ClinVar Miner

Submissions for variant NM_001354689.3(RAF1):c.770C>T (p.Ser257Leu) (rs80338796)

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Total submissions: 28
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000157426 SCV000616378 pathogenic Noonan syndrome 2017-04-03 reviewed by expert panel curation The c.770C>T (p.Ser257Leu) 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 17603482,22389993, 23877478, 23312806, 25706034). In vitro functional studies provide some evidence that the p.Ser257Leu variant may impact protein function (PS3; PMID 17603482). This variant was absent from large population studies (PM2; ExAC, 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). 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). 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 RCV000824754 SCV000200043 pathogenic Noonan syndrome with multiple lentigines; Noonan syndrome 2013-05-23 criteria provided, single submitter clinical testing The p.Ser257Leu variant has been associated with the clinical features of RASopa thy disorders (Razzaque 2007, Pandit 2007). This variant has been reported to ha ve occurred de novo in sporadic cases. Individuals with pathogenic variants in exon 7 or 17 in RAF1 have a high incidence of hypertrophic cardiomyopathy (80-95 %, Razzaque 2007, Pandit 2007). In summary, this variant meets criteria to be cl assified as pathogenic for RASopathy disorders in an autosomal dominant manner b ased upon published literature and de novo occurrence in affected individuals.
Blueprint Genetics RCV000157426 SCV000207169 pathogenic Noonan syndrome 2015-10-05 criteria provided, single submitter clinical testing
GeneDx RCV000157685 SCV000209016 pathogenic not provided 2019-01-03 criteria provided, single submitter clinical testing The S257L missense variant in the RAF1 gene has been published previously in association with Noonan syndrome (Razzaque et al., 2007; Kobayashi et al., 2010), and is consistent with a diagnosis of autosomal dominant Noonan syndrome. Additionally, the S257L variant has been seen to occur de novo in affected patients tested at GeneDx. The S257L variant is not observed in large population cohorts (Lek et al., 2016). The 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. Functional studies indicate that S257L produces a gain of function effect with higher kinase activity than wild-type protein (Razzaque et al., 2007). Missense variants in nearby residues (R256S, S259P/T/F, T260R/I, P261A/T/S/R/H/L) 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. We interpret S257L as a pathogenic variant.
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000157685 SCV000263046 pathogenic not provided 2015-07-21 criteria provided, single submitter clinical testing
Invitae RCV000149826 SCV000287743 pathogenic Rasopathy 2020-10-05 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 257 of the RAF1 protein (p.Ser257Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (rs80338796, ExAC no frequency). This variant has been reported in many individuals affected with Noonan syndrome, both with and without multiple lentigines (PMID: 17603482, 17603483, 20052757, 22389993). This variant was confirmed to be de novo in multiple affected individuals (PMID: 17603483, 23877478). ClinVar contains an entry for this variant (Variation ID: 13957). Experimental studies have shown that this missense change leads to increased activation of MEK, ERK, and ELK in vitro (PMID: 17603482, 20052757). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000157685 SCV000341105 pathogenic not provided 2016-04-14 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515222 SCV000611310 pathogenic LEOPARD syndrome 2; Noonan syndrome 5; Cardiomyopathy, dilated, 1NN 2017-05-18 criteria provided, single submitter clinical testing
Institute of Human Genetics, Klinikum rechts der Isar RCV000014985 SCV000680354 pathogenic Noonan syndrome 5 2017-11-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV000624417 SCV000741222 pathogenic Inborn genetic diseases 2015-12-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000149826 SCV000918146 pathogenic Rasopathy 2018-12-11 criteria provided, single submitter clinical testing Variant summary: RAF1 c.770C>T (p.Ser257Leu) results in a non-conservative amino acid change located in the CR2 domain of the encoded protein sequence that is involved in regulatory phosphorylation and association with the 14-3-3 protein (Razzaque 2007, Pandit 2007). Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246848 control chromosomes (gnomAD). c.770C>T has been reported in the literature in multiple individuals affected with Noonan Syndrome and Related Conditions, where several of these individuals also had hypertrophic cardiomyopathy or other cardiac manifestations (e.g. Razzaque 2007, Pandit 2007, Denayer 2010, Alfieri 2008, Croonen 2013, Zarare 2013, Lee 2011, Xu 2017). The variant has also been reported in some patients with LEOPARD syndrome (see e.g. Pandit 2007, Carcavilla 2013, Xu 2017). In all confirmed cases the variant occurred in heterozygous state as a de novo mutation (see e.g. Pandit 2007, Denayer 2010, Croonen 2013, Zarare 2013, Xu 2017). These data indicate that the variant is very likely to be associated with disease. Several publications reported experimental evidence evaluating an impact on protein function, demonstrating increased kinase activity (Razzaque 2007), increased activation of MEK and ERK (Lee 2011) and altered signaling in cardiomyocytes consistent with that observed in cardiac hypertrophy (Dhandapany 2011). 