VCV000013957.95 - ClinVar

NM_002880.4(RAF1):c.770C>T (p.Ser257Leu)

Germline

Top reviewed classifications are shown here.

Submission summary:

45 submissions

40 submitters

17 conditions

Reviewed by expert panel

Pathogenic

Apr 2017 by ClinGen RASopa… FDA Recognized Database

for Noonan syndrome

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002880.4(RAF1):c.770C>T (p.Ser257Leu)

Variation ID: 13957 Accession: VCV000013957.95

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p25.2 3: 12604200 (GRCh38) [ NCBI UCSC ] 3: 12645699 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Oct 20, 2024	Apr 3, 2017

HGVS

Nucleotide	Protein	Molecular consequence
NM_002880.4:c.770C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002871.1:p.Ser257Leu	missense
NM_001354689.3:c.770C>T	NP_001341618.1:p.Ser257Leu	missense
NM_001354690.3:c.770C>T	NP_001341619.1:p.Ser257Leu	missense
NM_001354691.3:c.527C>T	NP_001341620.1:p.Ser176Leu	missense
NM_001354692.3:c.527C>T	NP_001341621.1:p.Ser176Leu	missense
NM_001354693.3:c.671C>T	NP_001341622.1:p.Ser224Leu	missense
NM_001354694.3:c.527C>T	NP_001341623.1:p.Ser176Leu	missense
NM_001354695.3:c.428C>T	NP_001341624.1:p.Ser143Leu	missense
NR_148940.3:n.1101C>T		non-coding transcript variant
NR_148941.3:n.1101C>T		non-coding transcript variant
NR_148942.3:n.1101C>T		non-coding transcript variant
NC_000003.12:g.12604200G>A
NC_000003.11:g.12645699G>A
NG_007467.1:g.64980C>T
LRG_413:g.64980C>T
LRG_413t1:c.770C>T	LRG_413p1:p.Ser257Leu
LRG_413t2:c.770C>T	LRG_413p2:p.Ser257Leu
	P04049:p.Ser257Leu

... more HGVS ... less HGVS

Protein change

S257L, S224L, S143L, S176L

Other names

p.S257L:TCG>TTG
NM_002880.3(RAF1):c.770C>T

Canonical SPDI

NC_000003.12:12604199:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

UniProtKB: P04049#VAR_037808 OMIM: 164760.0001 dbSNP: rs80338796 ClinGen: CA235334 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
RAF1		No evidence available	No evidence available	GRCh38 GRCh37	1088	1143

