ClinVar Miner

Submissions for variant NM_000268.4(NF2):c.1340G>T (p.Arg447Met)

dbSNP: rs2066868182
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001054899 SCV001219257 uncertain significance Neurofibromatosis, type 2 2019-05-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with methionine at codon 447 of the NF2 protein (p.Arg447Met). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and methionine. This variant also falls at the last nucleotide of exon 12 of the NF2 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 an individual affected with clinical features of neurofibromatosis type 2 (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). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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