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

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 2, 2022
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:: RCV000618568.2

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]

Observations:

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

Recent activity

Clear Turn Off Turn On

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

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000740256	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Pathogenic (Jun 2, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 17603482, 17603483, 20683980, 22465605, 22781091, 26266034 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000740256

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Pathogenic
(Jun 2, 2022)

germline

clinical testing

PubMed (6)
[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	1	not provided	not provided	1	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 (6)

Details of each submission

From Ambry Genetics, SCV000740256.4

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

Description

The p.P261S pathogenic mutation (also known as c.781C>T), located in coding exon 6 of the RAF1 gene, results from a C to T substitution at nucleotide position 781. The proline at codon 261 is replaced by serine, an amino acid with similar properties. This alteration has been reported in a number of individuals with Noonan syndrome, including a de novo occurrence. This alteration was also reported to segregate with the disease in a few families (Pandit B et al. Nat. Genet., 2007 Aug;39:1007-12; Razzaque MA et al. Nat. Genet., 2007 Aug;39:1013-7; Longoni M et al. Am. J. Med. Genet. A, 2010 Sep;152A:2176-84; Digilio MC et al. Eur. J. Hum. Genet., 2013 Feb;21:200-4). In vitro studies have suggested a gain of function effect of this variant in the experimental system (Pandit B et al. Nat. Genet., 2007 Aug;39:1007-12; Razzaque MA et al. Nat. Genet., 2007 Aug;39:1013-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Alterations affecting the same amino acid have also been described in affected individuals (Ratola A et al. Pediatr Rep, 2015 May;7:5955; Ezquieta B et al. Rev Esp Cardiol (Engl Ed), 2012 May;65:447-55). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine