ClinVar Miner

Submissions for variant NM_000536.4(RAG2):c.1491_1506A[6]GCCTCCAATGGGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTAGGGAGGCCGAGGCGGGTGGATCATGAGGTCAGGNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAAAAAGCCTCCAATG[1] (p.Lys503delinsGlyArgAlaArgTrpLeuThrProValIleProAlaLeuArgGluAlaGluAlaGlyGlySerTer)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002835369 SCV003223220 pathogenic Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2022-07-18 criteria provided, single submitter clinical testing This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 2 of the RAG2 gene (c.1506_1507ins?), causing a frameshift at codon 503 (p.Lys503fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RAG2-related conditions. For these reasons, this variant has been classified as Pathogenic. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018) and loss-of-function variants in RAG2 are known to be pathogenic (PMID: 2618670, 21184155).

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