ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.529A>G (p.Ile177Val) (rs766213678)

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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 RCV000218907 SCV000277621 uncertain significance Hereditary cancer-predisposing syndrome 2015-08-08 criteria provided, single submitter clinical testing
Invitae RCV000550459 SCV000628657 uncertain significance Neurofibromatosis, type 1 2017-12-20 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 177 of the NF1 protein (p.Ile177Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs766213678, ExAC 0.002%) but has not been reported in the literature in individuals with a NF1-related disease. ClinVar contains an entry for this variant (Variation ID: 233278). 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.
PreventionGenetics,PreventionGenetics RCV000679399 SCV000806295 uncertain significance not provided 2016-12-16 criteria provided, single submitter clinical testing
GeneDx RCV000679399 SCV000808573 uncertain significance not provided 2018-02-15 criteria provided, single submitter clinical testing This variant is denoted NF1 c.529A>G at the cDNA level, p.Ile177Val (I177V) at the protein level, and results in the change of an Isoleucine to a Valine (ATA>GTA). This variant has not, to our knowledge, been published in the literature as germline variant; however, it has been reported as a somatic variant in a hemangioblastoma (Shankar 2014). NF1 Ile177Val was observed at an allele frequency of 0.003% (3/111,558) in individuals of European (Non-Finnish) ancestry 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 Ile177Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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