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Noonan syndrome 5	Pathogenic (9)	criteria provided, multiple submitters, no conflicts	May 22, 2022	RCV000014985.47
LEOPARD syndrome 2	Pathogenic (2)	criteria provided, single submitter	May 20, 2019	RCV000014986.34
Noonan syndrome with multiple lentigines	not provided (1)	no classification provided	-	RCV000020509.11
Noonan syndrome	Pathogenic (4)	reviewed by expert panel	Apr 3, 2017	RCV000157426.14
not provided	Pathogenic (12)	criteria provided, multiple submitters, no conflicts	Dec 1, 2022	RCV000157685.52
RASopathy	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Dec 24, 2023	RCV000149826.24
Lung adenocarcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000418940.9
Gastric adenocarcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000428775.9
Neoplasm of the large intestine	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000436233.9
Malignant melanoma of skin	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000435984.9
Dilated cardiomyopathy 1NN LEOPARD syndrome 2 Noonan syndrome 5	Pathogenic (1)	criteria provided, single submitter	Jul 1, 2021	RCV000515222.11
Noonan syndrome Noonan syndrome with multiple lentigines	Pathogenic (1)	criteria provided, single submitter	May 23, 2013	RCV000824754.12
Noonan syndrome 1	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	-	RCV000856803.12
RAF1-related disorder	Pathogenic (1)	criteria provided, single submitter	Oct 21, 2020	RCV001731288.9
Noonan syndrome and Noonan-related syndrome	Pathogenic (1)	criteria provided, single submitter	Apr 26, 2021	RCV001813205.11
Cardiovascular phenotype	Pathogenic (1)	criteria provided, single submitter	Aug 4, 2021	RCV002399323.9
See cases	Pathogenic (1)	criteria provided, single submitter	Apr 4, 2023	RCV003231105.8
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Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Apr 03, 2017)	reviewed by expert panel (ClinGen RASopathy ACMG Specifications v1) Method: curation	Noonan syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	ClinGen RASopathy Variant Curation Expert Panel FDA Recognized Database Accession: SCV000616378.4 First in ClinVar: Dec 19, 2017 Last updated: Dec 11, 2022	Publications: PubMed (5) PubMed: 17603482‚ 25706034‚ 29493581‚ 23877478‚ 22389993 Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/6eb64962-8efe-49ca-a5e1-499e4cddd80f Comment: 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 … (more) 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. (less)
Pathogenic (Apr 14, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000341105.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Publications: PubMed (3) PubMed: 17603482‚ 20052757‚ 24775816 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RAF1 Number of individuals with the variant: 1 Sex: mixed
Pathogenic (Dec 11, 2018)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Rasopathy Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000918146.1 First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019	Publications: PubMed (11) PubMed: 19953625‚ 17603483‚ 17603482‚ 19568997‚ 21784453‚ 10064593‚ 23312806‚ 23877478‚ 23321623‚ 21440552‚ 29084544 Comment: 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 … (more) 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. (less)
Pathogenic (May 23, 2013)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Noonan syndrome Noonan syndrome with multiple lentigines (Autosomal dominant inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000200043.5 First in ClinVar: Jan 30, 2015 Last updated: Aug 26, 2019	Publications: PubMed (3) PubMed: 17603482‚ 17603483‚ 25706034 Comment: 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 … (more) 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. (less) Number of individuals with the variant: 23
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome 1 Affected status: yes Allele origin: unknown	Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn Accession: SCV000999369.1 First in ClinVar: Dec 01, 2019 Last updated: Dec 01, 2019	Number of individuals with the variant: 1 Clinical Features: Hypertrophic cardiomyopathy (present) , Hypertelorism (present) , High forehead (present) , Short stature (present) , Global developmental delay (present) , Depressed nasal bridge (present) , … (more) Hypertrophic cardiomyopathy (present) , Hypertelorism (present) , High forehead (present) , Short stature (present) , Global developmental delay (present) , Depressed nasal bridge (present) , Failure to thrive in infancy (present) , Curly hair (present) , Polyhydramnios (present) , Low-set, posteriorly rotated ears (present) , Nevus flammeus (present) , Single umbilical artery (present) , Relative macrocephaly (present) , Strabismus (present) (less)
Pathogenic (Nov 16, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Noonan syndrome Affected status: yes Allele origin: germline	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute Accession: SCV000996383.2 First in ClinVar: Nov 02, 2019 Last updated: Nov 02, 2019	Publications: PubMed (7) PubMed: 17603482‚ 17603483‚ 25706034‚ 20052757‚ 24775816‚ 23877478‚ 29084544 Comment: 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 … (more) 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". (less)
Pathogenic (May 20, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	LEOPARD syndrome 2 Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001369226.2 First in ClinVar: Jul 06, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM1,PM2,PM5,PP2,PP3.
