Total submissions: 42
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
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. |
Laboratory for Molecular 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 | |
Gene |
RCV000157685 | SCV000209016 | pathogenic | not provided | 2022-09-09 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate that S257L produces a gain of function effect with higher kinase activity than wild-type protein (Razzaque et al., 2007; Lee et al., 2011); Not observed in large population cohorts (gnomAD); The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26918529, 23877478, 30384889, 35050212, 32506814, 31219622, 34184824, 30417923, 25706034, 24033266, 23312806, 22389993, 17603483, 20052757, 24775816, 24803665, 28973083, 29084544, 28777121, 30732632, 30138938, 30055033, 30355600, 30105547, 21784453, 21440552, 28991257, 30050098, 29907801, 31395954, 31560489, 31324109, 31163979, 32573669, 32668055, 34136434, 33318624, 17603482, 32981126, 33673806, 32410215, 33240318, 32746448, 32368696, 34006472, 24957944, 9689060, 15520807, 29493581) |
Molecular Diagnostics Lab, |
RCV000157685 | SCV000263046 | pathogenic | not provided | 2015-07-21 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV000149826 | SCV000287743 | pathogenic | RASopathy | 2023-12-24 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 257 of the RAF1 protein (p.Ser257Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome, both with and without multiple lentigines (PMID: 17603482, 17603483, 20052757, 22389993, 23877478). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13957). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RAF1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RAF1 function (PMID: 17603482, 20052757). For these reasons, this variant has been classified as Pathogenic. |
Eurofins Ntd Llc |
RCV000157685 | SCV000341105 | pathogenic | not provided | 2016-04-14 | criteria provided, single submitter | clinical testing | |
Fulgent Genetics, |
RCV000515222 | SCV000611310 | pathogenic | LEOPARD syndrome 2; Noonan syndrome 5; Dilated cardiomyopathy 1NN | 2021-07-01 | criteria provided, single submitter | clinical testing | |
Institute of Human Genetics Munich, |
RCV000014985 | SCV000680354 | pathogenic | Noonan syndrome 5 | 2017-11-15 | criteria provided, single submitter | clinical testing | |
Women's Health and 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. |
Agnes Ginges Centre for Molecular Cardiology, |
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 (http://exac.broadinstitute.org/), as well as the Genome Aggregation Database (http://gnomad.broadinstitute.org/). 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, |
RCV000856803 | SCV000999369 | pathogenic | Noonan syndrome 1 | criteria provided, single submitter | clinical testing | ||
Centre for Mendelian Genomics, |
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, |
RCV000157685 | SCV001473076 | pathogenic | not 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, |
RCV000157685 | SCV001714082 | pathogenic | not provided | 2022-06-15 | criteria provided, single submitter | clinical testing | PP2, PM1, PM2, PS2_very_strong, PS3, PS4 |
Rady Children's Institute for Genomic Medicine, |
RCV001731288 | SCV001984841 | pathogenic | RAF1-related disorder | 2020-10-21 | criteria provided, single submitter | clinical testing | This variant has been previously reported as a de novo change in patients with Noonan Syndrome (PMID: 17603482, 23877478) and LEOPARD syndrome 2 (PMID: 22389993, 24775816). This variant has been classified as Pathogenic by the ClinGen Rasopathy Expert Panel. Functional studies indicate that the p.Ser257Leu produces a gain-of-function effect with higher kinase activity than wild-type protein (PMID: 17603482). It is absent from the gnomAD population database and thus is presumed to be rare. In silico tools used to predict the effect of this variant on protein function yield discordant results. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.770C>T (p.Ser257Leu) variant is classified as Pathogenic. |
Centogene AG - |
RCV000014985 | SCV002059455 | pathogenic | Noonan syndrome 5 | 2020-02-11 | criteria provided, single submitter | clinical testing | |
Genome Diagnostics Laboratory, |
RCV001813205 | SCV002060975 | pathogenic | Noonan syndrome and Noonan-related syndrome | 2021-04-26 | criteria provided, single submitter | clinical testing | |
Centro Nacional de Genética Medica "Dr. |
RCV000157685 | SCV002098092 | pathogenic | not provided | 2022-02-02 | criteria provided, single submitter | clinical testing | |
Ce |
RCV000157685 | SCV002496785 | pathogenic | not provided | 2022-12-01 | criteria provided, single submitter | clinical testing | RAF1: PS2:Very Strong, PM2, PS3:Supporting |
