ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.7552+1G>T (rs1555536380)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000579308 SCV000681219 pathogenic not provided 2017-12-08 criteria provided, single submitter clinical testing The c.7552+1G>T variant in the NF1 gene has not, to our knowledge, been published in the literature. However, a different nucleotide change at the same splice position (c.7552+1G>A) has been reported in association with neurofibromatosis type 1 (Griffiths et al., 2007). This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. The c.7552+1G>T variant is not observed in large population cohorts (Lek et al., 2016). Based on the current evidence, we consider this variant to be pathogenic.
Invitae RCV000793470 SCV000932822 likely pathogenic Neurofibromatosis, type 1 2018-07-24 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 50 of the NF1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with NF1-related disease. ClinVar contains an entry for this variant (Variation ID: 489226). A different variant (c.7552+1G>A) affecting the same donor splice site has been reported in an individual affected with neurofibromatosis type 1 (NF1) (PMID: 16944272). 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. Donor and acceptor splice site variants 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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