Pathogenic (Jun 05, 2020)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001473076.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021	Comment: 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 … (more) 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. (less)
Pathogenic (Feb 11, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome 5 Affected status: yes Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV002059455.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022
Pathogenic (Oct 19, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome 5 Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002767731.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Comment: A heterozygous missense variant was identified, NM_002880.3(RAF1):c.770C>T in exon 7 of the RAF1 gene. This substitution is predicted to create a major amino acid change … (more) A heterozygous missense variant was identified, NM_002880.3(RAF1):c.770C>T in exon 7 of the RAF1 gene. This substitution is predicted to create a major amino acid change from a serine to a leucine at position 257 of the protein; NP_002871.1(RAF1):p.(Ser257Leu). The serine at this position has very high conservation (100 vertebrates, UCSC), and is not situated in a known functional domain (NCBI, PDB). In silico software predictions of the pathogenicity of this variant are conflicting (FATHMM, PolyPhen2, MutationAssessor, PROVEAN). The variant is not present in the gnomAD population database. It is located within a mutational hotspot and has been previously reported as pathogenic in patients with Noonan syndrome (ClinGen RASopathy Variant Curation Expert Panel). Analysis of parental samples indicated that this variant is de novo. Based on information available at the time of curation, this variant has been classified as PATHOGENIC. (less)
Pathogenic (Jul 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome 5 LEOPARD syndrome 2 Dilated cardiomyopathy 1NN Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000611310.2 First in ClinVar: Nov 11, 2017 Last updated: Dec 31, 2022
Pathogenic (Sep 09, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000209016.13 First in ClinVar: Feb 19, 2015 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (Mar 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome 5 Affected status: yes Allele origin: de novo	Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province Accession: SCV003915615.1 First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023	Publications: PubMed (5) PubMed: 33240318‚ 32981126‚ 32668055‚ 32573669‚ 32506814
Pathogenic (Jun 15, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001714082.2 First in ClinVar: Jun 15, 2021 Last updated: Jan 26, 2024	Publications: PubMed (32) PubMed: 17603482‚ 22389993‚ 23877478‚ 24775816‚ 24803665‚ 25706034‚ 26918529‚ 28777121‚ 28973083‚ 28991257‚ 29084544‚ 29907801‚ 30055033‚ 30105547‚ 30138938‚ 30384889‚ 30417923‚ 30732632‚ 31324109‚ 31395954‚ 31560489‚ 32410215‚ 32506814‚ 32573669‚ 32668055‚ 32981126‚ 33240318‚ 33318624‚ 33673806‚ 34006472‚ 34136434‚ 35050212 Comment: PP2, PM1, PM2, PS2_very_strong, PS3, PS4 Number of individuals with the variant: 14
Pathogenic (Dec 24, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	RASopathy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000287743.11 First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024	Publications: PubMed (6) PubMed: 28492532‚ 17603482‚ 17603483‚ 20052757‚ 22389993‚ 23877478 Comment: 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). … (more) 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. (less)
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Centre for Human Genetics Accession: SCV005199934.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024	Comment: 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) … (more) 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). (less) Number of individuals with the variant: 1 Secondary finding: no
Pathogenic (Jul 21, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: unknown, de novo	Molecular Diagnostics Lab, Nemours Children's Health, Delaware Accession: SCV000263046.1 First in ClinVar: Feb 19, 2015 Last updated: Feb 19, 2015	Publications: PubMed (2) PubMed: 17603483‚ 17603482 Observation 1: Number of individuals with the variant: 1 Clinical Features: Ventricular septal defect (present) , Hypertrphic cardiomyopathy (present) Age: 0-9 years Sex: female Ethnicity/Population group: unknown Observation 2: Number of individuals with the variant: 1 Age: 0-9 years Sex: male Ethnicity/Population group: unknown Observation 3: Number of individuals with the variant: 1 Clinical Features: Failure to thrive (present) , Cardiac hypertrophy (present) , Disorders of both mitral and tricuspid valves (present) , Esophageal reflux (present) , Delayed milestones (present) … (more) Failure to thrive (present) , Cardiac hypertrophy (present) , Disorders of both mitral and tricuspid valves (present) , Esophageal reflux (present) , Delayed milestones (present) , Nystagmus (present) , Down slanting palpebral fissures (present) , Mild deep palmar and plantar creases (present) , Increased extra axial cerebrospinal fluid (present) , Nasogastric tube as needed (present) , Mild ulnar deviation of wrist and fingers (present) , Short stature (<2nd centile) (present) , Relative macrocephaly (present) , Polyhydramnios (present) , Small pale optic nerve (present) (less) Age: 0-9 years Sex: male Ethnicity/Population group: unknown Observation 4: Number of individuals with the variant: 1 Age: 0-9 years Sex: male Ethnicity/Population group: unknown Observation 5: Number of individuals with the variant: 1 Clinical Features: Intra-uterine growth retardation (present) , Hypertrophic myocardiopathy (present) , Mental retardation (present) , Short stature (present) , Suggestive features (present) Age: 0-9 years Sex: male Ethnicity/Population group: unknown
