ClinVar Miner

Submissions for variant NM_002880.3(RAF1):c.775T>A (p.Ser259Thr) (rs3730271)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000522675 SCV000616422 pathogenic Rasopathy 2017-04-03 reviewed by expert panel curation The c.775T>A (p.Ser259Thr) variant in RAF1 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; APHP-Robert Debré Hospital internal data; GTR ID's: 28338). The p.Ser259Thr variant has been identified in at least 8 independent occurrences in patients with a RASopathy (PS4_Supporting; GeneDx, Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg internal data; GTR ID's: 26957, 21766, 506381 PMID: 21784453; ClinVar SCV000061360.5; SCV000209017.10). The p.Ser259Thr variant in RAF1 has been reported to segregate with clinical features of a RASopathy in at least 3 family members (PP1; GeneDx, Institute of Human Genetics, Otto von Guericke University Magdeburg internal data; GTR ID's: 26957, 506381; ClinVar SCV000209017.9). In vitro functional studies provide some evidence that the p.Ser259Thr variant may impact protein function (PS3; PMID: 21784453, 20052757). At least 2 other pathogenic missense variants have been previously identified at this codon of RAF1 which may indicate that this residue is critical to the function of the protein (PM5_Strong; ClinVar 40603, 40602, 228288). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). 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). 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.Ser259Thr variant may impact the protein (PP3). 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): PM6_Strong, PS4_Supporting, PP1, PM5_Strong, PM2, PM1, PP2, PP3, PS3.
GeneDx RCV000159074 SCV000209017 pathogenic not provided 2018-06-21 criteria provided, single submitter clinical testing The S259T missense variant has been reported previously in association with Noonan syndrome (Ko et al., 2008). The variant is not observed in large population cohorts (Lek et al., 2016). Functional studies have shown that S259T results in the increased activation of MEK and ERK (Kobayashi et al., 2010; Lee et al., 2011). Missense variants in the same residue (S259P/F/C/A) and in nearby residues (R256S, S257L, T260R/I, P261A/T/S/L/R/H/I, N262K, V263A/D) have been reported by the Human Gene Mutation Database and/or GeneDx in association with Noonan spectrum disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, we consider this variant to be pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037698 SCV000061360 likely pathogenic Noonan syndrome 2010-09-09 criteria provided, single submitter clinical testing The Ser259Thr variant in RAF1 has been previously identified in two individuals with clinical features of Noonan syndrome (Ko 2008, LMM unpublished data). In ad dition, two different amino acid changes at this location (Ser259Phe, Ser259Tyr) have been identified in individuals with Noonan spectrum features, suggesting a lterations at this amino acid are not tolerated (Pandit 2007, Kobayashi 2009; LM M unpublished data). Ser259 is also known to be of critical importance to the r egulation of the RAF1 protein (Kobayashi 2009). Therefore, it is likely that thi s variant is pathogenic.

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