ClinVar Miner

Submissions for variant NM_000448.2(RAG1):c.322C>T (p.Arg108Ter) (rs193922464)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000030393 SCV000053062 likely pathogenic Severe combined immunodeficiency disease 2011-08-18 criteria provided, single submitter curation Converted during submission to Likely pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000397265 SCV000337894 pathogenic not provided 2016-01-13 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778322 SCV000914508 pathogenic RAG1-Related Disorders 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 cellular and humoral immune defects with granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2019-04-04 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the RAG1 gene (p.Arg108*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 936 amino acids of the RAG1 protein. This variant is present in population databases (rs193922464, ExAC 0.02%). This variant has been observed in individuals affected with severe combined immunodeficiency (PMID: 21664875, 24290284, 30290665). ClinVar contains an entry for this variant (Variation ID: 36714). This variant has been reported to affect RAG1 protein function (PMID: 24290284). This variant disrupts the C-terminus of the RAG1 protein. Other variant(s) that disrupt this region (p.Trp959*) have been determined to be pathogenic (PMID: 11133745, 24290284, 24406074). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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.