Pathogenic (Oct 05, 2015)	criteria provided, single submitter (Variant Classification) Method: clinical testing	Noonan syndrome Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV000207169.3 First in ClinVar: Feb 06, 2015 Last updated: Dec 19, 2017	Publications: PubMed (2) PubMed: 17603482‚ 24775816 Number of individuals with the variant: 2
Pathogenic (Nov 15, 2017)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Noonan syndrome 5 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV000680354.1 First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018	Sex: female Tissue: blood
Pathogenic (Oct 21, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	RAF1-related disorders Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV001984841.1 First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021	Comment: 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, … (more) 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. (less)
Pathogenic (Apr 26, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome and Noonan-related syndrome Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002060975.1 First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022
Pathogenic (Feb 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Centro Nacional de Genética Medica "Dr. Eduardo E. Castilla", Administración Nacional de Laboratorios e Institutos de Salud Accession: SCV002098092.1 First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022	Clinical Features: Prominent forehead with flat capillary malformation (present) , sparse hair (present) , descending palpebral fissure (present) , low nasal bridge (present) , slight retrognathia (present) … (more) Prominent forehead with flat capillary malformation (present) , sparse hair (present) , descending palpebral fissure (present) , low nasal bridge (present) , slight retrognathia (present) , lowered rotated ears (present) , Hypertrophic cardiomyopathy (present) , Costello syndrome phenotype (present) (less) Sex: female Tissue: blood Secondary finding: no
Pathogenic (May 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome 5 Affected status: yes Allele origin: germline	3billion Accession: SCV002521319.1 First in ClinVar: Jun 05, 2022 Last updated: Jun 05, 2022	Publications: PubMed (7) PubMed: 23877478‚ 22389993‚ 17603482‚ 20052757‚ 17603483‚ 29493581‚ 25706034 Comment: 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 … (more) 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. (less) Clinical Features: Left ventricular hypertrophy (present)
Pathogenic (Apr 04, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	see cases Affected status: yes Allele origin: unknown	Institute of Human Genetics, University Hospital Muenster Accession: SCV003929505.1 First in ClinVar: Jun 10, 2023 Last updated: Jun 10, 2023	Comment: ACMG categories: PS3,PM1,PM2,PP3,PP5 Number of individuals with the variant: 1 Clinical Features: Global developmental delay (present) , Short stature (present) , Hypertrophic cardiomyopathy (present) , Cardiomyopathy (present) , Atrial septal defect (present) , Hypertelorism (present) , Low … (more) Global developmental delay (present) , Short stature (present) , Hypertrophic cardiomyopathy (present) , Cardiomyopathy (present) , Atrial septal defect (present) , Hypertelorism (present) , Low anterior hairline (present) , Webbed neck (present) (less) Age: 0-9 years Sex: female Tissue: blood
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome 5 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004047601.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023	Comment: 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 … (more) 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. (less) Clinical Features: Short stature (present) , Abnormal cardiovascular system morphology (present) , Enlarged thorax (present) , Prominent forehead (present) , Thickened skin (present) , Dry skin (present) … (more) Short stature (present) , Abnormal cardiovascular system morphology (present) , Enlarged thorax (present) , Prominent forehead (present) , Thickened skin (present) , Dry skin (present) , Webbed neck (present) , Abnormal facial shape (present) (less)
Pathogenic (Aug 04, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002669882.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (16) PubMed: 17603482‚ 17603483‚ 20052757‚ 23877478‚ 24775816‚ 26918529‚ 27631234‚ 28973083‚ 28991257‚ 29084544‚ 30105547‚ 30138938‚ 30384889‚ 31560489‚ 32573669‚ 33240318 Comment: 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 … (more) 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. (less)
Pathogenic (Jul 13, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005198036.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Dec 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002496785.18 First in ClinVar: Apr 11, 2022 Last updated: Oct 20, 2024	Comment: RAF1: PS2:Very Strong, PM2, PS3:Supporting Number of individuals with the variant: 2
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Rasopathy Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV000196668.1 First in ClinVar: Jan 17, 2015 Last updated: Jan 17, 2015	Publications: PubMed (3) PubMed: 17603482‚ 23312806‚ 23877478 Comment: Variant classified using ACMG guidelines
Pathogenic (Jan 15, 2015)	no assertion criteria provided Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV000207668.1 First in ClinVar: Feb 19, 2015 Last updated: Feb 19, 2015
