ClinVar Miner

Submissions for variant NM_000448.3(RAG1):c.2348C>G (p.Ser783Ter)

gnomAD frequency: 0.00003  dbSNP: rs754502950
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000695106 SCV000823586 pathogenic Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2023-10-04 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser783*) in the RAG1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 261 amino acid(s) of the RAG1 protein. This variant is present in population databases (rs754502950, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with RAG1-related conditions. ClinVar contains an entry for this variant (Variation ID: 573434). This variant disrupts a region of the RAG1 protein in which other variant(s) (p.R959*) 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768065 SCV000898927 likely pathogenic Combined immunodeficiency due to partial RAG1 deficiency; Combined immunodeficiency with skin granulomas; Histiocytic medullary reticulosis; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2021-03-30 criteria provided, single submitter clinical testing RAG1 NM_000448 exon 2 p.Ser738* (c.2348C>G): This variant has not been reported in the literature but is present in 3/15298 African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs754502950). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant creates a premature stop at this codon which results in an absent or abnormal protein; loss of function variants have been reported in association with disease for this gene (Matthews 2015 PMID:25849362). In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic.
Baylor Genetics RCV003472218 SCV004200489 likely pathogenic Combined immunodeficiency due to partial RAG1 deficiency 2024-03-25 criteria provided, single submitter clinical testing

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