ClinVar Miner

Submissions for variant NM_001354689.3(RAF1):c.781C>A (p.Pro261Thr) (rs121434594)

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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 RCV000037703 SCV000061365 pathogenic Noonan syndrome 2011-04-15 criteria provided, single submitter clinical testing The Pro261Thr variant has not been previously reported in the literature. This v ariant has been identified in one other proband with clinical features of Noonan syndrome tested by our laboratory and was found to have occurred de novo (LMM u npublished data). In addition, proline (Pro) at codon 261 is a highly conserved amino acid and other missense variants at this position (Pro261Ala, Pro261Leu, P ro261Arg, Pro261Ser) have previously been associated with Noonan syndrome (Razza que 2007, Pandit 2007). Therefore, the Pro261Thr variant is highly likely to be pathogenic. Individuals with pathogenic variants in exon 7 or 17 in RAF1 have a high incidence of hypertrophic cardiomyopathy (80-95%, Razzaque 2007).
Invitae RCV000149827 SCV000776868 pathogenic Rasopathy 2019-11-29 criteria provided, single submitter clinical testing This sequence change replaces proline with threonine at codon 261 of the RAF1 protein (p.Pro261Thr). The proline residue is highly conserved and there is a small physicochemical difference between proline and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in individuals affected with Noonan syndrome (PMID:22465605, 21784453, 29084544). ClinVar contains an entry for this variant (Variation ID: 40604). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different missense substitution at this codon (p.Pro261Ser) has been determined to be pathogenic in several individuals affected with Noonan syndrome (PMID: 17603482, 20683980, 17603483). This suggests that the proline residue is critical for RAF1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000149827 SCV000196669 pathogenic Rasopathy no assertion criteria provided clinical testing Variant classified using ACMG guidelines

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