ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.1553C>T (p.Thr518Ile) (rs587782696)

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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 RCV000132136 SCV000187207 uncertain significance Hereditary cancer-predisposing syndrome 2015-02-05 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;In silico models in agreement (benign);Rarity in general population databases (dbsnp, esp, 1000 genomes)
GeneDx RCV000681295 SCV000808757 uncertain significance not provided 2018-05-18 criteria provided, single submitter clinical testing This variant is denoted NF1 c.1553C>T at the cDNA level, p.Thr518Ile (T518I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACC>ATC). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. NF1 Thr518Ile was observed at an allele frequency of 0.0033% (1/30666) in individuals of South Asian ancestry 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 Thr518Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000693666 SCV000821544 uncertain significance Neurofibromatosis, type 1 2019-12-18 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 518 of the NF1 protein (p.Thr518Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs587782696, ExAC 0.002%). This variant has not been reported in the literature in individuals with NF1-related disease. ClinVar contains an entry for this variant (Variation ID: 142755). 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 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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