ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.6472C>T (p.Arg2158Cys) (rs878853908)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000568419 SCV000670288 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000681208 SCV000808667 uncertain significance not provided 2018-04-16 criteria provided, single submitter clinical testing This variant is denoted NF1 c.6472C>T at the cDNA level, p.Arg2158Cys (R2158C) 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 pathogenic or benign. NF1 Arg2158Cys was observed at an allele frequency of 0.003% (1/30,782) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether NF1 Arg2158Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Gharavi Laboratory,Columbia University RCV000681208 SCV000920694 uncertain significance not provided 2018-09-16 no assertion criteria provided research
Invitae RCV000230895 SCV000284496 uncertain significance Neurofibromatosis, type 1 2018-10-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 2158 of the NF1 protein (p.Arg2158Cys). 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 NF1-related disease. ClinVar contains an entry for this variant (Variation ID: 237586). 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: "Tolerated"; 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.

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