Pathogenic (Aug 01, 2007)	no assertion criteria provided Method: literature only	LEOPARD SYNDROME 2 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000035242.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 23, 2016	Publications: PubMed (2) PubMed: 17603483‚ 17603482 Comment on evidence: In 7 unrelated patients with Noonan syndrome (NS5; 611553) and 1 patient with LEOPARD syndrome-2 (LPRD2; 611554), Pandit et al. (2007) identified heterozygosity for a … (more) In 7 unrelated patients with Noonan syndrome (NS5; 611553) and 1 patient with LEOPARD syndrome-2 (LPRD2; 611554), Pandit et al. (2007) identified heterozygosity for a 770C-T transition in exon 7 of the RAF1 gene, resulting in a ser257-to-leu (S257L) substitution at a conserved residue in the CR2 domain. All patients had hypertrophic cardiomyopathy (CMH), including a 3.6-year-old girl with CMH at birth and a 35-year-old woman with LEOPARD syndrome. Ectopically expressed S257L mutants demonstrated increased kinase activity and enhanced ERK (see 176948) activation. Razzaque et al. (2007) identified the S257L mutation of the RAF1 gene in 4 unrelated patients with Noonan syndrome, 3 with obstructive and 1 with nonobstructive CMH. The mutation was not found in 100 control individuals or in 100 patients with CMH without Noonan syndrome. (less)
Pathogenic (Aug 01, 2007)	no assertion criteria provided Method: literature only	NOONAN SYNDROME 5 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000035241.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 23, 2016	Publications: PubMed (2) PubMed: 17603483‚ 17603482 Comment on evidence: In 7 unrelated patients with Noonan syndrome (NS5; 611553) and 1 patient with LEOPARD syndrome-2 (LPRD2; 611554), Pandit et al. (2007) identified heterozygosity for a … (more) In 7 unrelated patients with Noonan syndrome (NS5; 611553) and 1 patient with LEOPARD syndrome-2 (LPRD2; 611554), Pandit et al. (2007) identified heterozygosity for a 770C-T transition in exon 7 of the RAF1 gene, resulting in a ser257-to-leu (S257L) substitution at a conserved residue in the CR2 domain. All patients had hypertrophic cardiomyopathy (CMH), including a 3.6-year-old girl with CMH at birth and a 35-year-old woman with LEOPARD syndrome. Ectopically expressed S257L mutants demonstrated increased kinase activity and enhanced ERK (see 176948) activation. Razzaque et al. (2007) identified the S257L mutation of the RAF1 gene in 4 unrelated patients with Noonan syndrome, 3 with obstructive and 1 with nonobstructive CMH. The mutation was not found in 100 control individuals or in 100 patients with CMH without Noonan syndrome. (less)
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Neoplasm of the large intestine (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000507277.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000251849:c.770C>T
Likely pathogenic (May 13, 2016)	no assertion criteria provided Method: literature only	Noonan syndrome (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000507276.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (2) PubMed: 17603482‚ 1760348 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000251849:c.770C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	None (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000507278.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000251849:c.770C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Gastric adenocarcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000507279.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000251849:c.770C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Malignant melanoma of skin (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000507280.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000251849:c.770C>T
Pathogenic (May 31, 2019)	no assertion criteria provided Method: research	Noonan syndrome 5 Affected status: yes Allele origin: de novo	Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital Accession: SCV001482333.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001956376.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001974063.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Pathogenic (-)	no assertion criteria provided Method: research	Noonan syndrome 1 Affected status: yes Allele origin: unknown	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand Accession: SCV003840161.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Number of individuals with the variant: 1
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001743956.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Noonan syndrome 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Molecular Genetics, Centre for Human Genetics Accession: SCV004190086.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Number of individuals with the variant: 3 Secondary finding: no
not provided (-)	no classification provided Method: literature only	Noonan syndrome with multiple lentigines Affected status: not provided Allele origin: unknown	GeneReviews Accession: SCV000040960.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: PubMed (2) PubMed: 17603483‚ 20301557 BookShelf: NBK1383 BookShelf: NBK1383
not provided (-)	no classification provided Method: not provided	Noonan syndrome 5 Affected status: not provided Allele origin: germline	Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) Accession: SCV000143821.1 First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014
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Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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".

