ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.2990G>A (p.Arg997Lys)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000810271 SCV000950464 likely pathogenic Neurofibromatosis, type 1 2018-08-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 997 of the NF1 protein (p.Arg997Lys). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and lysine. This variant also falls at the last nucleotide of exon 22 of the NF1 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with neurofibromatosis type 1 (PMID: 23913538, 29673180, Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this nucleotide change can result in skipping of exon 22. Exon 22 is also known as exon 17 in the literature (PMID: 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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