ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.3217A>G (p.Met1073Val) (rs199474740)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000571527 SCV000670326 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000059182 SCV000616809 uncertain significance not provided 2017-09-06 criteria provided, single submitter clinical testing This variant is denoted NF1 c.3217A>G at the cDNA level, p.Met1073Val (M1073V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant was observed in 1/91 patients with features suggestive of Neurofibromatosis type 1; however, this individual did not meet NIH diagnostic criteria (Mattocks 2004). NF1 Met1073Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the GTPase activating protein domain (Xu 1990, Luo 2014). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether NF1 Met1073Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Gharavi Laboratory,Columbia University RCV000059182 SCV000920691 uncertain significance not provided 2018-09-16 criteria provided, single submitter research
Invitae RCV000542925 SCV000628502 uncertain significance Neurofibromatosis, type 1 2018-11-16 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 1073 of the NF1 protein (p.Met1073Val). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs199474740, ExAC 0.005%). This variant has been reported in an individual possibly affected with neurofibromatosis type 1 (PMID: 15060124). ClinVar contains an entry for this variant (Variation ID: 68330). 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.
UniProtKB/Swiss-Prot RCV000059182 SCV000090711 not provided not provided no assertion provided not provided

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