ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.695C>T (p.Thr232Ile) (rs769719064)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000632485 SCV000753670 uncertain significance Neurofibromatosis, type 1 2019-12-16 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 232 of the NF1 protein (p.Thr232Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs769719064, ExAC 0.006%). This variant has not been reported in the literature in individuals with NF1-related disease. 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.
GeneDx RCV000681214 SCV000808674 uncertain significance not provided 2018-04-18 criteria provided, single submitter clinical testing This variant is denoted NF1 c.695C>T at the cDNA level, p.Thr232Ile (T232I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACA>ATA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. NF1 Thr232Ile was observed at an allele frequency of 0.003% (1/30,768) 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 a deleterious effect. Based on currently available evidence, it is unclear whether NF1 Thr232Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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