Comment:

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.

Comment:

A heterozygous missense variant was identified, NM_002880.3(RAF1):c.770C>T in exon 7 of the RAF1 gene. This substitution is predicted to create a major amino acid change from a serine to a leucine at position 257 of the protein; NP_002871.1(RAF1):p.(Ser257Leu). The serine at this position has very high conservation (100 vertebrates, UCSC), and is not situated in a known functional domain (NCBI, PDB). In silico software predictions of the pathogenicity of this variant are conflicting (FATHMM, PolyPhen2, MutationAssessor, PROVEAN). The variant is not present in the gnomAD population database. It is located within a mutational hotspot and has been previously reported as pathogenic in patients with Noonan syndrome (ClinGen RASopathy Variant Curation Expert Panel). Analysis of parental samples indicated that this variant is de novo. Based on information available at the time of curation, this variant has been classified as PATHOGENIC.

Comment:

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)

Comment:

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.

Comment:

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).

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Noonan Syndrome with Multiple Lentigines.	Adam MP	-	2022	PMID: 20301557
Not Only Diagnostic Yield: Whole-Exome Sequencing in Infantile Cardiomyopathies Impacts on Clinical and Family Management.	Pezzoli L	Journal of cardiovascular development and disease	2021	PMID: 35050212
Strategies in Rapid Genetic Diagnostics of Critically Ill Children: Experiences From a Dutch University Hospital.	Imafidon ME	Frontiers in pediatrics	2021	PMID: 34136434
Exome sequencing reveals genetic architecture in patients with isolated or syndromic short stature.	Fan X	Journal of genetics and genomics = Yi chuan xue bao	2021	PMID: 34006472
Diagnostic yield of genetic testing in a heterogeneous cohort of 1376 HCM patients.	Hathaway J	BMC cardiovascular disorders	2021	PMID: 33673806
Genotype-phenotype association by echocardiography offers incremental value in patients with Noonan Syndrome with Multiple Lentigines.	Kauffman H	Pediatric research	2021	PMID: 33318624
A report on the impact of rapid prenatal exome sequencing on the clinical management of 52 ongoing pregnancies: a retrospective review.	Dempsey E	BJOG : an international journal of obstetrics and gynaecology	2021	PMID: 32981126
Application of Next-Generation Sequencing for Genetic Diagnosis in Neonatal Intensive Care Units: Results of a Multicenter Study in China.	Zhu T	Frontiers in genetics	2020	PMID: 33240318
Exome sequencing improves genetic diagnosis of fetal increased nuchal translucency.	Yang X	Prenatal diagnosis	2020	PMID: 32668055
Feasibility of Ultra-Rapid Exome Sequencing in Critically Ill Infants and Children With Suspected Monogenic Conditions in the Australian Public Health Care System.	Australian Genomics Health Alliance Acute Care Flagship	JAMA	2020	PMID: 32573669
Maternal SLE and brachytelephalangic chondrodysplasia punctata in a patient with unrelated de novo RAF1 and SIX2 variants.	Alkhunaizi E	American journal of medical genetics. Part A	2020	PMID: 32506814
Prenatal exome sequencing in fetuses with congenital heart defects.	Li R	Clinical genetics	2020	PMID: 32410215
Clinical and molecular characterization of children with Noonan syndrome and other RASopathies in Argentina.	Chinton J	Archivos argentinos de pediatria	2019	PMID: 31560489
Infant mortality: the contribution of genetic disorders.	Wojcik MH	Journal of perinatology : official journal of the California Perinatal Association	2019	PMID: 31395954
Prenatal diagnosis of Noonan syndrome in fetuses with increased nuchal translucency and a normal karyotype.	Matyášová M	Ceska gynekologie	2019	PMID: 31324109
Clinical and mutation profile of pediatric patients with RASopathy-associated hypertrophic cardiomyopathy: results from a Chinese cohort.	Chen H	Orphanet journal of rare diseases	2019	PMID: 30732632
Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation.	Bessis D	The British journal of dermatology	2019	PMID: 30417923
Genetic basis of hypertrophic cardiomyopathy in children.	Rupp S	Clinical research in cardiology : official journal of the German Cardiac Society	2019	PMID: 30105547
Comparative assessment of gene-specific variant distribution in prenatal and postnatal cohorts tested for Noonan syndrome and related conditions.	Leach NT	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 29907801
