ClinVar Miner

Submissions for variant NM_002880.3(RAF1):c.1423T>C (p.Phe475Leu) (rs730881003)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159085 SCV000209028 pathogenic not provided 2013-06-17 criteria provided, single submitter clinical testing p.Phe475Leu (TTT>CTT): c.1423 T>C in exon 14 of the RAF1 gene (NM_002880.3). An F475L missense mutation was identified in the RAF1 gene. It has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. However, this mutation has been seen several times previously at GeneDx in one proband and segregating with disease in another unrelated family; all were reported to have phenotypes consistent with the diagnosis of a disorder of the Noonan-CFC-Costello syndrome spectrum. F475L is a semi-conservative amino acid substitution with a non-polar aromatic residue (Phe) being replaced by a non-polar aliphatic residue (Leu). The position at which this mutation occurs is highly conserved across species and is located within 1 of 3 exons where all published mutations have been reported (Pandit et al., 2007 and Razzaque et al., 2007). In silico analysis (PolyPhen) predicts that this sequence variant is probably damaging to protein structure/function. Therefore, F475L is considered to be a disease-causing mutation consistent with the diagnosis. The variant is found in NOONAN panel(s).
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000602545 SCV000731707 likely pathogenic Noonan syndrome 2017-07-12 criteria provided, single submitter clinical testing The p.Phe475Leu variant in RAF1 has been reported in 2 individuals with clinical features of Noonan syndrome, was de novo in 1 of those individuals, and segrega ted with disease in 2 affected relatives from 1 family (personal communication, GeneDx). It was absent from large population studies. Computational prediction t ools and conservation analysis suggest that the p.Phe475Leu variant may impact t he protein, though this information is not predictive enough to determine pathog enicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Phe475Leu variant is likely pathogenic.

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