11 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (10x) / likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000157426 SCV000996383 pathogenic Noonan syndrome 2017-11-16 criteria provided, single submitter research The RAF1 Ser257Leu variant has been previously reported in multiple Noonan syndrome cases (see literature), including at least 6 cases where the variant was found to arise de novo (Zarate YA, et al., 2013; Kobayashi T, et al., 2010; Pandit B, et al., 2007). We identified this variant in a young male patient diagnosed with Noonan syndrome. RAF1 Ser257Leu is absent in the Exome Aggregation Consortium dataset (, as well as the Genome Aggregation Database ( In silico tools SIFT and MutationTaster predict this variant to be deleterious, however PolyPhen-2 predicts this variant to be "benign". In summary, based on rarity in the general population, presence in multiple Noonan syndrome patients, the high rate of de novo occurrences and because the variant is located in a functional 'hotspot' we classify the RAF1 Ser257Leu as "pathogenic".
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn RCV000856803 SCV000999369 pathogenic Noonan syndrome 1 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000014986 SCV001369226 pathogenic LEOPARD syndrome 2 2019-05-20 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM1,PM2,PM5,PP2,PP3.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286494 SCV001473076 pathogenic none provided 2020-06-05 criteria provided, single submitter clinical testing The RAF1 c.770C>T; p.Ser257Leu variant (rs80338796) has been reported in multiple individuals diagnosed with Noonan syndrome (Razzaque 2007, Pandit 2007, Kobayashi 2010, Zarate 2014, Hopper 2015) or LEOPARD syndrome (Pandit 2007, Carcavilla 2013). The variant is reported as pathogenic in ClinVar by multiple sources (Variation ID: 13957) absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant is located in a region critical for the phosphorylation of serine-259 and its association with 14-3-3, which is involved in the negative regulation of RAF1 activity (Razzaque 2007, Kobayashi 2010). Functional characterization of the p.Ser257Leu variant protein indicates a loss of serine-259 phosphorylation and reduced association with 14-3-3 (Kobayashi 2010). This leads to an over-activation of MEK and ERK signaling (Razzaque 2007, Kobayashi 2010), consistent with the established disease mechanisms of Noonan Syndrome. Based on available information, this variant is considered to be pathogenic. References: Carcavilla A et al. LEOPARD syndrome: a variant of Noonan syndrome strongly associated with hypertrophic cardiomyopathy. Rev Esp Cardiol (Engl Ed). 2013 May;66(5):350-6. Hopper R et al. Neonatal pulmonary arterial hypertension and Noonan syndrome: two fatal cases with a specific RAF1 mutation. Am J Med Genet A. 2015 Apr;167A(4):882-5. Kobayashi T et al. Molecular and clinical analysis of RAF1 in Noonan syndrome and related disorders: dephosphorylation of serine 259 as the essential mechanism for mutant activation. Hum Mutat. 2010 Mar;31(3):284-94. Pandit B et al. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet. 2007 Aug;39(8):1007-12. Razzaque M et al Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nat Genet. 2007 Aug;39(8):1013-7 Zarate Y et al. Unique cerebrovascular anomalies in Noonan syndrome with RAF1 mutation. J Child Neurol. 2014 Aug;29(8):NP13-7.
Mayo Clinic Laboratories, Mayo Clinic RCV000157685 SCV001714082 pathogenic not provided 2019-11-18 criteria provided, single submitter clinical testing PS3, PS4_Moderate, PM2
OMIM RCV000014985 SCV000035241 pathogenic Noonan syndrome 5 2007-08-01 no assertion criteria provided literature only
OMIM RCV000014986 SCV000035242 pathogenic LEOPARD syndrome 2 2007-08-01 no assertion criteria provided literature only
GeneReviews RCV000020509 SCV000040960 pathologic Noonan syndrome with multiple lentigines 2010-11-16 no assertion criteria provided curation Converted during submission to Pathogenic.
Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) RCV000014985 SCV000143821 not provided Noonan syndrome 5 no assertion provided not provided
Baylor Genetics RCV000149826 SCV000196668 pathogenic Rasopathy no assertion criteria provided clinical testing Variant classified using ACMG guidelines
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center RCV000157685 SCV000207668 pathogenic not provided 2015-01-15 no assertion criteria provided clinical testing
Database of Curated Mutations (DoCM) RCV000157426 SCV000507276 likely pathogenic Noonan syndrome 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436233 SCV000507277 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418940 SCV000507278 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428775 SCV000507279 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435984 SCV000507280 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital RCV000014985 SCV001482333 pathogenic Noonan syndrome 5 2019-05-31 no assertion criteria provided research

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