ClinVar Miner

Submissions for variant NM_001354689.3(RAF1):c.786T>A (p.Asn262Lys) (rs397516829)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037707 SCV000061369 pathogenic Noonan syndrome 2014-09-24 criteria provided, single submitter clinical testing The Asn262Lys variant has been reported in two individuals with clinical feature s of a RASopathy and was identified to occur de novo in both individuals (Kobaya shi 2010, LMM unpublished). It was absent from large population studies. Computa tional prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determin e pathogenicity. In vitro functional studies provide some evidence that the Asn2 62Lys variant may impact protein function (Chan 2002, Kobayashi 2010). However, these types of assays may not accurately represent biological function. Individu als with pathogenic variants in exon 7 or 17 in RAF1 have a high incidence of hy pertrophic cardiomyopathy (80-95%, Chan 2002). In summary, this variant meets ou r criteria to be classified as pathogenic (http://pcpgmwww.partners.org/personal izedmedicince/LMM).
GeneDx RCV000388842 SCV000329734 pathogenic not provided 2017-03-03 criteria provided, single submitter clinical testing The N262K variant has been reported previously as a de novo occurrence in a patient with Noonan spectrum disorder (Kobayashi et al., 2010). N262K is also reported as a pathogenic variant in ClinVar by a different clinical laboratory and apparently occurred de novo in a patient with Noonan syndrome (ClinVar SCV000061369.4; Landrum et al., 2015). It 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. The N262K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position within the CR2 domain that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants at the same (N262I) and in nearby residues (S257L, S259P/T/F, T260I/R, P261T/S/A/R/L/H, V263A/D) have been reported in the Human Gene Mutation Database in association with Noonan spectrum disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Additionally, functional studies of the N262K variant show that it inhibits the phosphorylation of nearby codon serine-259, which is necessary for RAF1 activation, abolishes binding of 14-3-3 protein complex, and results in partial activation of ERK (Kobayashi et al., 2010). Therefore, we interpret N262K as a pathogenic variant.
Mayo Clinic Laboratories, Mayo Clinic RCV000388842 SCV001714080 pathogenic not provided 2019-05-13 criteria provided, single submitter clinical testing PM1, PM2, PM5, PM6_Strong, PS3_Moderate

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