ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.1661A>G (p.Gln554Arg) (rs863224656)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000199877 SCV000254482 uncertain significance Neurofibromatosis, type 1 2018-10-24 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 554 of the NF1 protein (p.Gln554Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with NF1-related disease. ClinVar contains an entry for this variant (Variation ID: 216395). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 RCV000221342 SCV000278767 uncertain significance Hereditary cancer-predisposing syndrome 2015-10-13 criteria provided, single submitter clinical testing In silico models in agreement (benign);Insufficient or conflicting evidence
GeneDx RCV000681098 SCV000808554 uncertain significance not provided 2018-01-31 criteria provided, single submitter clinical testing This variant is denoted NF1 c.1661A>G at the cDNA level, p.Gln554Arg (Q554R) at the protein level, and results in the change of a Glutamine to an Arginine (CAG>CGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. NF1 Gln554Arg was not observed 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 Gln554Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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