ClinVar Genomic variation as it relates to human health
NM_002880.4(RAF1):c.781C>T (p.Pro261Ser)
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.781C>T (p.Pro261Ser)
Variation ID: 13958 Accession: VCV000013958.29
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p25.2 3: 12604189 (GRCh38) [ NCBI UCSC ] 3: 12645688 (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 Feb 27, 2016 Feb 28, 2024 Apr 3, 2017 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002880.4:c.781C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002871.1:p.Pro261Ser missense NM_001354689.1:c.781C>T NM_001354689.3:c.781C>T NP_001341618.1:p.Pro261Ser missense NM_001354690.3:c.781C>T NP_001341619.1:p.Pro261Ser missense NM_001354691.3:c.538C>T NP_001341620.1:p.Pro180Ser missense NM_001354692.3:c.538C>T NP_001341621.1:p.Pro180Ser missense NM_001354693.3:c.682C>T NP_001341622.1:p.Pro228Ser missense NM_001354694.3:c.538C>T NP_001341623.1:p.Pro180Ser missense NM_001354695.3:c.439C>T NP_001341624.1:p.Pro147Ser missense NR_148940.3:n.1112C>T non-coding transcript variant NR_148941.3:n.1112C>T non-coding transcript variant NR_148942.3:n.1112C>T non-coding transcript variant NC_000003.12:g.12604189G>A NC_000003.11:g.12645688G>A NG_007467.1:g.64991C>T LRG_413:g.64991C>T LRG_413t1:c.781C>T LRG_413p1:p.Pro261Ser LRG_413t2:c.781C>T LRG_413p2:p.Pro261Ser P04049:p.Pro261Ser - Protein change
- P261S, P180S, P147S, P228S
- Other names
- p.P261S:CCT>TCT
- NM_002880.3(RAF1):c.781C>T
- Canonical SPDI
- NC_000003.12:12604188: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 |
1070 | 1124 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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 (2) |
criteria provided, single submitter
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May 7, 2021 | RCV000014987.28 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Mar 14, 2023 | RCV000159076.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 14, 2015 | RCV000208421.1 | |
Pathogenic (3) |
reviewed by expert panel
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Apr 3, 2017 | RCV000211849.8 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 24, 2024 | RCV000468714.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 2, 2022 | RCV000618568.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 12, 2016 | RCV000622893.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 1, 2020 | RCV001813206.3 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV003450640.1 |
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
Help
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
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen RASopathy Variant Curation Expert Panel
Accession: SCV000616379.4
First in ClinVar: Dec 19, 2017 Last updated: Dec 11, 2022 |
Comment:
The c.781C>T (p.Pro261Ser) 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.781C>T (p.Pro261Ser) 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; PMID 17603482, 20683980). In vitro functional studies provide some evidence that the p.Pro261Leu variant may impact protein function (PS3; PMID 17603483, 17603482). 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). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). 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). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PP2, PM1, PM2, PS3, PM6_Strong. (less)
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Pathogenic
(Sep 11, 2018)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000920145.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: RAF1 c.781C>T (p.Pro261Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: RAF1 c.781C>T (p.Pro261Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 31494 control chromosomes (gnomAD and publications). c.781C>T has been reported in the literature in multiple individuals affected with Noonan Syndrome and Related Conditions (Pandit_2007, Razzaque_2007). These data indicate that the variant is very likely to be associated with disease. Multiple functional assessments found the variant to cause an increase in kinase activity. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. In addition, other mutations at this position, Pro261Ala and Pro261Thr, have been reported as pathogenic and associated with Noonan syndrome, indicating the location is a mutational hotspot and critical for gene function. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Mar 22, 2019)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061367.7
First in ClinVar: May 03, 2013 Last updated: Jul 06, 2020 |
Comment:
The p.Pro261Ser variant in RAF1 has been identified in >10 individuals with clinical features of Noonan syndrome (Razzaque 2007, Pandit 2007, Longoni 2010, LMM unpublished … (more)
