Submissions for variant NM_001042492.3(NF1):c.3113+5G>C

dbSNP: rs1555614549

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001977017	SCV002273913	pathogenic	Neurofibromatosis, type 1	2023-11-08	criteria provided, single submitter	clinical testing	This sequence change falls in intron 23 of the NF1 gene. It does not directly change the encoded amino acid sequence of the NF1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of neurofibromatosis type 1 (PMID: 12807981). ClinVar contains an entry for this variant (Variation ID: 1488501). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 23 (also known as exon 18) , but is expected to preserve the integrity of the reading-frame (PMID: 12807981; Invitae). This variant disrupts a region of the NF1 protein in which other variant(s) (p.Met1035Arg) have been determined to be pathogenic (PMID: 8807336; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV003154230	SCV003842894	pathogenic	not provided	2022-09-19	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: aberrant splicing causing skipping of the adjacent in-frame exon 23, which contains a portion of the GTPase activating protein domain (Xu et al., 1990; Ars et al., 2003; Pros et al., 2008; Luo et al., 2014); Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); Also known as IVS18+5G>C; This variant is associated with the following publications: (PMID: 18546366, 12807981, 2121369, 25486365, 17311297, 17576681)
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV001977017	SCV004123073	likely pathogenic	Neurofibromatosis, type 1	2023-07-01	criteria provided, single submitter	research
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV001977017	SCV005417680	likely pathogenic	Neurofibromatosis, type 1		criteria provided, single submitter	clinical testing	PM2_Supporting+PS3+PS4_Supporting+PP4