ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.2002-1G>A (rs1555613743)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Human Genetics, Inc RCV000660002 SCV000781934 pathogenic Neurofibromatosis, type 1 2016-11-01 criteria provided, single submitter clinical testing
GeneDx RCV000578644 SCV000680719 pathogenic not provided 2017-12-27 criteria provided, single submitter clinical testing The c.2002-1G>A splice site variant in the NF1 gene has been previously reported in at least one individual with a clinical diagnosis of neurofibromatosis type 1 (Griffiths et al., 2007). This pathogenic variant destroys the canonical splice acceptor site in intron 17, and is expected to cause abnormal gene splicing. The c.2002-1G>A variant is not observed in large population cohorts (Lek et al., 2016). Based on currently available evidence, we consider c.2002-1G>A to be pathogenic.
Invitae RCV000660002 SCV000827499 likely pathogenic Neurofibromatosis, type 1 2018-03-22 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 17 of the NF1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with neurofibromatosis type 1 (PMID: 16944272). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). 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. 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). 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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