ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.1662G>T (p.Gln554His) (rs147594815)

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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 RCV000223315 SCV000274751 uncertain significance Hereditary cancer-predisposing syndrome 2015-09-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
GeneDx RCV000681090 SCV000808545 uncertain significance not provided 2018-01-18 criteria provided, single submitter clinical testing This variant is denoted NF1 c.1662G>T at the cDNA level, p.Gln554His (Q554H) at the protein level, and results in the change of a Glutamine to a Histidine (CAG>CAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. NF1 Gln554His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the GTPase activating protein domain (Luo 2014). 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 Gln554His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000230263 SCV000284390 uncertain significance Neurofibromatosis, type 1 2018-10-02 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 554 of the NF1 protein (p.Gln554His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. This variant is present in population databases (rs147594815, ExAC 0.002%). This variant has not been reported in the literature in individuals with a NF1-related disease. ClinVar contains an entry for this variant (Variation ID: 231024). 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: "Probably 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.

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