ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.1062+3A>G (rs1057521098)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000583516 SCV000692340 uncertain significance Neurofibromatosis, type 1 2016-06-03 no assertion criteria provided clinical testing
GeneDx RCV000437730 SCV000521059 likely pathogenic not provided 2017-12-19 criteria provided, single submitter clinical testing The c.1062+3 A>G variant has been published previously in association with neurofibromatosis type 1 (Pros et al., 2008). The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Several in-silico splice prediction models predict that c.1062+3 A>G destroys the natural splice donor site of intron 9. Additionally, mRNA studies have suggested that the variant results in skipping of exon 9 (Pros et al., 2008); however, these studies were performed using patient mRNA, and in vitro functional studies have yet to be performed. Therefore, we consider this variant to be likely pathogenic.
Invitae RCV000583516 SCV000948669 pathogenic Neurofibromatosis, type 1 2019-01-09 criteria provided, single submitter clinical testing This sequence change falls in intron 9 of the NF1 gene. It does not directly change the encoded amino acid sequence of the NF1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals with clinical features of neurofibromatosis type 1 (NF1) (PMID: 18546366, Invitae). It has also been shown to segregate with NF1 in families (Invitae). ClinVar contains an entry for this variant (Variation ID: 381606). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 18546366). For these reasons, this variant has been classified as Pathogenic.

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