ClinVar Miner

Submissions for variant NM_000448.3(RAG1):c.775del (p.Ser259fs)

dbSNP: rs878853031
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen RCV003401159 SCV004102814 pathogenic Recombinase activating gene 1 deficiency 2023-11-14 reviewed by expert panel curation The nonsense variant NM_000448.3(RAG1):c.775del (p.Ser259AlafsTer5) occurs in exon 2 of 2 (the only coding exon of RAG1) and is not predicted to result in nonsense mediated decay but does truncate 75% of the protein, including the entirety of the core domain (amino acids 387-1011) which is critical to protein function (PMID: 26996199; PVS1). This variant is absent from gnomADv2.1.1 (PM2_Supporting). It has been reported homozygous in one patient with Omenn syndrome (PM3_supporting) with insufficient information to determine that the patient's phenotype is highly specific to recombinase activating gene 1 deficiency (PP4_NotMet). In summary, this variant meets the criteria to be classified as pathogenic for recombinase activating gene 1 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PVS1, PM3_Supporting, and PM2_Supporting. (VCEP specifications version 1).
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics RCV000224814 SCV000280984 pathogenic not provided 2016-02-17 criteria provided, single submitter clinical testing
GeneDx RCV000224814 SCV000616848 pathogenic not provided 2018-07-16 criteria provided, single submitter clinical testing The c.775delA variant has been reported previously in association with Omenn syndrome (Santagata et al., 2000; Sobacchi et al., 2006). The deletion causes a frameshift starting with codon Serine 259, changes this amino acid to an Alanine residue and creates a premature Stop codon at position 5 of the new reading frame, denoted p.Ser259AlafsX5. Functional studies have shown this variant results in decreased activity of the RAG1 protein and interferes with proper protein localization (Santagata et al., 2000). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In summary, we consider this variant to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001174963 SCV001338445 pathogenic Histiocytic medullary reticulosis 2020-04-01 criteria provided, single submitter clinical testing Variant summary: RAG1 c.775delA (p.Ser259AlafsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250934 control chromosomes (gnomAD). c.775delA has been reported in the literature in individuals affected with Omenn Syndrome (examples- Santagata_2000, Sobacchi_2006, Dobbs_2017). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, indicating that the variant results in reduced levels of V(D)J recombination and reduced nuclear localization of the protein (Santagata_2000). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV001854775 SCV002180919 pathogenic Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2023-02-15 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser259Alafs*5) in the RAG1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 785 amino acid(s) of the RAG1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Omenn syndrome (PMID: 11121059, 16960852, 28769923). This variant is also known as g.887delA. ClinVar contains an entry for this variant (Variation ID: 235411). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects RAG1 function (PMID: 11121059). This variant disrupts a region of the RAG1 protein in which other variant(s) (p.W959*) have been determined to be pathogenic (PMID: 11133745, 24290284, 24406074). 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.
Baylor Genetics RCV003475050 SCV004200510 pathogenic Combined immunodeficiency due to partial RAG1 deficiency 2024-03-17 criteria provided, single submitter clinical testing
OMIM RCV001174963 SCV000034283 pathogenic Histiocytic medullary reticulosis 2000-12-19 no assertion criteria provided literature only

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