ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.6727A>T (p.Ile2243Leu) (rs761213794)

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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 RCV000567145 SCV000663169 uncertain significance Hereditary cancer-predisposing syndrome 2016-07-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000681224 SCV000808684 uncertain significance not provided 2018-04-26 criteria provided, single submitter clinical testing This variant is denoted NF1 c.6727A>T at the cDNA level, p.Ile2243Leu (I2243L) at the protein level, and results in the change of an Isoleucine to a Leucine (ATA>TTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. NF1 Ile2243Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. 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 Ile2243Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000474611 SCV000542207 uncertain significance Neurofibromatosis, type 1 2016-05-12 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with leucine at codon 2243 of the NF1 protein (p.Ile2243Leu). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and leucine. This variant is present in population databases (rs761213794, ExAC <0.01%) but has not been reported in the literature in individuals with a NF1-related disease. 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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