ClinVar Miner

Submissions for variant NM_000448.2(RAG1):c.256_257del (p.Lys86fs) (rs772962160)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725574 SCV000337892 pathogenic not provided 2015-12-02 criteria provided, single submitter clinical testing
Invitae RCV000282657 SCV000638115 pathogenic Combined cellular and humoral immune defects with granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2019-01-29 criteria provided, single submitter clinical testing This sequence change deletes 2 nucleotides from exon 2 of the RAG1 mRNA (c.256_257delAA), causing a frameshift at codon 86. This creates a premature translational stop signal in the last exon of the RAG1 mRNA (p.Lys86Valfs*33). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated RAG1 protein. This variant is present in population databases (rs772962160, ExAC 0.008%). This variant has been reported as homozygous or compound heterozygous in multiple individuals affected with Omenn syndrome or severe combined immunodeficiency (PMID: 9630231, 25516070, 24290284, 23085344, 22424479). Experimental studies have shown that this sequence change is hypomorphic because translation can be reinitiated from the alternative start site methionine, resulting in an N-terminal truncated RAG1 protein with residual RAG1 activity (PMID: 10891452, 24418478, 25516070). For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000779060 SCV000915526 pathogenic RAG1-Related Disorders 2017-04-28 criteria provided, single submitter clinical testing The RAG1 c.256_257delAA (p.Lys86ValfsTer33) variant is a frameshift variant that is predicted to result in premature termination of the protein. The p.Lys86ValfsTer33 variant has been reported in five studies in which it is found in a total of 14 individuals with RAG1-related disorders, including in eight in a homozygous state, five in a compound heterozygous state, and one in a heterozygous state (Abraham et al. 2013; Lee et al. 2014; Buchbinder et al. 2015; Walter et al. 2015; Brauer et al. 2016). Homozygous individuals included six with severe combined immune deficiency (SCID) and two with Omenn syndrome (OS); compound heterozygous individuals included two with OS, one with common variable immunodeficiency disorder (CVID), two with combined immune deficiency with granuloma and/or autoimmunity (CID-G/A); the heterozygote had an unspecified immunodeficiency. Control data are unavailable for this variant, which is reported at a frequency of 0.00008 in the European (non-Finnish) population of the Exome Aggregation Consortium. The p.Lys86ValfsTer33 variant protein was found to have approximately three percent of wild type RAG1 recombinase activity when analyzed in pro-B cells that were deficient for wild type RAG1 (Abraham et al. 2013; Buchbinder et al. 2015; Brauer et al. 2016). Based on the evidence and potential impact of frameshift variants, the p.Lys86ValfsTer33 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.
Blueprint Genetics RCV000725574 SCV000927916 pathogenic not provided 2018-09-05 criteria provided, single submitter clinical testing

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