ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.1721+3A>G (rs1057518904)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000414938 SCV000492873 pathogenic Multiple cafe-au-lait spots; Neurofibromas 2014-12-01 criteria provided, single submitter clinical testing
Invitae RCV000457496 SCV000542219 pathogenic Neurofibromatosis, type 1 2019-12-16 criteria provided, single submitter clinical testing This sequence change falls in intron 15 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 reported in the literature in many individuals affected with neurofibromatosis, type 1 (PMID: 7981679, 15146469, 16944272, 18546366, 23404336, 26478990). This variant is also referred to as c.1720+3A>G in the literature. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this intronic change causes a splicing error leading to skipping of exon 15 (exon 11 in the literature) from the NF-1 mRNA and results in a translational frameshift and premature stop codon (PMID: 7981679). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000492226 SCV000581237 pathogenic Hereditary cancer-predisposing syndrome 2015-04-06 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626641 SCV000747343 pathogenic Multiple cafe-au-lait spots; Optic nerve glioma 2017-01-01 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000992429 SCV001144735 pathogenic not provided 2019-08-06 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality (0/263140 chr). Variant has been found in 6 or more unrelated symptomatic patients, while absent in large general pop studies. Predicted to negatively affect a known splice site. Damaging to protein function(s) relevant to disease mechanism. Inconclusive segregation with disease.

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