ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.746T>C (p.Leu249Pro) (rs1567826623)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000757562 SCV000885848 uncertain significance not provided 2018-01-02 criteria provided, single submitter clinical testing The NF1 c.746T>C; p.Leu249Pro variant is reported in the medical literature in an individual with some features of neurofibromatosis type I, but did not meet diagnostic criteria (Zhang 2015). The variant is not listed in the ClinVar database, in the dbSNP variant database, or in the population-based databases (Exome Variant Server, Genome Aggregation Database). The leucine at this position is highly conserved across species and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. Considering available information, there is insufficient evidence to classify this variant with certainty. References: Zhang J et al. Molecular Characterization of NF1 and Neurofibromatosis Type 1 Genotype-Phenotype Correlations in a Chinese Population. Sci Rep. 2015 Jun 9;5:11291.
Invitae RCV000806391 SCV000946386 uncertain significance Neurofibromatosis, type 1 2018-09-17 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 249 of the NF1 protein (p.Leu249Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with clinical features of neurofibromatosis type 1 (PMID: 26056819). 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: "Possibly 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.
Ambry Genetics RCV001026474 SCV001188864 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-22 criteria provided, single submitter clinical testing Insufficient evidence

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