The p.Pro261Ser variant in RAF1 has been identified in >10 individuals with clinical features of Noonan syndrome (Razzaque 2007, Pandit 2007, Longoni 2010, LMM unpublished data), reported de novo in 2 individuals and reported to segregate in 4 relatives with clinical features of Noonan syndrome from 2 families (Razzaque 2007, Pandit 2007). In addition, this variant was absent from large population studies and is classified as pathogenic by the ClinGen RASopathy variant curation expert panel. Individuals with pathogenic variants in exon 7 or 17 in RAF1 are reported to also have a higher incidence of hypertrophic cardiomyopathy (HCM 80-95%) than typically seen in Noonan syndrome (Razzaque 2007, Pandit 2007). Studies have shown that the Pro261Ser variant impacts protein function by increasing its kinase activity (Razzaque 2007, Pandit 2007). However, these in vitro assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PP2, PM1, PM2, PS3, PM6_Strong. (less)
Number of individuals with the variant: 7
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446688.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Short stature (present) , Macrocephaly (present)
Sex: male
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Pathogenic
(Mar 14, 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: SCV000209019.15
First in ClinVar: Feb 24, 2015 Last updated: Apr 01, 2023 |
Comment:
Published functional studies demonstrate that P261S increases kinase activity and MEK and ERK activation (Pandit et al., 2007; Razzaque et al., 2007); Not observed at … (more)
Published functional studies demonstrate that P261S increases kinase activity and MEK and ERK activation (Pandit et al., 2007; Razzaque et al., 2007); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; The majority of missense variants in this gene are considered pathogenic (HGMD); Reported in ClinVar as pathogenic by the ClinGen RASopathy Variant Curation Expert Panel (ClinVar Variant ID# 13958; ClinVar); This variant is associated with the following publications: (PMID: 30055033, 17603483, 22585553, 17603482, 20683980, 22781091, 24803665, 31219622, 33673806, 24957944, 9689060, 15520807, 29493581, 19020799, 34429303) (less)
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Pathogenic
(Sep 14, 2015)
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criteria provided, single submitter
Method: clinical testing
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Primary familial hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
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Blueprint Genetics
Accession: SCV000264165.2
First in ClinVar: Feb 27, 2016 Last updated: Feb 27, 2016 |
Number of individuals with the variant: 1
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Pathogenic
(Jun 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: SCV002060978.1
First in ClinVar: Jan 20, 2022 Last updated: Jan 20, 2022 |
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Pathogenic
(Jun 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000740256.4
First in ClinVar: Apr 14, 2018 Last updated: Nov 29, 2022 |
Comment:
The p.P261S pathogenic mutation (also known as c.781C>T), located in coding exon 6 of the RAF1 gene, results from a C to T substitution at … (more)
The p.P261S pathogenic mutation (also known as c.781C>T), located in coding exon 6 of the RAF1 gene, results from a C to T substitution at nucleotide position 781. The proline at codon 261 is replaced by serine, an amino acid with similar properties. This alteration has been reported in a number of individuals with Noonan syndrome, including a de novo occurrence. This alteration was also reported to segregate with the disease in a few families (Pandit B et al. Nat. Genet., 2007 Aug;39:1007-12; Razzaque MA et al. Nat. Genet., 2007 Aug;39:1013-7; Longoni M et al. Am. J. Med. Genet. A, 2010 Sep;152A:2176-84; Digilio MC et al. Eur. J. Hum. Genet., 2013 Feb;21:200-4). In vitro studies have suggested a gain of function effect of this variant in the experimental system (Pandit B et al. Nat. Genet., 2007 Aug;39:1007-12; Razzaque MA et al. Nat. Genet., 2007 Aug;39:1013-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Alterations affecting the same amino acid have also been described in affected individuals (Ratola A et al. Pediatr Rep, 2015 May;7:5955; Ezquieta B et al. Rev Esp Cardiol (Engl Ed), 2012 May;65:447-55). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Apr 12, 2016)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000741475.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Macrocephalus (present) , Hypertonia (present) , Global developmental delay (present) , Hypertelorism (present) , Posteriorly rotated ears (present) , High, narrow palate (present) , Depressed … (more)
