ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.3974G>C (p.Arg1325Thr) (rs863224447)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000199605 SCV000253692 likely pathogenic Neurofibromatosis, type 1 2015-05-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with threonine at codon 1325 of the NF1 protein (p.Arg1325Thr). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and threonine. It also falls at the last nucleotide of exon 29 of the NF1 mRNA, a highly conserved nucleotide near the donor splice site. This variant has been reported in the literature and is not present in population databases. This variant was reported in an individual affected with neurofibromatosis type 1 (PMID: 25074460). Segregation studies have not been reported for this variant. Another sequence change at the same nucleotide position (c.3974G>A) has been observed in an individual affected with neurofibromatosis type 1 and was reported to disrupt mRNA splicing (PMID: 17311297). Algorithms developed to predict the effect of nucleotide changes on mRNA splicing suggest that this intronic variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this is a rare sequence change previously observed in an individual affected with neurofibromatosis type 1. Based on the location within the NF1 gene, in silico predictive algorithms, and a similar sequence change reported to disrupt splicing, it is expected to result in altered mRNA splicing. However, disruption of mRNA splicing has not been demonstrated by experimental studies and segregation studies have not been reported for this variant. For these reasons, this variant has been classified as Likely Pathogenic.

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