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NM_002880.4(RAF1):c.1201C>T (p.Arg401Trp) AND Noonan syndrome 5

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Feb 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:
RCV002471491.1

Allele description [Variation Report for NM_002880.4(RAF1):c.1201C>T (p.Arg401Trp)]

NM_002880.4(RAF1):c.1201C>T (p.Arg401Trp)

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.1201C>T (p.Arg401Trp)
HGVS:
  • NC_000003.12:g.12590967G>A
  • NG_007467.1:g.78213C>T
  • NM_001354689.3:c.1261C>T
  • NM_001354690.3:c.1201C>T
  • NM_001354691.3:c.958C>T
  • NM_001354692.3:c.958C>T
  • NM_001354693.3:c.1102C>T
  • NM_001354694.3:c.1018C>T
  • NM_001354695.3:c.859C>T
  • NM_002880.4:c.1201C>TMANE SELECT
  • NP_001341618.1:p.Arg421Trp
  • NP_001341619.1:p.Arg401Trp
  • NP_001341620.1:p.Arg320Trp
  • NP_001341621.1:p.Arg320Trp
  • NP_001341622.1:p.Arg368Trp
  • NP_001341623.1:p.Arg340Trp
  • NP_001341624.1:p.Arg287Trp
  • NP_002871.1:p.Arg401Trp
  • NP_002871.1:p.Arg401Trp
  • LRG_413t1:c.1201C>T
  • LRG_413t2:c.1261C>T
  • LRG_413:g.78213C>T
  • LRG_413p1:p.Arg401Trp
  • LRG_413p2:p.Arg421Trp
  • NC_000003.11:g.12632466G>A
  • NM_001354689.1:c.1261C>T
  • NM_002880.3:c.1201C>T
  • NR_148940.3:n.1645C>T
  • NR_148941.3:n.1591C>T
  • NR_148942.3:n.1530C>T
Protein change:
R287W
Molecular consequence:
  • NM_001354689.3:c.1261C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354690.3:c.1201C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354691.3:c.958C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354692.3:c.958C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354693.3:c.1102C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354694.3:c.1018C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354695.3:c.859C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002880.4:c.1201C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_148940.3:n.1645C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_148941.3:n.1591C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_148942.3:n.1530C>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

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002768202Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Feb 2, 2022) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot 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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002768202.1

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

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. 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 with 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 arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional dimer interface of protein kinase domain (NCBI, PMID: 32269299). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024