ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.2131C>T (p.Arg711Cys) (rs1400902839)

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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 RCV000574194 SCV000663028 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000681115 SCV000808572 uncertain significance not provided 2018-02-14 criteria provided, single submitter clinical testing This variant is denoted NF1 c.2131C>T at the cDNA level, p.Arg711Cys (R711C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). 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 melanoma and prostate tumors (Hovelson 2015, de Unamuno Bustos 2017). NF1 Arg711Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the GTPase activating protein domain (Luo 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether NF1 Arg711Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000541994 SCV000628413 uncertain significance Neurofibromatosis, type 1 2018-04-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 711 of the NF1 protein (p.Arg711Cys). 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: 457565). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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