ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.2252-1G>A

dbSNP: rs587781577
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000557861 SCV000628426 pathogenic Neurofibromatosis, type 1 2024-09-17 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 18 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: 12872266; internal data). ClinVar contains an entry for this variant (Variation ID: 457575). 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.
Molecular Genetics, Royal Melbourne Hospital RCV000557861 SCV002503762 pathogenic Neurofibromatosis, type 1 2023-03-30 criteria provided, single submitter clinical testing This sequence change affects the canonical acceptor splice site in intron 18 of NF1. It is expected to disrupt RNA splicing (not confirmed in RNA assays) and likely results in an absent or disrupted protein product. Premature protein termination has been detected for another variant disrupting this splice site (PMID: 12872266). Loss of function is a well-established mechanism of disease for this gene (PVS1; ClinVar). The variant is absent in a large population cohort (PM2; gnomAD v2.1 and v3.0), and has been observed in at least two individuals with a clinical diagnosis of neurofibromatosis type 1 (PS4_Supporting; Royal Melbourne Hospital, Invitae - ClinVar ID: 457575). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM2, PS4_Supporting.
Genome-Nilou Lab RCV000557861 SCV002561736 pathogenic Neurofibromatosis, type 1 2022-03-15 criteria provided, single submitter clinical testing

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