ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.2971A>G (p.Met991Val) (rs1268543864)

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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 RCV000563360 SCV000666669 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-18 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000632519 SCV000753704 uncertain significance Neurofibromatosis, type 1 2019-03-07 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 991 of the NF1 protein (p.Met991Val). 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). This variant has not been reported in the literature in individuals with NF1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx RCV000680875 SCV000808324 uncertain significance not provided 2016-02-08 criteria provided, single submitter clinical testing This variant is denoted NF1 c.2971A>G at the cDNA level, p.Met991Val (M991V) 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 Met991Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Methionine and Valine share similar properties, this is considered a conservative amino acid substitution. NF1 Met991Val occurs at a position that is conserved across species and is not located in a known functional domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether NF1 Met991Val is pathogenic or benign. We consider it to be a variant of uncertain significance.

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