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

gnomAD frequency: 0.00004  dbSNP: rs193922464

Total submissions: 9

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000820376	SCV000961085	pathogenic	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2024-09-04	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 gene product 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
GeneDx	RCV000397265	SCV005906582	pathogenic	not provided	2024-10-06	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: reduced VDJ recombination activity (PMID: 24290284); Nonsense variant predicted to result in protein truncation, as the last 936 amino acids are lost, and other loss-of-function variants have been reported; This variant is associated with the following publications: (PMID: 21664875, 24290284, 28783691, 31589898, 31589614, 32888943, 35753512, 36790564, 36279417, 27825771, 30290665)
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