ClinVar Miner

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

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
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 Lines of evidence used in support of classification: Insufficient or Conflicting Evidence,in silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Athena Diagnostics Inc RCV000680997 SCV000842890 uncertain significance not provided 2017-10-09 criteria provided, single submitter clinical testing
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.
Invitae RCV000205307 SCV000260956 uncertain significance Neurofibromatosis, type 1 2018-11-21 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.