Submissions for variant NM_001042492.3(NF1):c.3114-2A>G

dbSNP: rs1428885377

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000559176	SCV000628489	pathogenic	Neurofibromatosis, type 1	2025-01-15	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 23 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 individual(s) with clinical features of neurofibromatosis, type 1 (PMID: 24789688, 39001468; internal data). ClinVar contains an entry for this variant (Variation ID: 457623). 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	RCV000680819	SCV000808266	pathogenic	not provided	2024-12-11	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24789688, 10712197, 16199547, 23913538, Ognibene2023, 2121369, 25486365)
Genome-Nilou Lab	RCV000559176	SCV002559930	likely pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002323924	SCV002607320	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2024-02-20	criteria provided, single submitter	clinical testing	The c.3114-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 24 in the NF1 gene. This variant has been reported in individual(s) with a clinical or suspected diagnosis of neurofibromatosis type 1 (Xu W et al. Int J Mol Med, 2014 Jul;34:53-60). RNA studies have demonstrated that this alteration results in skipping of exon 24 (Xu W et al. Int J Mol Med, 2014 Jul;34:53-60; Ambry internal data). 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. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Human Genetics Bochum, Ruhr University Bochum	RCV000559176	SCV002758583	likely pathogenic	Neurofibromatosis, type 1	2022-08-01	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant: PVS1, PM2, PP4
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV003327297	SCV004034114	likely pathogenic	RASopathy	2023-07-01	criteria provided, single submitter	research
NHS Central & South Genomic Laboratory Hub	RCV000559176	SCV005393909	pathogenic	Neurofibromatosis, type 1	2024-11-11	criteria provided, single submitter	clinical testing