ClinVar Miner

Submissions for variant NM_002880.3(RAF1):c.770C>T (p.Ser257Leu) (rs80338796)

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Total submissions: 22
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000624417 SCV000741222 pathogenic Inborn genetic diseases 2015-12-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Baylor Miraca Genetics Laboratories, RCV000149826 SCV000196668 pathogenic Rasopathy no assertion criteria provided clinical testing Variant classified using ACMG guidelines
Blueprint Genetics RCV000157426 SCV000207169 pathogenic Noonan syndrome 2015-10-05 criteria provided, single submitter clinical testing
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, 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). 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.
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
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
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.
GeneReviews RCV000020509 SCV000040960 pathologic Noonan syndrome with multiple lentigines 2010-11-16 no assertion criteria provided curation Converted during submission to Pathogenic.
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center RCV000157685 SCV000207668 pathogenic not provided 2015-01-15 no assertion criteria provided 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
Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) RCV000014985 SCV000143821 not provided Noonan syndrome 5 no assertion provided not provided
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000149826 SCV000287743 pathogenic Rasopathy 2018-10-23 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.
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.
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000157685 SCV000263046 pathogenic not provided 2015-07-21 criteria provided, single submitter clinical testing
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

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