Submissions for variant NM_001042492.3(NF1):c.586+1G>A

dbSNP: rs1555607126

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659963	SCV000781875	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Invitae	RCV000659963	SCV001392609	pathogenic	Neurofibromatosis, type 1	2023-06-22	criteria provided, single submitter	clinical testing	Disruption of this splice site has been observed in individuals with neurofibromatosis type 1 (PMID: 10712197, 17311297). ClinVar contains an entry for this variant (Variation ID: 547567). 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. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 5 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).
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000659963	SCV001479243	pathogenic	Neurofibromatosis, type 1	2020-10-26	criteria provided, single submitter	clinical testing
GeneDx	RCV001561578	SCV001784205	pathogenic	not provided	2021-06-11	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 (Lek 2016); This variant is associated with the following publications: (PMID: 30098238, 27535533, 23399325, 10712197)
3billion	RCV000659963	SCV002520956	pathogenic	Neurofibromatosis, type 1	2022-05-22	criteria provided, single submitter	clinical testing	Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. It is not observed in the gnomAD v2.1.1 dataset. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000547567). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genome-Nilou Lab	RCV000659963	SCV002561586	pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002352073	SCV002650282	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2021-08-20	criteria provided, single submitter	clinical testing	The c.586+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 5 of the NF1 gene. This mutation has been reported in individuals with neurofibromatosis type 1 (Fahsold R et al. Am J Hum Genet 2000 Mar;66(3):790-818; Sabbagh A et al. Hum Mutat 2013 Nov;34(11):1510-8). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.