ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.1549G>A (p.Glu517Lys) (rs587778548)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132222 SCV000187304 uncertain significance Hereditary cancer-predisposing syndrome 2016-01-09 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;In silico models in agreement (benign);Rarity in general population databases (dbsnp, esp, 1000 genomes)
Invitae RCV000195429 SCV000254480 uncertain significance Neurofibromatosis, type 1 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 517 of the NF1 protein (p.Glu517Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs587778548, 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: 134879). 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: "Benign"; 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.
GeneDx RCV000681180 SCV000808638 uncertain significance not provided 2018-04-05 criteria provided, single submitter clinical testing This variant is denoted NF1 c.1549G>A at the cDNA level, p.Glu517Lys (E517K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant was a identified in 1/43 healthy African European individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. NF1 Glu517Lys was observed at an allele frequency of 0.002% (2/111308) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether NF1 Glu517Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000121626 SCV001362234 uncertain significance not specified 2019-03-13 criteria provided, single submitter clinical testing Variant summary: NF1 c.1549G>A (p.Glu517Lys) results in a 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 allele was found at a frequency of 8.2e-06 in 245372 control chromosomes (gnomAD). 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.1549G>A in individuals affected with Neurofibromatosis Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
ITMI RCV000121626 SCV000085824 not provided not specified 2013-09-19 no assertion provided reference population

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