Submissions for variant NM_001042492.3(NF1):c.7146_7147insTTTTTTTTTTNNNNNNNNNNGGGGTTACACCGAGGTCTCGATCTCCTGACCTCGAGATCCGCACGCCTCGGCCTCCCAAAGAGCTGTGATTAAAGGCGTGAGCCACAGCGACCGGCCGGACTCAATTTC (p.Asn2383delinsPhePhePheXaaXaaXaaXaaGlyLeuHisArgGlyLeuAspLeuLeuThrSerArgSerAlaArgLeuGlyLeuProLysSerCysAspTer)

dbSNP: rs2151565142

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001385893	SCV001585909	pathogenic	Neurofibromatosis, type 1	2018-09-24	criteria provided, single submitter	clinical testing	This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 47 of the NF1 gene (c.7083_7084insAlu), causing a frameshift at codon p.Phe2361 (p.Phe2361fs). 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). 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 NF1 are known to be pathogenic (PMID: 10712197, 23913538). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with NF1-related disease.