ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.4703C>T (p.Thr1568Met) (rs185660700)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000195487 SCV000254503 uncertain significance Neurofibromatosis, type 1 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 1568 of the NF1 protein (p.Thr1568Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs185660700, ExAC 0.01%). This variant has not been reported in the literature in individuals with NF1-related disease. ClinVar contains an entry for this variant (Variation ID: 216405). 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.
Ambry Genetics RCV000213390 SCV000275473 uncertain significance Hereditary cancer-predisposing syndrome 2015-12-10 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
PreventionGenetics,PreventionGenetics RCV000679395 SCV000806286 uncertain significance not provided 2017-05-30 criteria provided, single submitter clinical testing
GeneDx RCV000679395 SCV000808483 uncertain significance not provided 2017-05-09 criteria provided, single submitter clinical testing This variant is denoted NF1 c.4703C>T at the cDNA level, p.Thr1568Met (T1568M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. NF1 Thr1568Met was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Threonine and Methionine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. NF1 Thr1568Met occurs at a position that is conserved across species and is not located in a known functional domain. 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 Thr1568Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Fulgent Genetics,Fulgent Genetics RCV000764113 SCV000895081 uncertain significance Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis 2018-10-31 criteria provided, single submitter clinical testing

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