ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.1769T>C (p.Met590Thr) (rs761559887)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000464426 SCV000542034 uncertain significance Neurofibromatosis, type 1 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 590 of the NF1 protein (p.Met590Thr). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is present in population databases (rs761559887, 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: 404460). 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.
Integrated Genetics/Laboratory Corporation of America RCV000780546 SCV000917892 uncertain significance not specified 2018-05-18 criteria provided, single submitter clinical testing Variant summary: NF1 c.1769T>C (p.Met590Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 276896 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in NF1 causing Neurofibromatosis Type 1 (1.1e-05 vs 0.00021), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1769T>C in individuals affected with Neurofibromatosis Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics RCV001013086 SCV001173625 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-22 criteria provided, single submitter clinical testing Insufficient evidence

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