ClinVar Miner

Submissions for variant NM_002880.3(RAF1):c.781C>G (p.Pro261Ala) (rs121434594)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000208199 SCV000264164 likely pathogenic Primary familial hypertrophic cardiomyopathy 2015-01-27 criteria provided, single submitter clinical testing
Database of Curated Mutations (DoCM) RCV000211848 SCV000510555 likely pathogenic Noonan syndrome 2016-05-13 no assertion criteria provided literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000354359 SCV000232168 pathogenic not provided 2014-09-17 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763094 SCV000893630 pathogenic LEOPARD syndrome 2; Noonan syndrome 5; Cardiomyopathy, dilated, 1NN 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000354359 SCV000329481 pathogenic not provided 2016-06-27 criteria provided, single submitter clinical testing The P261A variant has been published previously in association with RAF1-related disorders (Razzaque et al., 2007; Stevenson et al., 2011; Croonen et al., 2013). The variant 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. P261A 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 that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies have shown that P261A leads to increased activity of the RAF1 protein (Razzaque et al., 2007; Molzan et al., 2010). Missense variants in the same residue (P261T/S/H/L/R) and in nearby residues (R256S, S257L, S259P/T/F, T260I/R, N262I, N262K, V263A/D) have been reported in the Human Gene Mutation Database in association with RAF1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we consider this variant to be pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000211848 SCV000061366 pathogenic Noonan syndrome 2014-10-27 criteria provided, single submitter clinical testing The p.Pro261Ala variant in RAF1 has been identified in three individuals with cl inical features of Noonan syndrome (Razzaque 2007, Croonen 2013, LMM unpublished data), and was absent from large population studies (http://evs.gs.washington.e du/EVS/; dbSNP rs121434594). Different pathogenic amino acid changes (p.Pro261Le u, p.Pro261Ser, p.Pro261Thr) at this location have been identified in individual s with clinical features of Noonan syndrome, two of which (p.Pro261Leu, p.Pro261 Thr) were reported to have occurred de novo in one individual each (Razzaque 200 7, Pandit 2007, LMM unpublished data), suggesting that changes at this position are not tolerated. Studies have shown that the p.Pro261Ala variant impacts prote in function by increasing its kinase activity (Razzaque 2007). However, these in vitro assays may not accurately represent biological function. Individuals wit h pathogenic variants in exon 7 or 17 in RAF1 are reported to also have a higher incidence of hypertrophic cardiomyopathy (HCM 80-95%) than typically seen in No onan syndrome (Razzaque 2007, Pandit 2007). In summary, the p.Pro261Ala variant meets our criteria to be classified as pathogenic (http://personalizedmedicine.p artners.org/Laboratory-For-Molecular-Medicine/) based upon number of cases, abse nce from controls, evidence of other pathogenic variants in the same codon, and functional evidence.

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