ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.3496+1G>A

dbSNP: rs2067138719
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001864288 SCV002119976 pathogenic Neurofibromatosis, type 1 2021-06-28 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 26 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 (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Disruption of this splice site has been observed in individual(s) with neurofibromatosis type 1 (PMID: 31370276, 10712197, 9544853).
GeneDx RCV002280193 SCV002568678 pathogenic not provided 2022-08-29 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in a null allele, confirmed via RT-PCR and a minigene assay, in a gene for which loss-of-function is a known mechanism of disease (Giugliano et al., 2019; Morbidoni et al., 2021); Not observed in large population cohorts (gnomAD); Also known as IVS20+1G>A; This variant is associated with the following publications: (PMID: 17311297, 31370276, 31766501, 33673681)
Ambry Genetics RCV003164101 SCV003893697 likely pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2022-11-18 criteria provided, single submitter clinical testing The c.3496+1G>A intronic variant results from a G to A substitution one nucleotide(s) after coding exon 26 of the NF1 gene. RNA studies have demonstrated that this alteration results in skipping of exon 26 (Wimmer K et al. Hum Mutat, 2007 Jun;28:599-612). This alteration was identified in an individual with clinical features of neurofibromatosis type 1 (NF1) (Giugliano T et al. Genes (Basel), 2019 07;10:). Another alteration impacting the same donor site (c3496G>A) has been detected in individuals with a clinical diagnosis of NF1 (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 likely pathogenic.

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