ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.1721+1G>A (rs1131691096)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000549086 SCV000628385 pathogenic Neurofibromatosis, type 1 2019-12-05 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 15 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 the literature in two individuals with a diagnosis or clinical suspicion of neurofibromatosis type 1 (PMID: 18546366, 23913538), and another individual in the Leiden Open-source Variation Database (PMID: 21520333). Two other variants affecting this nucleotide (c.1721+1G>T and c.1721+1G>C) have been observed in individuals affected with NF1 (PMID: 23913538). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. Experimental studies have shown that this change causes exon skipping and a subsequent frameshift, leading to the introduction of a premature stop codon (PMID: 18546366). 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). For these reasons, this variant has been classified as Pathogenic.
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000549086 SCV000840414 pathogenic Neurofibromatosis, type 1 2018-03-05 criteria provided, single submitter clinical testing

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