Submissions for variant NM_001042492.3(NF1):c.2991-2A>C

dbSNP: rs1555614495

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000660025	SCV000781969	likely pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
GeneDx	RCV002282296	SCV002571334	pathogenic	not provided	2022-03-10	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame deletion of the adjacent exon; Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
Invitae	RCV000660025	SCV004408295	pathogenic	Neurofibromatosis, type 1	2022-12-21	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 22 of the NF1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. Disruption of this splice site has been observed in individual(s) with neurofibromatosis type 1 (PMID: 10543400, 10712197, 29673180). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the NF1 protein in which other variant(s) (p.Arg1000Pro) have been determined to be pathogenic (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. Studies have shown that disruption of this splice site results in skipping of exon 23, but is expected to preserve the integrity of the reading-frame (Invitae). ClinVar contains an entry for this variant (Variation ID: 547620).