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

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	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	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). For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with RAG2-related conditions. This variant is not present in population databases (gnomAD no frequency). 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.