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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Rattus norvegicus nuclear protein localization 4 homolog (S. cerevisiae), mRNA (...
Rattus norvegicus nuclear protein localization 4 homolog (S. cerevisiae), mRNA (cDNA clone MGC:124575 IMAGE:7930738), complete cds
gi|74353674|gb|BC101887.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002768202	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 2, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17603482, 17603483, 32269299, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002768202

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 2, 2022)

germline

clinical testing

PubMed (4)
[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	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 (4)

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002768202.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical 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

#	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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