ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.2902A>G (p.Met968Val) (rs587781499)

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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 RCV000129472 SCV000184242 uncertain significance Hereditary cancer-predisposing syndrome 2014-01-15 criteria provided, single submitter clinical testing
GeneDx RCV000681213 SCV000808673 uncertain significance not provided 2018-04-20 criteria provided, single submitter clinical testing This variant is denoted NF1 c.2902A>G at the cDNA level, p.Met968Val (M968V) 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 Met968Val was observed at an allele frequency of 0.01% (2/30782) in individuals of South Asian ancestry 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 Met968Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000819721 SCV000960397 uncertain significance Neurofibromatosis, type 1 2018-11-14 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 968 of the NF1 protein (p.Met968Val). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs587781499, ExAC 0.01%). This variant has not been reported in the literature in individuals with NF1-related disease. ClinVar contains an entry for this variant (Variation ID: 141107). 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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