ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.4463G>A (p.Arg1488His) (rs546073780)

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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 RCV000129797 SCV000184606 uncertain significance Hereditary cancer-predisposing syndrome 2016-02-05 criteria provided, single submitter clinical testing Insufficient or Conflicting Evidence;in silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Invitae RCV000205307 SCV000260956 uncertain significance Neurofibromatosis, type 1 2019-12-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1488 of the NF1 protein (p.Arg1488His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs546073780, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with NF1-related disease. ClinVar contains an entry for this variant (Variation ID: 141323). 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"). 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.
GeneDx RCV000680997 SCV000808446 uncertain significance not provided 2018-02-05 criteria provided, single submitter clinical testing This variant is denoted NF1 c.4463G>A at the cDNA level, p.Arg1488His (R1488H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). 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 hematologic and brain cancers (Kalender 2012, Zacher 2016). NF1 Arg1488His was observed at an allele frequency of 0.02% (5/25740) in individuals of non-Finnish European ancestry in large population cohorts (Lek 2016). Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. NF1 Arg1488His is located in the GTPase activating protein domain (Thomas 2012). In silico analysis, which includes protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether NF1 Arg1488His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Athena Diagnostics Inc RCV000680997 SCV000842890 uncertain significance not provided 2017-10-09 criteria provided, single submitter clinical testing

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