ClinVar Genomic variation as it relates to human health
NM_002880.4(RAF1):c.775T>A (p.Ser259Thr)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002880.4(RAF1):c.775T>A (p.Ser259Thr)
Variation ID: 40601 Accession: VCV000040601.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p25.2 3: 12604195 (GRCh38) [ NCBI UCSC ] 3: 12645694 (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, 2015 Feb 14, 2024 Apr 3, 2017 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002880.4:c.775T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002871.1:p.Ser259Thr missense NM_001354689.3:c.775T>A NP_001341618.1:p.Ser259Thr missense NM_001354690.3:c.775T>A NP_001341619.1:p.Ser259Thr missense NM_001354691.3:c.532T>A NP_001341620.1:p.Ser178Thr missense NM_001354692.3:c.532T>A NP_001341621.1:p.Ser178Thr missense NM_001354693.3:c.676T>A NP_001341622.1:p.Ser226Thr missense NM_001354694.3:c.532T>A NP_001341623.1:p.Ser178Thr missense NM_001354695.3:c.433T>A NP_001341624.1:p.Ser145Thr missense NR_148940.3:n.1106T>A non-coding transcript variant NR_148941.3:n.1106T>A non-coding transcript variant NR_148942.3:n.1106T>A non-coding transcript variant NC_000003.12:g.12604195A>T NC_000003.11:g.12645694A>T NG_007467.1:g.64985T>A LRG_413:g.64985T>A LRG_413t1:c.775T>A LRG_413p1:p.Ser259Thr LRG_413t2:c.775T>A LRG_413p2:p.Ser259Thr - Protein change
- S259T, S145T, S178T, S226T
- Other names
- p.S259T:TCC>ACC
- NM_002880.3(RAF1):c.775T>A
- Canonical SPDI
- NC_000003.12:12604194:A:T
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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
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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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
1070 | 1124 |
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
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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/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 21, 2022 | RCV000037698.7 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Mar 16, 2023 | RCV000159074.12 | |
Pathogenic (2) |
reviewed by expert panel
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Apr 3, 2017 | RCV000522675.9 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV003450656.1 |
Submissions - Germline
Classification
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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
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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
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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
(Apr 03, 2017)
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reviewed by expert panel
Method: curation
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Noonan syndrome and Noonan-related syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen RASopathy Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV000616422.4 First in ClinVar: Dec 19, 2017 Last updated: Dec 11, 2022 |
Comment:
The c.775T>A (p.Ser259Thr) variant in RAF1 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features … (more)
The c.775T>A (p.Ser259Thr) variant in RAF1 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; APHP-Robert Debré Hospital internal data; GTR ID's: 28338). The p.Ser259Thr variant has been identified in at least 8 independent occurrences in patients with a RASopathy (PS4_Supporting; GeneDx, Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg internal data; GTR ID's: 26957, 21766, 506381 PMID: 21784453; ClinVar SCV000061360.5; SCV000209017.10). The p.Ser259Thr variant in RAF1 has been reported to segregate with clinical features of a RASopathy in at least 3 family members (PP1; GeneDx, Institute of Human Genetics, Otto von Guericke University Magdeburg internal data; GTR ID's: 26957, 506381; ClinVar SCV000209017.9). In vitro functional studies provide some evidence that the p.Ser259Thr variant may impact protein function (PS3; PMID: 21784453, 20052757). At least 2 other pathogenic missense variants have been previously identified at this codon of RAF1 which may indicate that this residue is critical to the function of the protein (PM5_Strong; ClinVar 40603, 40602, 228288). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581). The variant is located in the RAF1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Ser259Thr variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6_Strong, PS4_Supporting, PP1, PM5_Strong, PM2, PM1, PP2, PP3, PS3. (less)
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Pathogenic
(Jun 23, 2019)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001714081.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment:
PM6_Strong, PS3, PS4_Supporting, PM1, PM2, PM5_Strong, PP2, PP3, PP1
Number of individuals with the variant: 1
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Likely pathogenic
(Sep 09, 2010)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061360.6
First in ClinVar: May 03, 2013 Last updated: Aug 26, 2019 |
Comment:
