ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.8427C>A (p.Phe2809Leu) (rs760550772)

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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 RCV000166910 SCV000217728 uncertain significance Hereditary cancer-predisposing syndrome 2015-07-29 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;In silico models in agreement (benign)
Invitae RCV000232715 SCV000284531 uncertain significance Neurofibromatosis, type 1 2019-11-26 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 2809 of the NF1 protein (p.Phe2809Leu). The phenylalanine residue is moderately conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs760550772, ExAC 0.02%). This variant has not been reported in the literature in individuals with NF1-related disease. ClinVar contains an entry for this variant (Variation ID: 187205). 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.
GeneDx RCV000681318 SCV000808780 uncertain significance not provided 2018-05-31 criteria provided, single submitter clinical testing This variant is denoted NF1 c.8427C>A at the cDNA level, p.Phe2809Leu (F2809L) at the protein level, and results in the change of a Phenylalanine to a Leucine (TTC>TTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. NF1 Phe2809Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the C-terminal domain (Luo 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether NF1 Phe2809Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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