ClinVar Miner

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

dbSNP: rs1428885377
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000559176 SCV000628489 likely pathogenic Neurofibromatosis, type 1 2019-11-14 criteria provided, single submitter clinical testing This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 23 of the NF1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant has been observed in individual(s) with definite or suspected NF1 (PMID: 24789688). ClinVar contains an entry for this variant (Variation ID: 457623). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Donor and acceptor splice site variants 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies.
GeneDx RCV000680819 SCV000808266 likely pathogenic not provided 2023-03-28 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.; Not observed at significant frequency in large population cohorts (gnomAD); Deletions involving coding exons of this gene are a known mechanism of disease (HGMD; other references); Also known as IVS18-2A>G; This variant is associated with the following publications: (PMID: 24789688, 10712197, 16199547, 23913538, 2121369, 25486365, Ognibene2023)
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

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