ClinVar Miner

Submissions for variant NM_000448.2(RAG1):c.2348C>G (p.Ser783Ter) (rs754502950)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000695106 SCV000823586 pathogenic Combined cellular and humoral immune defects with granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2017-11-01 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the RAG1 gene (p.Ser783*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 261 amino acids of the RAG1 protein. This variant is present in population databases (rs754502950, ExAC 0.01%). This variant has not been reported in the literature in individuals with RAG1-related disease. A different truncation (p.R959*) that lies downstream of this variant has been determined to be pathogenic (PMID: 11133745, 24290284, 24406074). This suggests that deletion of this region of the RAG1 protein is causative of disease. 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 Alpha/beta T-cell lymphopenia with gamma/delta T-cell expansion, severe cytomegalovirus infection, and autoimmunity; Combined cellular and humoral immune defects with granulomas; Histiocytic medullary reticulosis; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2018-02-01 criteria provided, single submitter clinical testing RAG1 NM_000448.2 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.

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