ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.3013A>G (p.Met1005Val) (rs1555614502)

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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 RCV000569679 SCV000666736 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
GeneDx RCV000681104 SCV000808560 uncertain significance not provided 2018-02-02 criteria provided, single submitter clinical testing This variant is denoted NF1 c.3013A>G at the cDNA level, p.Met1005Val (M1005V) 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 Met1005Val was not observed in large population cohorts (Lek 2016). This variant is located in the GTPase activating protein domain (Xu 1990, 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 Met1005Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000817182 SCV000957729 uncertain significance Neurofibromatosis, type 1 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 1005 of the NF1 protein (p.Met1005Val). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 481926). 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 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.

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