ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.5419C>T (p.Arg1807Trp) (rs1555533609)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000565224 SCV000674071 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-29 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000632461 SCV000753646 uncertain significance Neurofibromatosis, type 1 2019-11-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1807 of the NF1 protein (p.Arg1807Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with neurofibromatosis 1 (NF1) (PMID: 21362601). This variant is also known as c.5482 C>T (p.Arg1828Trp) in the literature. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx RCV000680830 SCV000808278 uncertain significance not provided 2018-07-31 criteria provided, single submitter clinical testing The R1807W variant in the NF1 gene has been reported previously in association with neurofibromatosis type 1 (Stenson et al., 2014; Polgar et al., 2011). However, additional clinical information was not available for review. The R1807W variant is not observed in large population cohorts (Lek et al., 2016). The R1807W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in nearby residues (R1809C, R1809L, L1812P) have been reported in association with NF1 in the Human Gene Mutation Database (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret R1807W as a variant of uncertain significance.

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