NM_002880.4(RAF1):c.770C>T (p.Ser257Leu) AND LEOPARD syndrome 2

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: May 20, 2019
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:: RCV000014986.34

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]

Condition(s)

Name:: LEOPARD syndrome 2 (LPRD2)
Identifiers:: MONDO: MONDO:0012691; MedGen: C1969056; Orphanet: 500; OMIM: 611554

Recent activity

Clear Turn Off Turn On

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
SCV000035242	OMIM	no assertion criteria provided	Pathogenic (Aug 1, 2007)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 17603483, 17603482
SCV001369226	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 20, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000035242

OMIM

no assertion criteria provided

Pathogenic
(Aug 1, 2007)

germline

literature only

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

SCV001369226

Centre for Mendelian Genomics, University Medical Centre Ljubljana

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 20, 2019)

unknown

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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

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

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

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000035242.2

#	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 Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV001369226.2

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

Description

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM1,PM2,PM5,PP2,PP3.

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

Last Updated: Nov 18, 2024

ClinVar

Relating variation to medicine