NM_002880.4(RAF1):c.781C>T (p.Pro261Ser) AND Noonan syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Apr 3, 2017
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000211849.8

Allele description [Variation Report for NM_002880.4(RAF1):c.781C>T (p.Pro261Ser)]

NM_002880.4(RAF1):c.781C>T (p.Pro261Ser)

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.781C>T (p.Pro261Ser)

Other names:

p.P261S:CCT>TCT; NM_002880.3(RAF1):c.781C>T

HGVS:

NC_000003.12:g.12604189G>A
NG_007467.1:g.64991C>T
NM_001354689.1:c.781C>T
NM_001354689.3:c.781C>T
NM_001354690.3:c.781C>T
NM_001354691.3:c.538C>T
NM_001354692.3:c.538C>T
NM_001354693.3:c.682C>T
NM_001354694.3:c.538C>T
NM_001354695.3:c.439C>T
NM_002880.4:c.781C>TMANE SELECT
NP_001341618.1:p.Pro261Ser
NP_001341619.1:p.Pro261Ser
NP_001341620.1:p.Pro180Ser
NP_001341621.1:p.Pro180Ser
NP_001341622.1:p.Pro228Ser
NP_001341623.1:p.Pro180Ser
NP_001341624.1:p.Pro147Ser
NP_002871.1:p.Pro261Ser
NP_002871.1:p.Pro261Ser
LRG_413t1:c.781C>T
LRG_413t2:c.781C>T
LRG_413:g.64991C>T
LRG_413p1:p.Pro261Ser
LRG_413p2:p.Pro261Ser
NC_000003.11:g.12645688G>A
NM_002880.3:c.781C>T
NM_002880.4:c.781C>T
NR_148940.3:n.1112C>T
NR_148941.3:n.1112C>T
NR_148942.3:n.1112C>T
P04049:p.Pro261Ser
c.781C>T

Protein change:

P147S; PRO261SER

Links:

UniProtKB: P04049#VAR_037814; OMIM: 164760.0002; dbSNP: rs121434594

NCBI 1000 Genomes Browser:

rs121434594

Molecular consequence:

NM_001354689.3:c.781C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354690.3:c.781C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354691.3:c.538C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354692.3:c.538C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354693.3:c.682C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354694.3:c.538C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354695.3:c.439C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_002880.4:c.781C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_148940.3:n.1112C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_148941.3:n.1112C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_148942.3:n.1112C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Name:: Noonan syndrome (NS)
Synonyms:: Noonan's syndrome; Pseudo-Turner syndrome
Identifiers:: MONDO: MONDO:0018997; MeSH: D009634; MedGen: C0028326; OMIM: PS163950

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000061367	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Mar 22, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17603483, 17603482, 24033266
SCV000510554	Database of Curated Mutations (DoCM)	no assertion criteria provided	Likely pathogenic (May 13, 2016)	somatic	literature only	PubMed (2) [See all records that cite these PMIDs] 17603487, 17603482 Citation Link,
SCV000616379	ClinGen RASopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen RASopathy ACMG Specifications v1)	Pathogenic (Apr 3, 2017)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 17603482, 20683980 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000061367

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Mar 22, 2019)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV000510554

Database of Curated Mutations (DoCM)

no assertion criteria provided

Likely pathogenic
(May 13, 2016)

somatic

literature only

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV000616379

ClinGen RASopathy Variant Curation Expert Panel

reviewed by expert panel

(ClinGen RASopathy ACMG Specifications v1)

Pathogenic
(Apr 3, 2017)

germline

curation

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	7	6	not provided	not provided	not provided	clinical testing, curation
not provided	somatic	yes	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy.

Pandit B, Sarkozy A, Pennacchio LA, Carta C, Oishi K, Martinelli S, Pogna EA, Schackwitz W, Ustaszewska A, Landstrom A, Bos JM, Ommen SR, Esposito G, Lepri F, Faul C, Mundel P, López Siguero JP, Tenconi R, Selicorni A, Rossi C, Mazzanti L, Torrente I, et al.

Nat Genet. 2007 Aug;39(8):1007-12. Epub 2007 Jul 1.

PubMed [citation]

PMID:: 17603483

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

See all PubMed Citations (5)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000061367.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	7	not provided	not provided	clinical testing	PubMed (3)

Description

The p.Pro261Ser variant in RAF1 has been identified in >10 individuals with clinical features of Noonan syndrome (Razzaque 2007, Pandit 2007, Longoni 2010, LMM unpublished data), reported de novo in 2 individuals and reported to segregate in 4 relatives with clinical features of Noonan syndrome from 2 families (Razzaque 2007, Pandit 2007). In addition, this variant was absent from large population studies and is classified as pathogenic by the ClinGen RASopathy variant curation expert panel. Individuals with pathogenic variants in exon 7 or 17 in RAF1 are reported to also have a higher incidence of hypertrophic cardiomyopathy (HCM 80-95%) than typically seen in Noonan syndrome (Razzaque 2007, Pandit 2007). Studies have shown that the Pro261Ser variant impacts protein function by increasing its kinase activity (Razzaque 2007, Pandit 2007). However, these in vitro assays may not accurately represent biological function. 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		7	not provided	6	not provided

From Database of Curated Mutations (DoCM), SCV000510554.1

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

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

From ClinGen RASopathy Variant Curation Expert Panel, SCV000616379.4

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

Description

The c.781C>T (p.Pro261Ser) 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, 20683980). In vitro functional studies provide some evidence that the p.Pro261Leu variant may impact protein function (PS3; PMID 17603483, 17603482). 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). 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). 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.

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

Last Updated: Mar 5, 2024

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