ClinVar Miner

Submissions for variant NM_001354689.3(RAF1):c.781C>T (p.Pro261Ser) (rs121434594)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000211849 SCV000616379 pathogenic Noonan syndrome 2017-04-03 reviewed by expert panel curation The c.781C>T (p.Pro261Ser) 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; PMID 17603482, 20683980). In vitro functional studies provide some evidence that the p.Pro261Leu variant may impact protein function (PS3; PMID 17603483, 17603482). 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). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). 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). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PP2, PM1, PM2, PS3, PM6_Strong.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000211849 SCV000061367 pathogenic Noonan syndrome 2019-03-22 criteria provided, single submitter clinical testing The p.Pro261Ser variant in RAF1 has been identified in >10 individuals with clinical features of Noonan syndrome (Razzaque 2007, Pandit 2007, Longoni 2010, LMM unpublished data), reported de novo in 2 individuals and reported to segregate in 4 relatives with clinical features of Noonan syndrome from 2 families (Razzaque 2007, Pandit 2007). In addition, this variant was absent from large population studies and is classified as pathogenic by the ClinGen RASopathy variant curation expert panel. Individuals with 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 Noonan syndrome (Razzaque 2007, Pandit 2007). Studies have shown that the Pro261Ser variant impacts protein function by increasing its kinase activity (Razzaque 2007, Pandit 2007). However, these in vitro assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PP2, PM1, PM2, PS3, PM6_Strong.
GeneDx RCV000159076 SCV000209019 pathogenic not provided 2018-08-31 criteria provided, single submitter clinical testing The P261S missense variant in the RAF1 gene has been reported previously in association with Noonan syndrome, including an apparently de novo occurrence (Pandit et al., 2007; Razzaque et al., 2007; Longoni et al., 2010; Digilio et al., 2013). The variant is not observed in large population cohorts (Lek et al., 2016). The P261S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in the same residue (P261A/T/H/L/R) and in nearby residues (S259T/P/F, T260R/I, N262I/K, V263D/A) 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. In addition, functional studies have shown that P261S increases kinase activity and MEK and ERK activation (Razzaque et al., 2007). In summary, this variant is pathogenicIt is important to note that about 80% of individuals with a RAF1 pathogenic variant develop hypertrophic cardiomyopathy. All but two patients reported to harbor the P261S missense variant were diagnosed with hypertrophic cardiomyopathy, all were diagnosed with at least one heart defect, and about 50% of these individuals had multiple heart defects.
Blueprint Genetics RCV000208421 SCV000264165 pathogenic Primary familial hypertrophic cardiomyopathy 2015-09-14 criteria provided, single submitter clinical testing
Invitae RCV000468714 SCV000552088 pathogenic Rasopathy 2020-10-10 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 261 of the RAF1 protein (p.Pro261Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with Noonan syndrome (PMID: 17603482, 20683980, 17603483). ClinVar contains an entry for this variant (Variation ID: 13958). Experimental studies have shown that this missense change increases the kinase activity of the RAF1 protein and results in higher ERK activation than wild-type protein in vitro (PMID: 17603482, 17603483). Different missense substitutions at this codon (p.Pro261Ala, p.Pro261Thr, p.Pro261Leu) have been determined to be pathogenic (PMID: 20052757, 17603483, 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.
Ambry Genetics RCV000618568 SCV000740256 pathogenic Cardiovascular phenotype 2017-12-12 criteria provided, single submitter clinical testing The p.P261S pathogenic mutation (also known as c.781C>T), located in coding exon 6 of the RAF1 gene, results from a C to T substitution at nucleotide position 781. The proline at codon 261 is replaced by serine, an amino acid with similar properties. This alteration has been reported in a number of individuals with Noonan syndrome, including a de novo occurrence. This alteration was also reported to segregate with the disease in a few families (Pandit B et al. Nat. Genet., 2007 Aug;39:1007-12; Razzaque MA et al. Nat. Genet., 2007 Aug;39:1013-7; Longoni M et al. Am. J. Med. Genet. A, 2010 Sep;152A:2176-84; Digilio MC et al. Eur. J. Hum. Genet., 2013 Feb;21:200-4). In vitro studies have suggested a gain of function effect of this variant in the experimental system (Pandit B et al. Nat. Genet., 2007 Aug;39:1007-12; Razzaque MA et al. Nat. Genet., 2007 Aug;39:1013-7). Alterations affecting the same amino acid have also been described in affected individuals (Ratola A et al. Pediatr Rep, 2015 May;7:5955; Ezquieta B et al. Rev Esp Cardiol (Engl Ed), 2012 May;65:447-55). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Ambry Genetics RCV000622893 SCV000741475 pathogenic Inborn genetic diseases 2016-04-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000468714 SCV000920145 pathogenic Rasopathy 2018-09-11 criteria provided, single submitter clinical testing Variant summary: RAF1 c.781C>T (p.Pro261Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 31494 control chromosomes (gnomAD and publications). c.781C>T has been reported in the literature in multiple individuals affected with Noonan Syndrome and Related Conditions (Pandit_2007, Razzaque_2007). These data indicate that the variant is very likely to be associated with disease. Multiple functional assessments found the variant to cause an increase in kinase activity. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. In addition, other mutations at this position, Pro261Ala and Pro261Thr, have been reported as pathogenic and associated with Noonan syndrome, indicating the location is a mutational hotspot and critical for gene function. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000159076 SCV001446688 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
OMIM RCV000014987 SCV000035243 pathogenic Noonan syndrome 5 2007-08-01 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000211849 SCV000510554 likely pathogenic Noonan syndrome 2016-05-13 no assertion criteria provided literature only

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