ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.4750A>G (p.Ile1584Val) (rs199474766)

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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 RCV000213560 SCV000275324 uncertain significance Hereditary cancer-predisposing syndrome 2015-04-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence,In silico models in agreement (benign)
GeneDx RCV000059207 SCV000808272 uncertain significance not provided 2018-04-20 criteria provided, single submitter clinical testing This variant is denoted NF1 c.4750A>G at the cDNA level, p.Ile1584Val (I1584V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). This variant was observed in an individual with neurofibromatosis type 1 (Fahsold 2000). Functional assays showed this variant to be similar to wildtype with respect to protein expression, stability, and folding, but it was also shown to result in reduced lipid binding activity (Welti 2011). NF1 Ile1584Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. 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 Ile1584Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Gharavi Laboratory,Columbia University RCV000059207 SCV000920693 uncertain significance not provided 2018-09-16 criteria provided, single submitter research
Invitae RCV000457745 SCV000541973 uncertain significance Neurofibromatosis, type 1 2018-10-04 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 1584 of the NF1 protein (p.Ile1584Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (rs199474766, ExAC no frequency). This variant has been reported in an individual affected with neurofibromatosis type 1 (PMID: 10712197). ClinVar contains an entry for this variant (Variation ID: 68354) An experimental study has shown that this variant does not reduce the amount of NF1 protein that is expressed in cells. Furthermore, the structure and folding of the NF1 protein with this variant is comparable to that of wild-type NF1 (PMID: 21089070). 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 RCV000059207 SCV000090736 not provided not provided no assertion provided not provided

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