ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.1855A>G (p.Arg619Gly) (rs587781821)

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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 RCV000130098 SCV000184928 uncertain significance Hereditary cancer-predisposing syndrome 2014-02-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000681033 SCV000808486 uncertain significance not provided 2017-06-15 criteria provided, single submitter clinical testing This variant is denoted NF1 c.1855A>G at the cDNA level, p.Arg619Gly (R619G) at the protein level, and results in the change of an Arginine to a Glycine (AGA>GGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. NF1 Arg619Gly was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. NF1 Arg619Gly occurs at a position that is conserved across species and is located within the GTPase activating protein domain (Luo 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether NF1 Arg619Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000471843 SCV000542026 uncertain significance Neurofibromatosis, type 1 2017-08-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 619 of the NF1 protein (p.Arg619Gly). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and glycine. 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: 141531). 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, this variant is a rare missense change with uncertain impact on 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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