Submissions for variant NM_024782.3(NHEJ1):c.569_570insTTTTTTTTTTTTTTTTTTTTNNNNNNNNNNCTGTCCTCGTGATACGCCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCGCGCCCGGCCGAAAATTCCTTCTT (p.Leu190fs)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001949465	SCV002245613	pathogenic	Cernunnos-XLF deficiency	2021-09-02	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with NHEJ1-related conditions. This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 5 of the NHEJ1 gene (c.569_570ins?), causing a frameshift at codon 190 (p.Leu190Phefs). 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 (ExAC no frequency). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 NHEJ1 are known to be pathogenic (PMID: 16439204, 20597108). For these reasons, this variant has been classified as Pathogenic.