ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.2325+2T>C

dbSNP: rs1567847972
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000680815 SCV000808262 pathogenic not provided 2018-05-17 criteria provided, single submitter clinical testing This variant is denoted NF1 c.2325+2T>C or IVS19+2T>C and consists of a T>C nucleotide substitution at the +2 position of intron 19 of the NF1 gene. Splicing assays have demonstrated that this variant, also defined as NF1 IVS14+2T>C using alternate exon/intron numbering, results in skipping of exon 19, reported as exon 14 (Origone 2003). This disruption would be predicted to lead to an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. NF1 2325+2T>C has been observed in individuals with features consistent with neurofibromatosis type 1 syndrome (Origone 2003, Sabbagh 2013). Based on currently available evidence, we consider this variant to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV000809142 SCV000949283 pathogenic Neurofibromatosis, type 1 2022-06-15 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 561504). This sequence change affects a donor splice site in intron 19 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: 12687660, 23758643; Invitae). 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.
Genome-Nilou Lab RCV000809142 SCV002561745 pathogenic Neurofibromatosis, type 1 2022-03-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000680815 SCV005624683 pathogenic not provided 2024-08-21 criteria provided, single submitter clinical testing The NF1 c.2325+2T>C variant disrupts a canonical splice-donor site and interferes with normal NF1 mRNA splicing. This variant has been reported in the published literature in an individual with neurofibromatosis 1 (PMID: 12687660 (2003)). Functional studies demonstrated that this variant disrupted mRNA splicing (PMID: 12687660 (2003)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.

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