ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.4382T>C (p.Ile1461Thr) (rs746994734)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000232352 SCV000284462 uncertain significance Neurofibromatosis, type 1 2018-11-15 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 1461 of the NF1 protein (p.Ile1461Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs746994734, ExAC 0.03%). This variant has not been reported in the literature in individuals with NF1-related disease. ClinVar contains an entry for this variant (Variation ID: 237567). 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: "Probably 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.
Ambry Genetics RCV000561738 SCV000662917 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000681209 SCV000808668 uncertain significance not provided 2018-04-16 criteria provided, single submitter clinical testing This variant is denoted NF1 c.4382T>C at the cDNA level, p.Ile1461Thr (I1461T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATA>ACA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. NF1 Ile1461Thr was observed at an allele frequency of 0.02% (4/18858) in individuals of East Asian ancestry in large population cohorts (Lek 2016). This variant is located in the GTPase activating protein domain (Thomas 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether NF1 Ile1461Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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