medical Center at Tel HaShomer	RCV000681598	SCV000693946	likely pathogenic	Histiocytic medullary reticulosis; Recombinase activating gene 2 deficiency; Inborn error of immunity	2018-03-06	criteria provided, single submitter	research
Invitae	RCV001389163	SCV001590429	pathogenic	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2023-09-27	criteria provided, single submitter	clinical testing	Experimental studies have shown that this missense change affects RAG2 function (PMID: 18033247, 20234091). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RAG2 protein function. ClinVar contains an entry for this variant (Variation ID: 496630). This missense change has been observed in individual(s) with Omenn syndrome (PMID: 10891502, 12200379). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 453 of the RAG2 protein (p.Trp453Arg).
Natera, Inc.	RCV001834861	SCV002090422	pathogenic	Histiocytic medullary reticulosis	2020-12-09	no assertion criteria provided	clinical testing