ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.6302C>T (p.Thr2101Ile) (rs878853907)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000234347 SCV000284494 uncertain significance Neurofibromatosis, type 1 2019-09-23 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 2101 of the NF1 protein (p.Thr2101Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with an NF1-related disease. ClinVar contains an entry for this variant (Variation ID: 237585). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on NF1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000568056 SCV000670368 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-02 criteria provided, single submitter clinical testing Insufficient evidence
Integrated Genetics/Laboratory Corporation of America RCV000780543 SCV000917889 uncertain significance not specified 2018-04-23 criteria provided, single submitter clinical testing Variant summary: NF1 c.6302C>T (p.Thr2101Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 246036 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.6302C>T in individuals affected with Neurofibromatosis Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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