ClinVar Miner

Submissions for variant NM_002880.3(RAF1):c.1472C>T (p.Thr491Ile) (rs80338799)

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
ClinGen RASopathy Variant Curation Expert Panel RCV000523483 SCV000616380 pathogenic Rasopathy 2017-04-03 reviewed by expert panel curation The c.1472C>T (p.Thr491Ile) variant in RAF1 has been reported in the literature in at least one individual with clinical features of a RASopathy (PS4 not met; PMID 17603483). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the RAF1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Thr491Ile variant may impact the protein (PP3). In vitro functional studies provide some evidence that the p.Thr491Ile variant may impact protein function (PS3; 20679480). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PP3, PM1, PM2, PS3.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037676 SCV000061338 pathogenic Noonan syndrome 2013-05-28 criteria provided, single submitter clinical testing The Thr491Ile has been identified in our laboratory in two probands with clinica l features of Noonan syndrome. In addition, this variant was not identified in t he parents of one proband in our laboratory, and therefore occurred de novo. Thi s variant has also been reported in the literature in one individual with clinic al features of Noonan syndrome and was not identified in 210 control individuals (Pandit 2007). Computational analyses (biochemical amino acid properties, conse rvation, AlignGVGD, and SIFT) suggest that the Thr491Ile variant may impact the protein. In summary, this variant meets our criteria to be classified as pathoge nic based on its de novo occurrence (http://pcpgm.partners.org/LMM).
GeneDx RCV000159086 SCV000209029 pathogenic not provided 2016-12-30 criteria provided, single submitter clinical testing The T491I missense variant in the RAF1 gene has been reported previously in association with Noonan syndrome (Pandit et al., 2007). The T491I variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). T491I occurs in the activation segment of the CR3 (conserved region 3) domain of the resulting protein. In vitro functional studies demonstrated that that presence of the T491I variant results in impaired MEK kinase expression and results in constitutive ERK activation (Pandit et al., 2007). Another missense variant at the same location (T491R) has also been reported in association with Noonan syndrome, indicating the functional importance of this residue. About 80% of individuals with a RAF1 variant develop hypertrophic cardiomyopathy (HCM). However, at least one patient with the T491I variant has been reported without HCM (Pandit et al., 2007).
Ambry Genetics RCV000621393 SCV000739974 likely pathogenic Cardiovascular phenotype 2016-07-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s)
GeneReviews RCV000020507 SCV000040958 pathologic Noonan syndrome with multiple lentigines 2010-11-16 no assertion criteria provided curation Converted during submission to Pathogenic.
Database of Curated Mutations (DoCM) RCV000037676 SCV000510557 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.