ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.7457C>T (p.Thr2486Ile) (rs149055633)

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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 RCV000130522 SCV000185391 uncertain significance Hereditary cancer-predisposing syndrome 2015-12-05 criteria provided, single submitter clinical testing 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 RCV000421743 SCV000521069 uncertain significance not provided 2018-04-16 criteria provided, single submitter clinical testing This variant is denoted NF1 c.7457C>T at the cDNA level, p.Thr2486Ile (T2486I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACC>ATC). This variant was observed in at least two individuals with a clinical diagnosis of neurofibromatosis type 1 (Fahsold 2000, Brinckmann 2007). NF1 Thr2486Ile was observed at an allele frequency of 0.01% (14/111,698) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in 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 Thr2486Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000475666 SCV000542110 uncertain significance Neurofibromatosis, type 1 2019-12-29 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 2486 of the NF1 protein (p.Thr2486Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs149055633, ExAC 0.009%). This variant has been reported in individuals affected with neurofibromatosis type 1 (PMID: 10712197), and in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 141844). 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. 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.
PreventionGenetics,PreventionGenetics RCV000421743 SCV000806317 uncertain significance not provided 2017-08-23 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764117 SCV000895085 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

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