ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.3975-2A>G

dbSNP: rs864622431
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000205081 SCV000260623 pathogenic Neurofibromatosis, type 1 2023-10-08 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 29 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 present in population databases (no rsID available, gnomAD 0.0009%). Disruption of this splice site has been observed in individuals with neurofibromatosis type 1 (PMID: 10712197, 16786508, 18546366). This variant is also known as IVS23.1-2A>G. ClinVar contains an entry for this variant (Variation ID: 220232). 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.
Ambry Genetics RCV002317739 SCV000670491 pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2024-01-25 criteria provided, single submitter clinical testing The c.3975-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 30 in the NF1 gene. This mutation has been reported in multiple individuals with neurofibromatosis type 1 and has been found to cause aberrant mRNA splicing (Upadhyaya M et al. Hum. Genet., 1997 Jan;99:88-92; Fahsold R et al. Am. J. Hum. Genet., 2000 Mar;66:790-818; Griffiths S et al. Fam. Cancer, 2007;6:21-34; Upadhyaya M et al. Hum. Mutat., 2006 Jul;27:716; Pros E et al. Hum. Mutat., 2008 Sep;29:E173-93; Ambry internal data). In addition to the clinical data presented in the literature, 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.
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV000205081 SCV001479210 pathogenic Neurofibromatosis, type 1 2020-10-26 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000205081 SCV002560012 pathogenic Neurofibromatosis, type 1 2022-03-15 criteria provided, single submitter clinical testing
GeneDx RCV003317151 SCV004021680 pathogenic not provided 2023-07-21 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as IVS23.1-2A>G; This variant is associated with the following publications: (PMID: 10712197, 25525159, 9003501, 16786508, 16944272, 18546366, 31776437)

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