ClinVar Miner

Submissions for variant NM_001354689.3(RAF1):c.782C>G (p.Pro261Arg) (rs397516828)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037706 SCV000061368 pathogenic Noonan syndrome 2016-02-17 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000159077 SCV000209020 pathogenic not provided 2014-01-10 criteria provided, single submitter clinical testing The P261R missense mutation was identified in the RAF1 gene. It has not been published as a pathogenic variant or benign polymorphism, to our knowledge. However, this variant has been observed previously in multiple unrelated patients referred for Noonan syndrome testing. P261R is a non-conservative missense mutation that occurs in a highly conserved portion of the RAF1 gene, at an amino acid residue where many other gain-of-function variants (P261A, P261S and P261L) have also been reported in Noonan syndrome (Pandit et al., 2007 and Razzaque et al., 2007). Therefore, P261R is considered to be a pathogenic variant that is consistent with a diagnosis of an autosomal dominant RAF1-related disorder.
Eurofins NTD, LLC RCV000159077 SCV000333074 pathogenic not provided 2015-07-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590070 SCV000698127 likely pathogenic Rasopathy 2017-07-10 criteria provided, single submitter clinical testing Variant summary: The RAF1 c.782C>G (p.Pro261Arg) variant involves the alteration of a highly conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 121388 control chromosomes and has been reported in the literature in at least 2 Noonan Syndrome patients, one in whom the variant was absent in both parents (assumed de novo [Ratola_2015, VanTrier_2015]). Other variants affecting the same codon (Pro261Ala, Pro261Leu) have been classified as pathogenic/likely pathogenic by our lab, indicating the variant to be located in a mutational hotspot. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic.
Invitae RCV000590070 SCV000829989 pathogenic Rasopathy 2018-02-16 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 261 of the RAF1 protein (p.Pro261Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individual affected with Noonan syndrome (NS) (PMID: 26266034). This variant has also been reported in several additional, unrelated NS affected individuals (PMID: 25862627, 28777121). ClinVar contains an entry for this variant (Variation ID: 40606). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Different missense substitutions at this codon (p.Pro261Ser, p.Pro261Thr, p.Pro261Ala, p.Pro261Leu) have been determined to be pathogenic (PMID: 17603482, 20683980, 17603483, 22465605, 21784453). 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 RCV000277865 SCV000854623 pathogenic Noonan syndrome 5 2018-11-18 no assertion criteria provided clinical testing

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