ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.467G>T (p.Arg156Leu) (rs754096545)

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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 RCV000216562 SCV000277237 uncertain significance Hereditary cancer-predisposing syndrome 2015-07-16 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Rarity in general population databases (dbsnp, esp, 1000 genomes)
Invitae RCV000632459 SCV000753643 uncertain significance Neurofibromatosis, type 1 2019-08-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 156 of the NF1 protein (p.Arg156Leu). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is present in population databases (rs754096545, ExAC 0.006%). This variant has not been reported in the literature in individuals with NF1-related disease. ClinVar contains an entry for this variant (Variation ID: 232959). 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, 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 RCV000681084 SCV000808538 uncertain significance not provided 2018-01-09 criteria provided, single submitter clinical testing This variant is denoted NF1 c.467G>T at the cDNA level, p.Arg156Leu (R156L) at the protein level, and results in the change of an Arginine to a Leucine (CGC>CTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. NF1 Arg156Leu was observed at an allele frequency of 0.0032% (1/30,780) in individuals of South 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 a deleterious effect. Based on currently available evidence, it is unclear whether NF1 Arg156Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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