ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.2330G>C (p.Trp777Ser) (rs199474745)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000632274 SCV000753449 likely pathogenic Neurofibromatosis, type 1 2018-12-14 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with serine at codon 777 of the NF1 protein (p.Trp777Ser). The tryptophan residue is moderately conserved and there is a large physicochemical difference between tryptophan and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with neurofibromatosis type 1 (PMID: 10712197, 15146469, 17726231). ClinVar contains an entry for this variant (Variation ID: 68315). 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"). A different missense substitution at this codon (p.Trp777Arg) has been determined to be pathogenic (PMID: 16005615, 27322474). This suggests that the tryptophan residue is critical for NF1 protein function and that other missense substitutions at this position may also be pathogenic. 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.
UniProtKB/Swiss-Prot RCV000059167 SCV000090696 not provided not provided no assertion provided not provided

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