NM_002880.4(RAF1):c.770C>T (p.Ser257Leu) AND Noonan syndrome 5

Germline classification:: Pathogenic (9 submissions)
Last evaluated:: May 22, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000014985.47

Allele description [Variation Report for NM_002880.4(RAF1):c.770C>T (p.Ser257Leu)]

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

Gene:

RAF1:Raf-1 proto-oncogene, serine/threonine kinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p25.2

Genomic location:

Preferred name:

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

Other names:

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

HGVS:

NC_000003.12:g.12604200G>A
NG_007467.1:g.64980C>T
NM_001354689.3:c.770C>T
NM_001354690.3:c.770C>T
NM_001354691.3:c.527C>T
NM_001354692.3:c.527C>T
NM_001354693.3:c.671C>T
NM_001354694.3:c.527C>T
NM_001354695.3:c.428C>T
NM_002880.4:c.770C>TMANE SELECT
NP_001341618.1:p.Ser257Leu
NP_001341619.1:p.Ser257Leu
NP_001341620.1:p.Ser176Leu
NP_001341621.1:p.Ser176Leu
NP_001341622.1:p.Ser224Leu
NP_001341623.1:p.Ser176Leu
NP_001341624.1:p.Ser143Leu
NP_002871.1:p.Ser257Leu
NP_002871.1:p.Ser257Leu
LRG_413t1:c.770C>T
LRG_413t2:c.770C>T
LRG_413:g.64980C>T
LRG_413p1:p.Ser257Leu
LRG_413p2:p.Ser257Leu
NC_000003.11:g.12645699G>A
NM_001354689.1:c.770C>T
NM_002880.2:c.770C>T
NM_002880.3:c.770C>T
NM_002880.4:c.770C>T
NR_148940.3:n.1101C>T
NR_148941.3:n.1101C>T
NR_148942.3:n.1101C>T
P04049:p.Ser257Leu

Protein change:

S143L; SER257LEU

Links:

UniProtKB: P04049#VAR_037808; OMIM: 164760.0001; dbSNP: rs80338796

NCBI 1000 Genomes Browser:

rs80338796

Molecular consequence:

NM_001354689.3:c.770C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354690.3:c.770C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354691.3:c.527C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354692.3:c.527C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354693.3:c.671C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354694.3:c.527C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354695.3:c.428C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_002880.4:c.770C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_148940.3:n.1101C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_148941.3:n.1101C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_148942.3:n.1101C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Noonan syndrome 5 (NS5)
Synonyms:: RAF1 gene related Noonan syndrome
Identifiers:: MONDO: MONDO:0012690; MedGen: C1969057; Orphanet: 648; OMIM: 611553

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000035241	OMIM	no assertion criteria provided	Pathogenic (Aug 1, 2007)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 17603483, 17603482
SCV000143821	Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP)	no classification provided	not provided	germline	not provided	PubMed (1) [See all records that cite this PMID]
SCV000680354	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (Nov 15, 2017)	germline	clinical testing	Citation Link,
SCV001482333	Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital	no assertion criteria provided	Pathogenic (May 31, 2019)	de novo	research
SCV002059455	Centogene AG - the Rare Disease Company	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 11, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002521319	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 22, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 23877478, 22389993, 17603482, 20052757, 17603483, 29493581, 25706034, 25741868
SCV002767731	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 19, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003915615	Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 22, 2022)	de novo	clinical testing	PubMed (6) [See all records that cite these PMIDs] 33240318, 32981126, 32668055, 32573669, 32506814, 25741868
SCV004047601	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	not provided	not provided	2	not provided	clinical testing
not provided	de novo	yes	not provided	not provided	not provided	not provided	not provided	clinical testing, research
not provided	germline	not provided	not provided	not provided	not provided	1	not provided	literature only

Citations

PubMed

Unique cerebrovascular anomalies in Noonan syndrome with RAF1 mutation.

Zarate YA, Lichty AW, Champion KJ, Clarkson LK, Holden KR, Matheus MG.

J Child Neurol. 2014 Aug;29(8):NP13-7. doi: 10.1177/0883073813492384. Epub 2013 Jul 21.

PubMed [citation]

PMID:: 23877478

Two cases of LEOPARD syndrome--RAF1 mutations firstly described in children.

Kuburović V, Vukomanović V, Carcavilla A, Ezquieta-Zubicaray B, Kuburović N.

Turk J Pediatr. 2011 Nov-Dec;53(6):687-91.

PubMed [citation]

PMID:: 22389993

See all PubMed Citations (13)

Details of each submission

From OMIM, SCV000035241.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), SCV000143821.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	not provided	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	1	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV000680354.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	blood	not provided		1	not provided	not provided	not provided

From Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital, SCV001482333.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Centogene AG - the Rare Disease Company, SCV002059455.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV002521319.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (8)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002767731.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province, SCV003915615.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV004047601.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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