ClinVar Miner

Submissions for variant NM_001354689.3(RAF1):c.782C>T (p.Pro261Leu) (rs397516828)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000211850 SCV000200039 pathogenic Noonan syndrome 2013-11-19 criteria provided, single submitter clinical testing The Pro261Leu variant in RAF1 has been reported as a de novo variant in one indi vidual with clinical features of Noonan syndrome (Pandit 2007). Recurrent missen se variants at this amino acid position (Pro261Leu, Pro261Ser, Pro261Thr, Pro261 Ala, and Pro261Arg) have been identified by our laboratory in individuals with c linical features associated with Noonan syndrome. Of note, individuals with path ogenic variants in exon 7 or 17 in RAF1 have a high incidence of hypertrophic ca rdiomyopathy (80-95%, Razzaque 2007, Pandit 2007). In summary, this variant meet s our criteria to be classified as pathogenic based on its de novo occurrence (h ttp://pcpgm.partners.org/LMM).
GeneDx RCV000519236 SCV000616847 pathogenic not provided 2017-08-01 criteria provided, single submitter clinical testing The P261L variant in the RAF1 gene has been reported previously in an individual with Noonan syndrome with clinical features including short stature, hypertrophic cardiomyopathy, and pectus anomaly (Pandit et al., 2007). The P261L variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P261L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution is not within a known functional domain and occurs at a position that is conserved across species. Functional studies have shown that P261L leads to increased activity of the RAF1 protein (Molzan et al., 2010). Missense variants in the same residue (P261A, P261T, P261S, P261H, P261R) and in nearby residues (R256S, S257L, S259P, S259T, S259F, T260I, T260R, N262I, N262K, V263D, V263A) have been reported in association with RAF1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret P261L as a pathogenic variant.
Invitae RCV001221447 SCV001393494 pathogenic Rasopathy 2019-08-13 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 261 of the RAF1 protein (p.Pro261Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with Noonan syndrome and has been observed in other individuals with clinical features of this disease (PMID: 17603483, 20052757, 28991257). ClinVar contains an entry for this variant (Variation ID: 120246). This variant has been reported to affect RAF1 protein function (PMID: 20679480). This variant disrupts the p.Pro261 amino acid residue in RAF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20052757, 17603482, 23885229, 22465605, 21784453, 29084544). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Genomics England Pilot Project,Genomics England RCV001542564 SCV001760105 likely pathogenic Cardiomyopathy, dilated, 1NN criteria provided, single submitter clinical testing
Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) RCV000106325 SCV000143822 not provided Noonan syndrome 5 no assertion provided not provided
Database of Curated Mutations (DoCM) RCV000211850 SCV000510556 likely pathogenic Noonan syndrome 2016-05-13 no assertion criteria provided literature only

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.