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

Germline classification:
Pathogenic (1 submission)
Last evaluated:
May 23, 2013
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:
RCV000824754.12

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:
23

Condition(s)

Name:
Noonan syndrome with multiple lentigines (NSML)
Synonyms:
Lentigines, Electrocardiographic conduction abnormalities, Ocular hypertelorism, Pulmonic stenosis, Abnormal genitalia, Retardation of growth, Deafness; Cardiomyopathic lentiginosis; LEOPARD syndrome
Identifiers:
MONDO: MONDO:0007893; MedGen: C0175704; Orphanet: 500; OMIM: PS151100
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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000200043Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)		Pathogenic
(May 23, 2013) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided2323not providednot providednot providedclinical 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 (4)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000200043.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided23not providednot providedclinical testing PubMed (4)

Description

The p.Ser257Leu variant has been associated with the clinical features of RASopa thy disorders (Razzaque 2007, Pandit 2007). This variant has been reported to ha ve occurred de novo in sporadic cases. Individuals with pathogenic variants in exon 7 or 17 in RAF1 have a high incidence of hypertrophic cardiomyopathy (80-95 %, Razzaque 2007, Pandit 2007). In summary, this variant meets criteria to be cl assified as pathogenic for RASopathy disorders in an autosomal dominant manner b ased upon published literature and de novo occurrence in affected individuals.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided23not provided23not provided

Last Updated: Oct 26, 2024