ClinVar Miner

Submissions for variant NM_000448.3(RAG1):c.2850del (p.Ile950fs)

dbSNP: rs2133298263
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV002285496 SCV002569910 likely pathogenic Histiocytic medullary reticulosis 2022-04-05 criteria provided, single submitter clinical testing A heterozygous single base pair deletion in exon 2 of the RAG1 gene that results in frameshift and premature truncation of the protein 28 amino acid downstream to codon 950 was detected. The observed variant has not been reported in the 1000 genomes and gnomAD databases and has minor allele frequency of 0.008% in our internal database. The in silico prediction of the variant are possibly damaging by Mutation taster2. The reference codon is conserved across species. In summary, the variant meets out criteria to be classified as variant of likely pathogenic.
Baylor Genetics RCV003475086 SCV004200492 pathogenic Combined immunodeficiency due to partial RAG1 deficiency 2023-07-07 criteria provided, single submitter clinical testing
Invitae RCV003772142 SCV004579580 pathogenic Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2023-04-16 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the RAG1 protein in which other variant(s) (p.Lys992Glu) have been determined to be pathogenic (PMID: 11313270, 18442948, 24290284). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 1323517). This premature translational stop signal has been observed in individual(s) with severe combined immunodeficiency (PMID: 30778343). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile950Metfs*28) in the RAG1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 94 amino acid(s) of the RAG1 protein.

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