ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.7291C>T (p.Arg2431Cys) (rs377662483)

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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 RCV000571589 SCV000666582 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Fulgent Genetics,Fulgent Genetics RCV000764115 SCV000895083 uncertain significance Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000681043 SCV000808496 uncertain significance not provided 2018-05-07 criteria provided, single submitter clinical testing This variant is denoted NF1 c.7291C>T at the cDNA level, p.Arg2431Cys (R2431C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. NF1 Arg2431Cys was observed at an allele frequency of 0.0065%, (1/15,300) in individuals of African ancestry in large population cohorts (Lek 2016). NF1 Arg2431Cys is located in the C-terminal domain (Luo 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether NF1 Arg2431Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000203720 SCV000260538 uncertain significance Neurofibromatosis, type 1 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 2431 of the NF1 protein (p.Arg2431Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs377662483, ExAC 0.001%). This variant has not been reported in the literature in individuals with NF1-related disease. ClinVar contains an entry for this variant (Variation ID: 220184). 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.

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