Submissions for variant NM_001033855.3(DCLRE1C):c.1489_1490insCACTTTGGGAGGCCGAGGCGGGCGGATCACGAGGTCAGGAGATCGAGACCACGGTGAAACCCCGTCTCTACTAANNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAAAGAAATG (p.Asp497delinsAlaLeuTrpGluAlaGluAlaGlyGlySerArgGlyGlnGluIleGluThrThrValLysProArgLeuTyrTer)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003039812	SCV003343805	pathogenic	Severe combined immunodeficiency due to DCLRE1C deficiency	2022-04-11	criteria provided, single submitter	clinical testing	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 14 of the DCLRE1C gene (c.1489_1490ins?), causing a frameshift at codon 496 (p.Asn496fs). 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 has not been reported in the literature in individuals affected with DCLRE1C-related conditions. 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 DCLRE1C are known to be pathogenic (PMID: 21664875, 26123418). For these reasons, this variant has been classified as Pathogenic.