ClinVar Genomic variation as it relates to human health
NM_002880.4(RAF1):c.776C>T (p.Ser259Phe)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002880.4(RAF1):c.776C>T (p.Ser259Phe)
Variation ID: 40603 Accession: VCV000040603.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p25.2 3: 12604194 (GRCh38) [ NCBI UCSC ] 3: 12645693 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jan 31, 2016 Feb 28, 2024 Jan 4, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002880.4:c.776C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002871.1:p.Ser259Phe missense NM_001354689.3:c.776C>T NP_001341618.1:p.Ser259Phe missense NM_001354690.3:c.776C>T NP_001341619.1:p.Ser259Phe missense NM_001354691.3:c.533C>T NP_001341620.1:p.Ser178Phe missense NM_001354692.3:c.533C>T NP_001341621.1:p.Ser178Phe missense NM_001354693.3:c.677C>T NP_001341622.1:p.Ser226Phe missense NM_001354694.3:c.533C>T NP_001341623.1:p.Ser178Phe missense NM_001354695.3:c.434C>T NP_001341624.1:p.Ser145Phe missense NR_148940.3:n.1107C>T non-coding transcript variant NR_148941.3:n.1107C>T non-coding transcript variant NR_148942.3:n.1107C>T non-coding transcript variant NC_000003.12:g.12604194G>A NC_000003.11:g.12645693G>A NG_007467.1:g.64986C>T LRG_413:g.64986C>T LRG_413t1:c.776C>T LRG_413p1:p.Ser259Phe LRG_413t2:c.776C>T LRG_413p2:p.Ser259Phe P04049:p.Ser259Phe - Protein change
- S259F, S226F, S145F, S178F
- Other names
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- Canonical SPDI
- NC_000003.12:12604193:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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RAF1 | No evidence available | No evidence available |
GRCh38 GRCh37 |
1073 | 1128 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Jan 14, 2022 | RCV000204940.6 | |
Likely pathogenic (1) |
no assertion criteria provided
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May 13, 2016 | RCV000423120.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 1, 2020 | RCV001813266.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 4, 2023 | RCV002504857.3 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Oct 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV002817211.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple individuals with clinical features associated with … (more)
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple individuals with clinical features associated with this gene (PMID: 17603483, 20052757, 23613113). Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 17603483, 20052757). This variant is located in a region that is considered important for protein function and/or structure (PMID: 17603483, 20052757, 21784453).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. (less)
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Pathogenic
(Jan 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004564291.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The RAF1 c.776C>T; p.Ser259Phe variant (rs397516827) is reported in the literature in individuals affected with Noonan syndrome (Kobayashi 2010, Pandit 2007). This variant is also … (more)
The RAF1 c.776C>T; p.Ser259Phe variant (rs397516827) is reported in the literature in individuals affected with Noonan syndrome (Kobayashi 2010, Pandit 2007). This variant is also reported in ClinVar (Variation ID: 40603), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The serine at codon 259 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.786). The serine at residue 259 is critical for regulation of the protein, and amino acid changes to this residue and others in the CR2 domain lead to increased RAF1 kinase activity (Kobayashi 2010, Pandit 2007). Indeed, other amino acid substitutions at this codon (Cys, Pro, Thr, Tyr, Leu) have been reported in individuals with Noonan syndrome and are considered pathogenic (Bowling 2022, Croonen 2013, Jaouadi 2019, Kauffman 2021). Based on available information, the p.Ser259Phe variant is considered to be pathogenic. References: Bowling KM et al. Genome sequencing as a first-line diagnostic test for hospitalized infants. Genet Med. 2022 Apr;24(4):851-861. PMID: 34930662. Croonen EA et al. Prenatal diagnostic testing of the Noonan syndrome genes in fetuses with abnormal ultrasound findings. Eur J Hum Genet. 2013 Sep;21(9):936-42. PMID: 23321623. Jaouadi H et al. A severe clinical phenotype of Noonan syndrome with neonatal hypertrophic cardiomyopathy in the second case worldwide with RAF1 S259Y neomutation. Genet Res (Camb). 2019 Apr 29;101:e6. PMID: 31030682. Kauffman H et al. Genotype-phenotype association by echocardiography offers incremental value in patients with Noonan Syndrome with Multiple Lentigines. Pediatr Res. 2021 Aug;90(2):444-451. PMID: 33318624. Kobayashi T et al. Molecular and clinical analysis of RAF1 in Noonan syndrome and related disorders: dephosphorylation of serine 259 as the essential mechanism for mutant activation. Hum Mutat. 2010 Mar;31(3):284-94. PMID: 20052757. Pandit B et al. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet. 2007 Aug;39(8):1007-12. PMID: 17603483. (less)
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Pathogenic
(Feb 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome and Noonan-related syndrome
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002060976.1
First in ClinVar: Jan 20, 2022 Last updated: Jan 20, 2022 |
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Pathogenic
(Jan 14, 2022)
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criteria provided, single submitter
Method: clinical testing
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RASopathy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000259338.5
First in ClinVar: Jan 31, 2016 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This missense change is located in a region of the RAF1 protein where a significant … (more)
For these reasons, this variant has been classified as Pathogenic. This missense change is located in a region of the RAF1 protein where a significant number of previously reported RAF1 missense mutations are found (PMID: 17603483) Experimental studies have shown that this missense change affects RAF1 function (PMID: 17603483, 20052757, 21784453). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RAF1 protein function. ClinVar contains an entry for this variant (Variation ID: 40603). This missense change has been observed in individuals with Noonan syndrome (PMID: 17603483, 20052757, 22465605). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 259 of the RAF1 protein (p.Ser259Phe). (less)
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Likely pathogenic
(May 13, 2016)
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no assertion criteria provided
Method: literature only
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Noonan syndrome
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000510513.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Alterations in RAS-MAPK genes in 200 Spanish patients with Noonan and other neuro-cardio-facio-cutaneous syndromes. Genotype and cardiopathy. | Ezquieta B | Revista espanola de cardiologia (English ed.) | 2012 | PMID: 22465605 |
Spectrum of mutations in Noonan syndrome and their correlation with phenotypes. | Lee BH | The Journal of pediatrics | 2011 | PMID: 21784453 |
Molecular and clinical analysis of RAF1 in Noonan syndrome and related disorders: dephosphorylation of serine 259 as the essential mechanism for mutant activation. | Kobayashi T | Human mutation | 2010 | PMID: 20052757 |
Common variants in WFS1 confer risk of type 2 diabetes. | Sandhu MS | Nature genetics | 2007 | PMID: 17603484 |
Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. | Pandit B | Nature genetics | 2007 | PMID: 17603483 |
Germline gain-of-function mutations in RAF1 cause Noonan syndrome. | Razzaque MA | Nature genetics | 2007 | PMID: 17603482 |
http://docm.genome.wustl.edu/variants/ENST00000442415:c.776C>T | - | - | - | - |
Text-mined citations for rs397516827 ...
HelpRecord last updated May 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.