ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.2329T>A (p.Trp777Arg) (rs876658853)

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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 RCV000219741 SCV000274636 likely pathogenic Hereditary cancer-predisposing syndrome 2015-03-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting pathogenic classification,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Well-characterized mutation at same position
GeneDx RCV000414491 SCV000491436 likely pathogenic not provided 2016-02-16 criteria provided, single submitter clinical testing Although this exact nucleotide substitution (c.2329T>A) has not been previously reported in the literature, another nucleotide substitution (c.2329T>C) resulting in the same amino acid substitution (W777R) has been reported in a Chinese Han family with neurofibromatosis type 1 (NF1) (Cai et al., 2005); however, little clinical and segregation information is available in this publication. Additionally, other missense variants at this residue (W777S and W777G), have been reported in the Human Gene Mutation Database in association with neurofibromatosis type 1 (Stenson et al., 2014). The W777R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The W777R 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. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The W777R variant is a strong candidate for a pathogenic variant; however, the possibility it may be a rare benign variant cannot be excluded.
Invitae RCV000541442 SCV000628433 likely pathogenic Neurofibromatosis, type 1 2017-05-04 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 777 of the NF1 protein (p.Trp777Arg). The tryptophan residue is moderately conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is not present in population databases (ExAC no frequency). A different variant (c.2329T>C) giving rise to the same protein effect observed here (p.Trp777Arg) has been reported in an individual affected with neurofibromatosis type 1. This variant was observed to arise de novo in an affected individual (PMID: 27322474), and segregate with disease in another family (PMID: 16005615). These observations indicates that this residue may be critical for protein function. 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"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. However, a different variant that gives rise to the same protein affected has been observed in individuals and families affected with neurofibromatosis type 1. These evidence indicate that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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