3billion | RCV000014985 | SCV002521319 | pathogenic | Noonan syndrome 5 | 2022-05-22 | criteria provided, single submitter | clinical testing | The variant is not observed in the gnomAD v2.1.1 dataset. The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 17603482, 20052757). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.65; 3Cnet: 0.08). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013957). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 17603483, 23877478) and as assumed (i.e. paternity and maternity not confirmed) de novo in at least two similarly affected unrelated individuals (PMID: 17603482, 22389993, 23877478, 25706034). Different missense changes at the same codon (p.Ser257Pro, p.Ser257Thr) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040600, VCV000618340). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. |
Ambry Genetics | RCV002399323 | SCV002669882 | pathogenic | Cardiovascular phenotype | 2021-08-04 | criteria provided, single submitter | clinical testing | The p.S257L pathogenic mutation (also known as c.770C>T), located in coding exon 6 of the RAF1 gene, results from a C to T substitution at nucleotide position 770. The serine at codon 257 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in numerous individuals with a diagnosis of Noonan syndrome or LEOPARD syndrome, including as a de novo alteration in two individuals in which paternity was confirmed (Pandit B et al. Nat Genet, 2007 Aug;39:1007-12; Razzaque MA et al. Nat Genet, 2007 Aug;39:1013-7; Kobayashi T et al. Hum Mutat, 2010 Mar;31:284-94; Carcavilla A et al. Rev Esp Cardiol (Engl Ed), 2013 May;66:350-6; Xu S et al. BMC Med Genomics, 2017 10;10:62; Vasilescu C et al. J Am Coll Cardiol, 2018 11;72:2324-2338; Chinton J et al. Arch Argent Pediatr, 2019 10;117:330-337). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
Victorian Clinical Genetics Services, |
RCV000014985 | SCV002767731 | pathogenic | Noonan syndrome 5 | 2024-10-09 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene. Gain of function is associated with Noonan (MIM#611553) and LEOPARD syndromes (MIM#2611554), while loss of function is associated with non-HCM-associated variants (PMIDs: 17603483, 17603482). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to leucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by an expert panel in ClinVar. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
Medical Genetics Center, |
RCV000014985 | SCV003915615 | pathogenic | Noonan syndrome 5 | 2022-03-22 | criteria provided, single submitter | clinical testing | |
Institute of Human Genetics, |
RCV003231105 | SCV003929505 | pathogenic | See cases | 2023-04-04 | criteria provided, single submitter | clinical testing | ACMG categories: PS3,PM1,PM2,PP3,PP5 |
Neuberg Centre For Genomic Medicine, |
RCV000014985 | SCV004047601 | pathogenic | Noonan syndrome 5 | criteria provided, single submitter | clinical testing | The missense variant c.770C>T (p.Ser257Leu) in RAF1 gene has been reported in heterozygous state in many individuals affected with Noonan syndrome, both with and without multiple lentigines (Kobayashi T et al., 2010). Experimental studies have shown that this missense change leads to increased activation of MEK, ERK, and ELK in vitro (Razzaque et al., 2007). The p.Ser257Leu variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. The amino acid Ser at position 257 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ser257Leu in RAF1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted to be probably damaging by PolyPhen 2 and deleterious by SIFT. For these reasons, this variant has been classified as Pathogenic. | |
Clinical Genetics Laboratory, |
RCV000157685 | SCV005198036 | pathogenic | not provided | 2022-07-13 | criteria provided, single submitter | clinical testing | |
Centre for Human Genetics | RCV000856803 | SCV005199934 | likely pathogenic | Noonan syndrome 1 | criteria provided, single submitter | clinical testing | The RAF1 c.770C>T (p.Ser257Leu) variant 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). | |
Juno Genomics, |
RCV000515222 | SCV005416118 | pathogenic | LEOPARD syndrome 2; Noonan syndrome 5; Dilated cardiomyopathy 1NN | criteria provided, single submitter | clinical testing | PS4+PS2+PS3+PM1+PM2_Supporting | |
Center for Genomic Medicine, |
RCV000014985 | SCV005438498 | likely pathogenic | Noonan syndrome 5 | 2024-12-18 | 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 | |
Gene |
RCV000020509 | SCV000040960 | not provided | Noonan syndrome with multiple lentigines | no assertion provided | literature only | ||
Institute of Molecular Pathology and Immunology of the University of Porto |
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, |
RCV000157685 | SCV000207668 | pathogenic | not provided | 2015-01-15 | no assertion criteria provided | clinical testing | |
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, |
RCV000014985 | SCV001482333 | pathogenic | Noonan syndrome 5 | 2019-05-31 | no assertion criteria provided | research | |
Diagnostic Laboratory, |
RCV000157685 | SCV001743956 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000157685 | SCV001956376 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000157685 | SCV001974063 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Division of Human Genetics, |
RCV000856803 | SCV003840161 | pathogenic | Noonan syndrome 1 | no assertion criteria provided | research | ||
Molecular Genetics, |
RCV000856803 | SCV004190086 | pathogenic | Noonan syndrome 1 | no assertion criteria provided | clinical testing |