The Ser259Thr variant in RAF1 has been previously identified in two individuals with clinical features of Noonan syndrome (Ko 2008, LMM unpublished data). In ad … (more)
The Ser259Thr variant in RAF1 has been previously identified in two individuals with clinical features of Noonan syndrome (Ko 2008, LMM unpublished data). In ad dition, two different amino acid changes at this location (Ser259Phe, Ser259Tyr) have been identified in individuals with Noonan spectrum features, suggesting a lterations at this amino acid are not tolerated (Pandit 2007, Kobayashi 2009; LM M unpublished data). Ser259 is also known to be of critical importance to the r egulation of the RAF1 protein (Kobayashi 2009). Therefore, it is likely that thi s variant is pathogenic. (less)
Number of individuals with the variant: 2
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Pathogenic
(Jun 21, 2022)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002761577.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
Comment:
The RAF1 c.775T>A variant is classified as a Pathogenic variant (PS4, PS3, PM5, PP3) This variant is a single nucleotide change in exon 7/18 of … (more)
The RAF1 c.775T>A variant is classified as a Pathogenic variant (PS4, PS3, PM5, PP3) This variant is a single nucleotide change in exon 7/18 of the RAF1 gene, which is predicted to change the amino acid serine at position 259 in the protein to threonine. The variant has been reported multiple times in patients with Noonan syndrome and with clinical features of a RASopathy (PMID: 19020799, 21784453, 33318624, 29493581). This variant is in dbSNP (rs3730271) but is absent from population databases (PS4). Functional studies have shown that this variant may impact protein function by increasing activation of MEK and ERK (PMID: 21784453) (PS3). Missense variants in the same residue (p.S259C, p.S259F, p.S259P, p.A259Y) have been previously reported as pathogenic in association with Noonan spectrum disorders (PM5).The variant has been reported in the ClinVar and HGMD as pathogenic/ disease causing. Computational predictions support a deleterious effect on the gene or gene product (PP3). (less)
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Pathogenic
(Mar 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000209017.12
First in ClinVar: Feb 24, 2015 Last updated: Mar 26, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate increased activation of MEK and ERK (Kobayashi et al., 2010; Lee … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate increased activation of MEK and ERK (Kobayashi et al., 2010; Lee et al., 2011); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20052757, 24957944, 9689060, 15520807, 17603483, 17603482, 29493581, 19020799, 33318624, 21784453) (less)
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Pathogenic
(Jan 10, 2022)
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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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Revvity Omics, Revvity
Accession: SCV003819033.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Nov 19, 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: SCV001379118.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser259 amino acid residue in RAF1. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser259 amino acid residue in RAF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17603483, 20052757, 21784453). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects RAF1 function (PMID: 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: 40601). This missense change has been observed in individuals with Noonan syndrome (PMID: 19020799; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 259 of the RAF1 protein (p.Ser259Thr). (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Noonan syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Molecular Genetics, Centre for Human Genetics
Accession: SCV004190087.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Number of individuals with the variant: 1
Secondary finding: no
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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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Genotype-phenotype association by echocardiography offers incremental value in patients with Noonan Syndrome with Multiple Lentigines. | Kauffman H | Pediatric research | 2021 | PMID: 33318624 |
ClinGen's RASopathy Expert Panel consensus methods for variant interpretation. | Gelb BD | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29493581 |
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 |
PTPN11, SOS1, KRAS, and RAF1 gene analysis, and genotype-phenotype correlation in Korean patients with Noonan syndrome. | Ko JM | Journal of human genetics | 2008 | PMID: 19020799 |
Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. | Pandit B | Nature genetics | 2007 | PMID: 17603483 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/70e55828-a26c-447c-863d-156419f819e2 | - | - | - | - |
Text-mined citations for rs3730271 ...
HelpRecord last updated Mar 17, 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.