NM_002880.4(RAF1):c.781C>T (p.Pro261Ser) AND Noonan syndrome 5

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: May 6, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000014987.29

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_001354689.3:c.781C>T
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]

Condition(s)

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

Recent activity

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Mus musculus immunoglobulin superfamily containing leucine-rich repeat 2 (Islr2)...
Mus musculus immunoglobulin superfamily containing leucine-rich repeat 2 (Islr2), transcript variant 8, mRNA
gi|238859615|ref|NM_001161541.1|

Nucleotide
719239[uid] AND (alive[prop]) (1)
Gene
FLT3LG fms related receptor tyrosine kinase 3 ligand [Macaca mulatta]
FLT3LG fms related receptor tyrosine kinase 3 ligand [Macaca mulatta]
Gene ID:719239

Gene
Hif1an hypoxia-inducible factor 1, alpha subunit inhibitor [Mus musculus]
Hif1an hypoxia-inducible factor 1, alpha subunit inhibitor [Mus musculus]
Gene ID:319594

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000035243	OMIM	no assertion criteria provided	Pathogenic (Aug 1, 2007)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 17603483, 17603482
SCV003921791	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 6, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17603482, 17603483, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000035243

OMIM

no assertion criteria provided

Pathogenic
(Aug 1, 2007)

germline

literature only

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

SCV003921791

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 6, 2021)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Germline gain-of-function mutations in RAF1 cause Noonan syndrome.

Razzaque MA, Nishizawa T, Komoike Y, Yagi H, Furutani M, Amo R, Kamisago M, Momma K, Katayama H, Nakagawa M, Fujiwara Y, Matsushima M, Mizuno K, Tokuyama M, Hirota H, Muneuchi J, Higashinakagawa T, Matsuoka R.

Nat Genet. 2007 Aug;39(8):1013-7. Epub 2007 Jul 1.

PubMed [citation]

PMID:: 17603482

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

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000035243.2

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

Description

In 5 affected individuals of 2 unrelated families with Noonan syndrome (NS5; 611553), Pandit et al. (2007) identified heterozygosity for a 781C-T transition in exon 7 of the RAF1 gene, resulting in a pro261-to-ser (P261S) substitution at a conserved residue in the CR2 domain. Four of the 5 patients had hypertrophic cardiomyopathy (CMH); the 1 individual with a P261S change but without CMH was a 6-year-old girl whose 38-year-old mother had the same mutation and had been diagnosed with CMH at 23 years of age. The mutation was not found in 210 control individuals.

Razzaque et al. (2007) identified the P261S mutation in 3 Noonan syndrome patients, a 1-year-old boy and his 33-year-old father and an unrelated 16-year-old boy. All 3 displayed CMH. The mutation was not found in 100 control individuals or in 100 individuals with CMH without Noonan syndrome. Transfection studies in HEK293 cells demonstrated that P261S behaved as a gain-of-function mutant with increased kinase and ERK (see 176948) activation compared with wildtype RAF1.

#	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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV003921791.2

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

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene. Gain of function is associated with Noonan (MIM#611553) and LEOPARD syndromes (MIM#2611554), while loss of function is associated non-HCM-associated variants (PMID: 17603483, 17603482). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been classified as Pathogenic by ClinGen's RASopathy expert panel (ClinVar). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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: Sep 29, 2024

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