ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.3906T>G (p.Asp1302Glu) (rs549058591)

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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 RCV000164143 SCV000214759 uncertain significance Hereditary cancer-predisposing syndrome 2015-10-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000681119 SCV000808577 uncertain significance not provided 2018-02-19 criteria provided, single submitter clinical testing This variant is denoted NF1 c.3906T>G at the cDNA level, p.Asp1302Glu (D1302E) at the protein level, and results in the change of an Aspartic Acid to a Glutamic Acid (GAT>GAG). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in a melanoma (Krauthammer 2015). NF1 Asp1302Glu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the GTPase activating protein domain (Thomas 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether NF1 Asp1302Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000542427 SCV000628556 uncertain significance Neurofibromatosis, type 1 2018-08-09 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 1302 of the NF1 protein (p.Asp1302Glu). The aspartic acid residue is weakly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a NF1-related disease. ClinVar contains an entry for this variant (Variation ID: 184818). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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