ClinVar Miner

Submissions for variant NM_001354689.3(RAF1):c.66T>G (p.Phe22Leu) (rs397516824)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000168020 SCV000616418 likely benign Rasopathy 2017-04-03 reviewed by expert panel curation The c.66T>G (p.Phe22Leu) variant has been identified in patients with clinical features of a RASopathy, however the variant did not segregate with disease in affected family members (BS4; GeneDx, Partners LMM, Invitae internal data GTR ID's: 26957, 21766, 500031; ClinVar SCV000218672.4; SCV000061358.5). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; LMM internal data; SCV000061358.5). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS4, BP5.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037696 SCV000061358 likely benign not specified 2016-02-10 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Invitae RCV000168020 SCV000218672 uncertain significance Rasopathy 2019-08-23 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 22 of the RAF1 protein (p.Phe22Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This sequence change has not been reported in the literature and is present in population databases (rs397516824, <0.01%). In a family tested at Invitae, this variant was found in a parent but not a child, both of whom had features consistent with Noonan syndrome. The clinical significance of this observation is uncertain. 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: tolerated; PolyPhen-2: “possibly damaging”, Align-GVGD: Class C0). In summary, this is a rare missense change with uncertain impact on protein function that did not segregate with Noonan features in a family. However, in the absence of conclusive segregation evidence, it has been classified as a Variant of Uncertain Significance.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.