ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.2077A>G (p.Met693Val) (rs1555613794)

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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 RCV000575226 SCV000670461 uncertain significance Hereditary cancer-predisposing syndrome 2016-07-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000681177 SCV000808635 uncertain significance not provided 2018-03-22 criteria provided, single submitter clinical testing This variant is denoted NF1 c.2077A>G at the cDNA level, p.Met693Val (M693V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. NF1 Met693Val was not observed in large population cohorts (Lek 2016). This variant is located within the GTPase activating protein 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 Met693Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000549001 SCV000628411 uncertain significance Neurofibromatosis, type 1 2017-03-31 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 693 of the NF1 protein (p.Met693Val). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and valine. This variant is not present in population databases (ExAC no frequency) and 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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