ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.6982C>T (p.Arg2328Cys) (rs56013763)

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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 RCV000563550 SCV000663131 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000681044 SCV000808497 uncertain significance not provided 2017-10-02 criteria provided, single submitter clinical testing This variant is denoted NF1 c.6982C>T at the cDNA level, p.Arg2328Cys (R2328C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in Merkel cell carcinoma (Wong 2015). NF1 Arg2328Cys was not observed in large population cohorts (Lek 2016). Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. NF1 Arg2328Cys occurs at a position that is not conserved and is located in the C-terminal domain (Luo 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether NF1 Arg2328Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000469056 SCV000542229 uncertain significance Neurofibromatosis, type 1 2018-12-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 2328 of the NF1 protein (p.Arg2328Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a NF1-related disease. ClinVar contains an entry for this variant (Variation ID: 404609). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on NF1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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