Macrocephalus (present) , Hypertonia (present) , Global developmental delay (present) , Hypertelorism (present) , Posteriorly rotated ears (present) , High, narrow palate (present) , Depressed nasal bridge (present) , Multiple cafe-au-lait spots (present) , Oral motor hypotonia (present) , Skull asymmetry (present) (less)
Sex: female
Ethnicity/Population group: Caucasian/Belgian/Italian/Dutch
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Pathogenic
(May 07, 2021)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome 5
Affected status: yes
Allele origin:
de novo
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Accession: SCV003921791.1
First in ClinVar: May 06, 2023 Last updated: May 06, 2023 |
Comment:
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) … (more)
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 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 proline to serine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been classified as Pathogenic by ClinGen's RASopathy expert panel (ClinVar). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Jan 24, 2024)
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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: SCV000552088.10
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 261 of the RAF1 protein (p.Pro261Ser). … (more)
This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 261 of the RAF1 protein (p.Pro261Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 17603482, 17603483, 20683980). ClinVar contains an entry for this variant (Variation ID: 13958). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RAF1 function (PMID: 17603482, 17603483). This variant disrupts the p.Pro261 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. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 01, 2007)
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no assertion criteria provided
Method: literature only
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NOONAN SYNDROME 5
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000035243.2
First in ClinVar: Apr 04, 2013 Last updated: Aug 29, 2016 |
Comment on evidence:
In 5 affected individuals of 2 unrelated families with Noonan syndrome (NS5; 611553), Pandit et al. (2007) identified heterozygosity for a 781C-T transition in exon … (more)
In 5 affected individuals of 2 unrelated families with Noonan syndrome (NS5; 611553), Pandit et al. (2007) identified heterozygosity for a 781C-T transition in exon 7 of the RAF1 gene, resulting in a pro261-to-ser (P261S) substitution at a conserved residue in the CR2 domain. Four of the 5 patients had hypertrophic cardiomyopathy (CMH); the 1 individual with a P261S change but without CMH was a 6-year-old girl whose 38-year-old mother had the same mutation and had been diagnosed with CMH at 23 years of age. The mutation was not found in 210 control individuals. Razzaque et al. (2007) identified the P261S mutation in 3 Noonan syndrome patients, a 1-year-old boy and his 33-year-old father and an unrelated 16-year-old boy. All 3 displayed CMH. The mutation was not found in 100 control individuals or in 100 individuals with CMH without Noonan syndrome. Transfection studies in HEK293 cells demonstrated that P261S behaved as a gain-of-function mutant with increased kinase and ERK (see 176948) activation compared with wildtype RAF1. (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: SCV000510554.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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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: SCV004190088.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Number of individuals with the variant: 2
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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A Novel Noonan Syndrome RAF1 Mutation: Lethal Course in a Preterm Infant. | Ratola A | Pediatric reports | 2015 | PMID: 26266034 |
Atrioventricular canal defect in patients with RASopathies. | Digilio MC | European journal of human genetics : EJHG | 2013 | PMID: 22781091 |
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 |
Noonan syndrome associated with both a new Jnk-activating familial SOS1 and a de novo RAF1 mutations. | Longoni M | American journal of medical genetics. Part A | 2010 | PMID: 20683980 |
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 |
Selective loading of high-affinity peptides onto major histocompatibility complex class I molecules by the tapasin-ERp57 heterodimer. | Wearsch PA | Nature immunology | 2007 | PMID: 17603487 |
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.781C>T | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/563677cb-406b-41f7-9c7d-7fc9d73cbbe2 | - | - | - | - |
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Text-mined citations for rs121434594 ...
HelpRecord last updated Mar 05, 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.