ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.4333-2del

dbSNP: rs886041630
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000390451 SCV000330330 pathogenic not provided 2016-03-11 criteria provided, single submitter clinical testing The c.4270-2delA pathogenic variant in the NF1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.4270-2delA variant results in the deletion of a nucleotide at the intron 31/exon 32 boundary, which destroys the canonical splice acceptor site in intron 31. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.4270-2delA variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.4270-2delA as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp RCV005090331 SCV005736127 likely pathogenic Neurofibromatosis, type 1 2024-02-01 criteria provided, single submitter clinical testing This sequence change affects a splice site in intron 31 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). This variant has not been reported in the literature in individuals affected with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 280419). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.

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