Submissions for variant NM_001042492.3(NF1):c.2325+1G>A

dbSNP: rs1555613933

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000657903	SCV000779668	pathogenic	not provided	2022-02-14	criteria provided, single submitter	clinical testing	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); Also known as IVS14+1G>A; This variant is associated with the following publications: (PMID: 31243023, 17668375, 30694527, 23758643)
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000660011	SCV000781947	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002139	SCV001159994	pathogenic	not specified	2018-09-19	criteria provided, single submitter	clinical testing	The NF1 c.2325+1G>A variant has been described in individuals affected with neurofibromatosis, type 1 (NF1; Nemethova 2013, Sabbagh 2013). It is reported as pathogenic in ClinVar (Variation ID: 546100) 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 donor site of intron 19, and mRNA studies demonstrate skipping of exon 19 (Sabbagh 2013) which results in an out-of-frame protein product. Based on available information, this variant is considered pathogenic. References: Nemethova M et al. Thirty-nine novel neurofibromatosis 1 (NF1) gene mutations identified in Slovak patients. Ann Hum Genet. 2013 Sep;77(5):364-79. 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.
Ambry Genetics	RCV002319076	SCV001176000	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2018-09-22	criteria provided, single submitter	clinical testing	The c.2325+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 19 of the NF1 gene. This mutation was detected in an individual satisfying diagnostic criteria for Neurofibromatosis type 1 (NF1) (Nemethova M et al. Ann. Hum. Genet., 2013 Sep;77:364-79). 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.
Invitae	RCV000660011	SCV001415837	pathogenic	Neurofibromatosis, type 1	2023-02-21	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 19 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 (PMID: 23758643; Invitae). ClinVar contains an entry for this variant (Variation ID: 546100). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000660011	SCV002561744	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000657903	SCV004703532	pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	NF1: PVS1, PM2, PS4:Moderate