Genetic Basis of Severe Childhood-Onset Cardiomyopathies.	Vasilescu C	Journal of the American College of Cardiology	2018	PMID: 30384889
Genetic Evaluation of 114 Chinese Short Stature Children in the Next Generation Era: a Single Center Study.	Huang Z	Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology	2018	PMID: 30138938
Nonreentrant atrial tachycardia occurs independently of hypertrophic cardiomyopathy in RASopathy patients.	Levin MD	American journal of medical genetics. Part A	2018	PMID: 30055033
ClinGen's RASopathy Expert Panel consensus methods for variant interpretation.	Gelb BD	Genetics in medicine : official journal of the American College of Medical Genetics	2018	PMID: 29493581
Targeted/exome sequencing identified mutations in ten Chinese patients diagnosed with Noonan syndrome and related disorders.	Xu S	BMC medical genomics	2017	PMID: 29084544
Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands.	Jin SC	Nature genetics	2017	PMID: 28991257
Use of Exome Sequencing for Infants in Intensive Care Units: Ascertainment of Severe Single-Gene Disorders and Effect on Medical Management.	Meng L	JAMA pediatrics	2017	PMID: 28973083
RAF1 variants causing biventricular hypertrophic cardiomyopathy in two preterm infants: further phenotypic delineation and review of literature.	Thompson D	Clinical dysmorphology	2017	PMID: 28777121
Approaching the facts between genetic mutation and clinical practice of hypertrophic cardiomyopathy: A case report with RAF1 770C>T mutant.	Wang X	Medicine	2016	PMID: 27631234
Retrospective study of prenatal ultrasound findings in newborns with a Noonan spectrum disorder.	Hakami F	Prenatal diagnosis	2016	PMID: 26918529
Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.	Chang MT	Nature biotechnology	2016	PMID: 26619011
Neonatal pulmonary arterial hypertension and Noonan syndrome: two fatal cases with a specific RAF1 mutation.	Hopper RK	American journal of medical genetics. Part A	2015	PMID: 25706034
Structure-energy-based predictions and network modelling of RASopathy and cancer missense mutations.	Kiel C	Molecular systems biology	2014	PMID: 24803665
Unique cerebrovascular anomalies in Noonan syndrome with RAF1 mutation.	Zarate YA	Journal of child neurology	2014	PMID: 23877478
LEOPARD syndrome: a variant of Noonan syndrome strongly associated with hypertrophic cardiomyopathy.	Carcavilla A	Revista espanola de cardiologia (English ed.)	2013	PMID: 24775816
Prenatal diagnostic testing of the Noonan syndrome genes in fetuses with abnormal ultrasound findings.	Croonen EA	European journal of human genetics : EJHG	2013	PMID: 23321623
Two cases of LEOPARD syndrome--RAF1 mutations firstly described in children.	Kuburović V	The Turkish journal of pediatrics	2011	PMID: 22389993
Spectrum of mutations in Noonan syndrome and their correlation with phenotypes.	Lee BH	The Journal of pediatrics	2011	PMID: 21784453
Cyclosporine attenuates cardiomyocyte hypertrophy induced by RAF1 mutants in Noonan and LEOPARD syndromes.	Dhandapany PS	Journal of molecular and cellular cardiology	2011	PMID: 21440552
Molecular and clinical analysis of RAF1 in Noonan syndrome and related disorders: dephosphorylation of serine 259 as the essential mechanism for mutant activation.	Kobayashi T	Human mutation	2010	PMID: 20052757
Tumor spectrum in children with Noonan syndrome and SOS1 or RAF1 mutations.	Denayer E	Genes, chromosomes & cancer	2010	PMID: 19953625
Visual function in Noonan and LEOPARD syndrome.	Alfieri P	Neuropediatrics	2008	PMID: 19568997
Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy.	Pandit B	Nature genetics	2007	PMID: 17603483
Germline gain-of-function mutations in RAF1 cause Noonan syndrome.	Razzaque MA	Nature genetics	2007	PMID: 17603482
Activation of the Raf/MAP kinase cascade by the Ras-related protein TC21 is required for the TC21-mediated transformation of NIH 3T3 cells.	Rosário M	The EMBO journal	1999	PMID: 10064593
Downgrading of arts-centered education in state schools.	Partridge S	Nursing standard (Royal College of Nursing (Great Britain) : 1987)	1991	PMID: 1760348
http://docm.genome.wustl.edu/variants/ENST00000251849:c.770C>T	-	-	-	-
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RAF1	-	-	-	-
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/6eb64962-8efe-49ca-a5e1-499e4cddd80f	-	-	-	-
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Text-mined citations for rs80338796 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_002880.4(RAF1):c.770C>T (p.Ser257Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs80338796 ...