Submissions for variant NM_001042492.3(NF1):c.2991-1G>A

dbSNP: rs1060500273

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000458745	SCV000542030	pathogenic	Neurofibromatosis, type 1	2023-09-27	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 22 of the NF1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with neurofibromatosis type 1 (NF1) and/or neurofibromatosis-Noonan syndrome (PMID: 8829638, 10712197, 24357598). ClinVar contains an entry for this variant (Variation ID: 404458). Studies have shown that disruption of this splice site is associated with altered splicing resulting in an unknown protein product (PMID: 8829638, 10712197). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	RCV000712404	SCV000842887	pathogenic	not provided	2018-05-09	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000712404	SCV001157939	pathogenic	not provided	2020-08-19	criteria provided, single submitter	clinical testing	The NF1 c.2991-1G>A variant has been described in individuals affected with neurofibromatosis type 1 (NF1; Fahsold 2000, Perrin 1996). It is reported as pathogenic in ClinVar (Variation ID: 404458) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant abolishes the canonical splice acceptor site of intron 22, and experimental data demonstrates that this variant causes skipping of exon 23 in the mRNA transcript (Fahsold 2010, Perrin 1996). Skipping of exon 23 would result in the deletion of 41 amino acid residues, leaving the rest of the protein in-frame. Additionally, other variants at this nucleotide position (c.2991-1G>C, c.2991-1G>T) have been described in individuals with NF1 and are considered pathogenic (Fahsold 2010, Sabbagh 2013). Based on available information, the c.2991-1G>A variant is considered pathogenic. REFERENCES Fahsold R et al. Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain. Am J Hum Genet. 2000 Mar;66(3):790-818. Perrin G et al. Two novel mutations affecting mRNA splicing of the neurofibromatosis type 1 (NF1) gene. Hum Mutat. 1996;7(2):172-5. Sabbagh A et al. NF1 molecular characterization and neurofibromatosis type I genotype-phenotype correlation: the French experience. Hum Mutat. 2013 Nov;34(11):1510-8.
GeneDx	RCV000712404	SCV001788010	pathogenic	not provided	2024-08-27	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); This variant is associated with the following publications: (PMID: 25525159, 10712197, 24357598, 18546366, 8829638, 23913538, 25486365, 2121369, 34860164, 34944956, 34646065, 37149759)
Genome-Nilou Lab	RCV000458745	SCV002561820	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002436386	SCV002751469	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-04-29	criteria provided, single submitter	clinical testing	The c.2991-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 23 of the NF1 gene. This alteration has been observed in multiple individuals with a diagnosis or clinical suspicion of neurofibromatosis type 1 and has been reported to cause abnormal splicing (Ekvall S et al. Am J Med Genet A, 2014 Mar;164A:579-87; Fahsold R et al. Am J Hum Genet, 2000 Mar;66:790-818; Perrin G et al. Hum Mutat, 1996;7:172-5; Pros E et al. Hum Mutat, 2008 Sep;29:E173-93). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Hauer Lab, Department Of Pediatric Oncology, Technical University Munich	RCV003446064	SCV004174255	pathogenic	Hereditary cancer-predisposing syndrome		criteria provided, single submitter	research	ACMG/AMP, PVS1, PM2, PP5
Baylor Genetics	RCV003463846	SCV004199004	pathogenic	Juvenile myelomonocytic leukemia	2021-12-06	criteria provided, single submitter	clinical testing