ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.1185+2T>C

dbSNP: rs1555611043
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001043018 SCV001206729 pathogenic Neurofibromatosis, type 1 2019-11-25 criteria provided, single submitter clinical testing This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 10 of the NF1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. Disruption of this splice site has been reported in individuals affected with neurofibromatosis type 1 (PMID: 18546366, 16835897, 10607834, 26056819). For these reasons, this variant has been classified as 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.
Neuberg Centre For Genomic Medicine, NCGM RCV001043018 SCV005438845 likely pathogenic Neurofibromatosis, type 1 2023-07-22 criteria provided, single submitter clinical testing The observed invariant splice donor c.1185+2T>C variant in NF1 gene has not been previously reported as pathogenic variant nor as a benign variant, to our knowledge. Another splice donor variants on same position [c.1185+2T>A; c.1185+1G>A] has been previously reported in individuals affected with Neurofibromatosis Lee et al., 2006; Zhang et al., 2015; Pros et al., 2008; Fahsold et al., 2000; Riva et al., 2022. The c.1185+2T>C variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic. The SpliceAI predicts a score of 0.87 for this variant. Loss of function variants in NF1 gene have been previously reported to be disease causing Fahsold et al., 2000. Additional functional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic.

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