ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.7333A>G (p.Ile2445Val) (rs748027595)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000575889 SCV000666660 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Fulgent Genetics,Fulgent Genetics RCV000764116 SCV000895084 uncertain significance Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000681161 SCV000808619 uncertain significance not provided 2018-03-14 criteria provided, single submitter clinical testing This variant is denoted NF1 c.7333A>G at the cDNA level, p.Ile2445Val (I2445V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. NF1 Ile2445Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the C-terminal domain (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 Ile2445Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000200710 SCV000254511 uncertain significance Neurofibromatosis, type 1 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 2445 of the NF1 protein (p.Ile2445Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs748027595, ExAC 0.003%). This variant has not been reported in the literature in individuals with a NF1-related disease. ClinVar contains an entry for this variant (Variation ID: 216411). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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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