Submissions for variant NM_001042492.3(NF1):c.2990+1G>A

dbSNP: rs1135402836

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000497054	SCV000829850	pathogenic	Neurofibromatosis, type 1	2024-12-11	criteria provided, single submitter	clinical testing	This sequence change affects a donor 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 (PMID: 17311297; internal data). ClinVar contains an entry for this variant (Variation ID: 431613). 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.
GeneDx	RCV002289682	SCV002578407	likely pathogenic	not provided	2022-04-06	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as IVS17+1G>A; This variant is associated with the following publications: (PMID: 17311297)
Ambry Genetics	RCV002438206	SCV002746907	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2021-08-20	criteria provided, single submitter	clinical testing	The c.2990+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 22 of the NF1 gene. The mutation has been identified in individuals with a clinical diagnosis or suspicion of neurofibromatosis type 1 (Wimmer K et al. Hum Mutat, 2007 Jun;28:599-612; Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing (Wimmer K et al. Hum Mutat, 2007 Jun;28:599-612; Ambry internal data). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002289682	SCV005624554	likely pathogenic	not provided	2024-11-03	criteria provided, single submitter	clinical testing	The NF1 c.2990+1G>A variant disrupts a canonical splice-donor site and is predicted to interfere with normal NF1 mRNA splicing. This variant has been reported in the published literature in individuals affected with neurofibromatosis type 1 (PMIDs: 23913538 (2013), 17311297 (2007)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as likely pathogenic.
Medical Genetics, University of Parma	RCV000497054	SCV000588752	likely pathogenic	Neurofibromatosis, type 1	2017-02-02	no assertion criteria provided	clinical testing