ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.7421C>T (p.Ser2474Phe) (rs757245615)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164602 SCV000215262 uncertain significance Hereditary cancer-predisposing syndrome 2015-07-02 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)
Invitae RCV000465877 SCV000542223 uncertain significance Neurofibromatosis, type 1 2018-11-16 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 2474 of the NF1 protein (p.Ser2474Phe). The serine residue is highly conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is present in population databases (rs757245615, ExAC 0.006%). This variant has not been reported in the literature in individuals with NF1-related disease. 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, 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 RCV000681280 SCV000808742 uncertain significance not provided 2018-05-08 criteria provided, single submitter clinical testing This variant is denoted NF1 c.7421C>T at the cDNA level, p.Ser2474Phe (S2474F) at the protein level, and results in the change of a Serine to a Phenylalanine (TCC>TTC). This variant has not, to our knowledge, been published in the literature as a germline pathogenic or benign variant. NF1 Ser2474Phe was observed at an allele frequency of 0.007% (2/30,780) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is located in the C-terminal domain (Luo 2014). 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 Ser2474Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Mendelics RCV000465877 SCV000839162 uncertain significance Neurofibromatosis, type 1 2018-07-02 criteria provided, single submitter clinical testing

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