ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.1070T>G (p.Leu357Arg) (rs137854563)

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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 RCV000216480 SCV000276673 likely pathogenic Hereditary cancer-predisposing syndrome 2015-07-02 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Good segregation with disease (lod 1.5-3 = 5-9 meioses);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Rarity in general population databases (dbsnp, esp, 1000 genomes)
GeneDx RCV000487279 SCV000570971 likely pathogenic not provided 2016-07-11 criteria provided, single submitter clinical testing This variant is denoted NF1 c.1070T>G at the cDNA level, p.Leu357Arg (L357R) at the protein level, and results in the change of a Leucine to an Arginine (CTT>CGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. However, another variant at the same residue, NF1 Leu357Pro was reported in a family demonstrating segregation with café-au-lait macules and spinal neurofibromas in four adults and café-au-lait macules in three children (Messiaen 2003), and was also observed in an unrelated individual with a clinical diagnosis of NF1 syndrome (Fahsold 2000). NF1 Leu357Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. NF1 Leu357Arg occurs at a position that is conserved across species and is not located in a known functional domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider NF1 Leu357Arg to be a likely pathogenic variant.
Invitae RCV000808095 SCV000948186 uncertain significance Neurofibromatosis, type 1 2018-12-30 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 357 of the NF1 protein (p.Leu357Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine 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 conditions. ClinVar contains an entry for this variant (Variation ID: 232517). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Leu357 amino acid residue in NF1. Other variant(s) that disrupt this residue have been observed in individuals with NF1-related conditions (PMID: 12566521, 10712197), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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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