ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.2023G>A (p.Gly675Arg) (rs779546178)

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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 RCV000213385 SCV000274219 uncertain significance Hereditary cancer-predisposing syndrome 2015-09-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (benign)
GeneDx RCV000681229 SCV000808691 uncertain significance not provided 2018-04-26 criteria provided, single submitter clinical testing This variant is denoted NF1 c.2023G>A at the cDNA level, p.Gly675Arg (G675R) at the protein level, and results in the change of a Glycine to an Arginine (GGA>AGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. NF1 Gly675Arg was observed at an allele frequency of 0.04% (7/18840) in individuals of East Asian 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 that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether NF1 Gly675Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000559747 SCV000628403 uncertain significance Neurofibromatosis, type 1 2018-06-01 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 675 of the NF1 protein (p.Gly675Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 230614). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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