ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.2191C>T (p.Leu731Phe) (rs185204667)

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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 RCV000165395 SCV000216122 likely benign Hereditary cancer-predisposing syndrome 2014-08-09 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;In silico models in agreement (benign);Other strong data supporting benign classification
Invitae RCV000460161 SCV000542125 uncertain significance Neurofibromatosis, type 1 2019-10-06 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 731 of the NF1 protein (p.Leu731Phe). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs185204667, ExAC 0.08%). This variant has not been reported in the literature in individuals with NF1-related disease. ClinVar contains an entry for this variant (Variation ID: 185893). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The phenylalanine 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.
PreventionGenetics,PreventionGenetics RCV000679379 SCV000806264 uncertain significance not provided 2017-10-13 criteria provided, single submitter clinical testing
GeneDx RCV000679379 SCV000808521 uncertain significance not provided 2017-12-14 criteria provided, single submitter clinical testing This variant is denoted NF1 c.2191C>T at the cDNA level, p.Leu731Phe (L731F) at the protein level, and results in the change of a Leucine to a Phenylalanine (CTC>TTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. NF1 Leu731Phe was not observed at a significant allele frequency in large population cohorts (Lek 2016). NF1 Leu731Phe is located in the GTPase activating protein domain (Luo 2014). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether NF1 Leu731Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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