ClinVar Miner

Submissions for variant NM_001354689.3(RAF1):c.769T>C (p.Ser257Pro) (rs727505017)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000520189 SCV000616421 likely pathogenic Rasopathy 2017-04-03 reviewed by expert panel curation The c.769T>C (p.Ser257Pro) variant in RAF1 has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; GeneDx, Partners LMM, Blueprint Genetics internal data; GTR ID: 26957, 21766, 500188; ClinVar SCV000209015.8, SCV000206160.4, SCV000264162.1). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). A different pathogenic missense variant has been previously identified at this codon of RAF1 which may indicate that this residue is critical to the function of the protein (PM5; ClinVar 13957, 376514). 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). Computational prediction tools and conservation analysis suggest that the p.Ser257Pro variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6, PM2, PM5, PM1, PP2, PP3.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000156441 SCV000206160 pathogenic Noonan syndrome 2016-07-12 criteria provided, single submitter clinical testing The p.Ser257Pro variant in the RAF1 gene has been identified in 6 individuals wi th clinical features of a RASopathy, including as a de novo variant in one indiv idual (LMM data and GeneDx personal communication). This variant was absent from large population studies. In addition, another disease-causing variant (p.Ser25 7Leu) at the same codon has been identified in >20 individuals with a RASopathy (Razzaque 2007, Pandit 2007, LMM data) and studies show it impacts the protein ( Light 2002), suggesting that changes at this position (Ser257) may not be tolera ted. In summary, this variant meets our criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner.
GeneDx RCV000159073 SCV000209015 likely pathogenic not provided 2019-03-19 criteria provided, single submitter clinical testing The S257P variant in the RAF1 gene has not been published as a pathogenic variant or as a benign polymorphism, to our knowledge. However, S257P has been observed several times in samples submitted for Noonan syndrome testing. In addition, a different missense substitution at the same residue (S257L) has been published in association with Noonan syndrome (Razzaque et al., 2007). S257P is a non-conservative missense mutation that occurs in a highly conserved portion of the RAF1 gene, where many other gain-of-function variants have been reported at residues 256, 259, 260, and 261 in Noonan syndrome (Pandit et al., 2007). Furthermore, the S257P mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, S257P in the RAF1 gene is interpreted as a likely pathogenic variant.
Blueprint Genetics RCV000208439 SCV000264162 likely pathogenic Primary familial hypertrophic cardiomyopathy 2015-04-07 criteria provided, single submitter clinical testing
Database of Curated Mutations (DoCM) RCV000426760 SCV000505235 likely pathogenic Melanoma 2014-12-26 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.