ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.6858+3A>G (rs1085307885)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489844 SCV000577589 uncertain significance not provided 2016-11-07 criteria provided, single submitter clinical testing The c.6858+3 A>G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In-silico splice prediction models predict that c.6858+3 A>G destroys the natural splice donor site of intron 45, which may lead to abnormal gene splicing; however, in the absence of RNA/functional studies, the actual effect of this sequence change is unknown. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000528456 SCV000628741 likely pathogenic Neurofibromatosis, type 1 2017-06-05 criteria provided, single submitter clinical testing This sequence change falls in intron 45 of the NF1 gene. It does not directly change the encoded amino acid sequence of the NF1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been shown to segregate with neurofibromatosis type 1 (NF1) in a single family (Invitae). This variant has been also observed in an individual with NF1 in the Leiden Open-source Variation Database (PMID: 23656349). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. 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.
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000722026 SCV000853202 likely pathogenic Pre-B-cell acute lymphoblastic leukemia 2016-08-08 criteria provided, single submitter clinical testing

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