Submissions for variant NM_000536.4(RAG2):c.829dup (p.Tyr277fs)

dbSNP: rs1851074524

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV003399209	SCV004102757	pathogenic	Recombinase activating gene 2 deficiency	2023-11-14	reviewed by expert panel	curation	The NM_000536.4:c.829dup variant in RAG2 is a frameshift variant predicted to result in a truncated protein (p.Tyr277Leufs*4). Although this variant is expected to escape nonsense-mediated decay (NMD), it would be expected to disrupt approximately 47% of the RAG2 protein. In addition, this variant would be expected to disrupt/remove the entire PHD domain (amino acids 414-487), which is defined as a mutational hotspot/critical functional domain by the ClinGen SCID VCEP (PMID: 15964836). PVS1 met. This variant is absent in gnomAD, which is below the threshold for max filtering allele frequency for PM2_Supporting set by the ClinGen SCID VCEP for RAG2 (<0.0000588). In an experimental study, this variant demonstrates zero recombination activity, which is below the threshold outlined by the ClinGen SCID VCEP (< 25% wildtype activity) for PS3_Moderate (PMID: 31058115). This variant has been reported in three patients. One patient in a cohort of SCID patients (0.5p) with T-B-NK+ immunophenotype (0.5p) was identified with this variant along with a co-occurring RAG2 p.Phe183Asn variant, though phase was not reported (PMID: 24144642) (1p, PP4). A second patient with a later onset CID-like phenotype was identified with this variant along with a co-occurring RAG2 p.Glu170Gly variant (only one parent tested and was heterozygous for the variant) (PMID: 31058115). The p.Phe183Asn and p.Glu170Gly variants have not yet been classified by the ClinGen SCID VCEP. A third patient with Omenn syndrome was identified with this variant; however, the variant was heterozygous, and a second variant in RAG2 was not identified (PMID: 34851571). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive SCID based on the ACMG criteria applied: PVS1, PM2_Supporting, PS3_Moderate, and PP4 as specified by the ClinGen SCID VCEP (VCEP specifications version 1).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001389166	SCV001590432	pathogenic	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2023-09-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr277Leufs*4) in the RAG2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 251 amino acid(s) of the RAG2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with severe combined immunodeficiency (PMID: 24144642, 31058115). ClinVar contains an entry for this variant (Variation ID: 1075544). This variant disrupts a region of the RAG2 protein in which other variant(s) (p.Ile427Glyfs*12, p.His468Argfs*16, p.Glu480*) have been determined to be pathogenic (PMID: 21624848, 26476733, 26915675, 29772310). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002499812	SCV002808518	pathogenic	Combined immunodeficiency with skin granulomas; Histiocytic medullary reticulosis; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2022-01-13	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV004570970	SCV005054071	pathogenic	Combined immunodeficiency with skin granulomas	2023-12-26	criteria provided, single submitter	clinical testing
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV004719160	SCV005326353	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive		criteria provided, single submitter	clinical testing	The p.Tyr277Leufs*4 variant results in substitution of tyrosine at amino acid position 277 with leucine followed by a premature termination codon after four amino acids. RAG2 is a single exon gene; therefore, this frameshift is expected to result in a truncated protein, rather than nonsense-mediated decay. This truncated protein would lack part of the core domain (amino acids 1-383) and all of the PHD-type zinc finger domain (amino acids: 416-484, PMID: 26692406). This frameshift variant has been reported previously in affected individuals (PMID: 24144642, 31058115). This variant is found at a low frequency in large population studies (5 of 1,461,850 alleles, no homozygotes, gnomAD v4.0.0)).