ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.8153T>C (p.Ile2718Thr) (rs752541243)

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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 RCV000163527 SCV000214085 uncertain significance Hereditary cancer-predisposing syndrome 2016-02-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000681032 SCV000808485 uncertain significance not provided 2018-07-09 criteria provided, single submitter clinical testing This variant is denoted NF1 c.8153T>C at the cDNA level, p.Ile2718Thr (I2718T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. NF1 Ile2718Thr was observed at an allele frequency of 0.03% (2/6610 alleles) in individuals of Finnish ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. NF1 Ile2718Thr occurs at a position that is conserved across species and is located in the C-terminal domain (Luo 2014) In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether NF1 Ile2718Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000226237 SCV000284523 uncertain significance Neurofibromatosis, type 1 2018-11-05 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 2718 of the NF1 protein (p.Ile2718Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs752541243, 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: 184299). 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: "Deleterious"; 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.

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