ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.2410G>C (p.Ala804Pro) (rs761109477)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000469403 SCV000542000 uncertain significance Neurofibromatosis, type 1 2019-11-23 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 804 of the NF1 protein (p.Ala804Pro). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and proline. 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 conditions. ClinVar contains an entry for this variant (Variation ID: 404441). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Ambry Genetics RCV000562880 SCV000663200 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-14 criteria provided, single submitter clinical testing Insufficient evidence
GeneDx RCV000681141 SCV000808599 uncertain significance not provided 2018-03-12 criteria provided, single submitter clinical testing This variant is denoted NF1 c.2410G>C at the cDNA level, p.Ala804Pro (A804P) at the protein level, and results in the change of an Alanine to a Proline (GCT>CCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. NF1 Ala804Pro was observed at an allele frequency of 0.0009% (1/109362) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the GTPase activating protein domain (Luo 2014). While protein-based in silico analysis supports that this variant does not alter protein structure/function, multiple splicing models predict that this variant may destroy the nearby natural splice site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether NF1 Ala804Pro is a pathogenic or benign variant. We consider it to be 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.