ClinVar Miner

Submissions for variant NM_000448.3(RAG1):c.322C>T (p.Arg108Ter)

gnomAD frequency: 0.00004  dbSNP: rs193922464
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000030393 SCV000053062 likely pathogenic Severe combined immunodeficiency disease 2011-08-18 criteria provided, single submitter curation Converted during submission to Likely pathogenic.
Eurofins Ntd Llc (ga) RCV000397265 SCV000337894 pathogenic not provided 2016-01-13 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000778322 SCV000914508 pathogenic RAG1-related disorder 2018-12-03 criteria provided, single submitter clinical testing The RAG1 c.322C>T (p.Arg108Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Arg108Ter variant has been reported in at least three studies in which it is found in a total of four individuals including in one in a homozygous state and three in a compound heterozygous state (Lee et al. 2014; Bai et al. 2016; Sharapova et al. 2016; Chi et al. 2018). Two of these individuals were described as having combined immune deficiency with one specifically diagnosed with Omenn syndrome. Control data are not available for the p.Arg108Ter variant which is reported at a frequency of 0.000159 in the East Asian population of the Genome Aggregation Database. Functional studies in cultured cells by Lee et al. (2014) demonstrated that the variant results in significantly reduced enzyme activity compared to wild type. Based on the potential impact of stop-gained variants and the supporting evidence from the literature, the p.Arg108Ter variant is classified as pathogenic for RAG1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000820376 SCV000961085 pathogenic Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2023-10-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg108*) in the RAG1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 936 amino acid(s) of the RAG1 protein. This variant is present in population databases (rs193922464, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with severe combined immunodeficiency (PMID: 21664875, 24290284, 30290665). ClinVar contains an entry for this variant (Variation ID: 36714). 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: 24290284). This variant disrupts a region of the RAG1 protein in which other variant(s) (p.Trp959*) 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 RCV001336880 SCV001530392 pathogenic Combined immunodeficiency due to partial RAG1 deficiency 2024-02-10 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000397265 SCV001808300 pathogenic not provided no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000397265 SCV001962746 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000397265 SCV001967317 pathogenic not provided no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.