ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.1845+1_1845+5del

dbSNP: rs1135402822
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000497051 SCV001207031 pathogenic Neurofibromatosis, type 1 2024-07-01 criteria provided, single submitter clinical testing This sequence change affects a splice site in intron 16 of the NF1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with neurofibromatosis type 1 (PMID: 9195229, 10712197, 11292340). ClinVar contains an entry for this variant (Variation ID: 431598). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Juno Genomics, Hangzhou Juno Genomics, Inc RCV000497051 SCV005415678 pathogenic Neurofibromatosis, type 1 criteria provided, single submitter clinical testing PM2_Supporting+PVS1+PS4_Supporting
Ambry Genetics RCV004992277 SCV005454573 pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2024-08-07 criteria provided, single submitter clinical testing The c.1845+1_1845+5delGTAAG intronic variant, located in intron 16 of the NF1 gene, results from a deletion of 5 nucleotides within intron 16 of the NF1 gene. This variant was reported in multiple individuals with features consistent with neurofibromatosis type 1 (Fahsold R et al. Am J Hum Genet, 2000 Mar;66:790-818; von Stedingk K et al. Sci Rep, 2021 Mar;11:5307; Ambry internal data). Other alterations impacting the same donor site (c.1845+1G>A and c.1845+1G>T) have been detected in multiple individuals with neurofibromatosis type 1 (Abernathy CR et al. Hum Mutat, 1997;9:548-54; Fang LJ et al. J Mol Biol, 2001 Apr;307:1261-70; Chai P et al. BMC Med Genet, 2019 Sep;20:158). c.1845+1_1845+5delGTAAG is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Medical Genetics, University of Parma RCV000497051 SCV000588735 likely pathogenic Neurofibromatosis, type 1 2017-02-02 no assertion criteria provided clinical testing

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