ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.3103A>G (p.Met1035Val) (rs771694969)

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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 RCV000572733 SCV000666711 uncertain significance Hereditary cancer-predisposing syndrome 2016-03-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Insufficient or conflicting evidence
GeneDx RCV000681296 SCV000808758 uncertain significance not provided 2018-05-16 criteria provided, single submitter clinical testing This variant is denoted NF1 c.3103A>G at the cDNA level, p.Met1035Val (M1035V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant was observed in an individual with features of Neurofibromatosis type 1 (Rodenhiser 1997). NF1 Met1035Val was not observed at a significant allele frequency 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 Met1035Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000204972 SCV000260684 uncertain significance Neurofibromatosis, type 1 2018-11-25 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 1035 of the NF1 protein (p.Met1035Val). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs771694969, ExAC 0.02%). This variant has been observed in an individual affected with neurofibromatosis type 1 (PMID: 9042399). ClinVar contains an entry for this variant (Variation ID: 220267). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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