The c.1741A>G (p.Asn581Asp) variant in BRAF has been reported in the literature as a non-maternity/paternity confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PM6_Strong; PMID 25463315). In vitro functional studies provide some evidence that the p.Asn581Asp variant may impact protein function (PS3; 19376813, 16474404). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the BRAF 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). Furthermore, this variant is located in the catalytic loop of BRAF (PM1; 16474404, 29493581). Computational prediction tools and conservation analysis suggest that the p.Asn581Asp 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): PP2, PP3, PM1, PM2, PM6_Strong, PS3.
ClinVar Genomic variation as it relates to human health
NM_004333.6(BRAF):c.1741A>G (p.Asn581Asp)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Pathogenic
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_004333.6(BRAF):c.1741A>G (p.Asn581Asp)
Variation ID: 13979 Accession: VCV000013979.27
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7q34 7: 140754187 (GRCh38) [ NCBI UCSC ] 7: 140453987 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Aug 22, 2016 Jul 23, 2024 Apr 3, 2017 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004333.6:c.1741A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004324.2:p.Asn581Asp missense NM_001374258.1:c.1861A>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001361187.1:p.Asn621Asp missense NM_001354609.2:c.1741A>G NP_001341538.1:p.Asn581Asp missense NM_001374244.1:c.1861A>G NP_001361173.1:p.Asn621Asp missense NM_001378467.1:c.1750A>G NP_001365396.1:p.Asn584Asp missense NM_001378468.1:c.1741A>G NP_001365397.1:p.Asn581Asp missense NM_001378469.1:c.1675A>G NP_001365398.1:p.Asn559Asp missense NM_001378470.1:c.1639A>G NP_001365399.1:p.Asn547Asp missense NM_001378471.1:c.1630A>G NP_001365400.1:p.Asn544Asp missense NM_001378472.1:c.1585A>G NP_001365401.1:p.Asn529Asp missense NM_001378473.1:c.1585A>G NP_001365402.1:p.Asn529Asp missense NM_001378474.1:c.1741A>G NP_001365403.1:p.Asn581Asp missense NM_001378475.1:c.1477A>G NP_001365404.1:p.Asn493Asp missense NC_000007.14:g.140754187T>C NC_000007.13:g.140453987T>C NG_007873.3:g.175578A>G LRG_299:g.175578A>G LRG_299t1:c.1741A>G - Protein change
- N581D, N547D, N529D, N559D, N584D, N621D, N493D, N544D
- Other names
-
p.N581D:AAT>GAT
NM_004333.4(BRAF):c.1741A>G
- Canonical SPDI
- NC_000007.14:140754186:T:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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. |
|||
| BRAF | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1254 | 1368 | |
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. |
|---|---|---|---|---|
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jul 17, 2023 | RCV000015013.33 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Mar 9, 2023 | RCV000033329.19 | |
| Pathogenic (4) |
reviewed by expert panel
|
Apr 3, 2017 | RCV000211751.7 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 25, 2022 | RCV000474979.8 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV003450642.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 25, 2023 | RCV004018631.1 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Apr 03, 2017)
|
reviewed by expert panel
Method: curation
|
Cardio-facio-cutaneous syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen RASopathy Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV000616362.4 First in ClinVar: Dec 19, 2017 Last updated: Dec 11, 2022 |
Comment:
The c.1741A>G (p.Asn581Asp) variant in BRAF has been reported in the literature as a non-maternity/paternity confirmed de novo occurrence in at least 2 patients with … (more)
The c.1741A>G (p.Asn581Asp) variant in BRAF has been reported in the literature as a non-maternity/paternity confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PM6_Strong; PMID 25463315). In vitro functional studies provide some evidence that the p.Asn581Asp variant may impact protein function (PS3; 19376813, 16474404). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the BRAF 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). Furthermore, this variant is located in the catalytic loop of BRAF (PM1; 16474404, 29493581). Computational prediction tools and conservation analysis suggest that the p.Asn581Asp 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): PP2, PP3, PM1, PM2, PM6_Strong, PS3. (less)
|
|
|
Pathogenic
(Jul 12, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
Cardio-facio-cutaneous syndrome
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061593.5
First in ClinVar: May 03, 2013 Last updated: Dec 19, 2017 |
Comment:
The Asn581Asp variant has been reported in the literature in eight individuals w ith clinical features of Cardio-facio-cutaneous syndrome and was absent from at least … (more)
The Asn581Asp variant has been reported in the literature in eight individuals w ith clinical features of Cardio-facio-cutaneous syndrome and was absent from at least 180 control chromosomes (Rodriguez-Viciana 2006, Niihori 2006, Schulz 2008 , Yoon 2007, Hazan 2012). This variant was observed to have occurred de novo in at least three of these individuals (Rodriguez-Viciana 2006, Hazan 2012). The As n581Asp variant has also been identified by our laboratory in one individual wit h Cardio-facio-cutaneous syndrome (LMM unpublished data), and was not identified in this individual's parents. Additionally, the Asparagine (Asn) residue at pos ition 581 is highly conserved across evolutionarily distant species, and the var iant was not identified in large population studies. In summary, this variant me ets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based upon segregation studies, de novo occurrence, and absence from controls. (less)
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Sep 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002022065.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jul 25, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
RASopathy
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000553829.5
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which … (more)
This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 581 of the BRAF protein (p.Asn581Asp). This missense change has been observed in individual(s) with features of cardio-facio-cutaneous (CFC) syndrome (PMID: 16439621, 16474404, 17366577, 18042262, 22876591, 24037001, 25463315). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects BRAF function (PMID: 19376813). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 13979). (less)
|
|
|
Pathogenic
(Jul 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiofaciocutaneous syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005086386.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with LEOPARD syndrome 3 (MIM#613707), cardiofaciocutaneous syndrome (MIM#115150) and Noonan syndrome 7 (MIM#613706) (PMID: 28783719, PMID: 29540830). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to aspartic acid. (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. This variant has been reported many times as pathogenic, and observed in individuals with cardiofaciocutaneous syndrome. One of these reports is by an expert panel (ClinVar). (SP) 1102 - Strong phenotype match for this individual. (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)
|
|
|
Pathogenic
(Nov 04, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Cardio-facio-cutaneous syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000698333.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
Comment:
Variant summary: The BRAF c.1741A>G (p.Asn581Asp) variant involves the alteration of a conserved nucleotide and is located in the catalytic loop of the protein kinase … (more)
Variant summary: The BRAF c.1741A>G (p.Asn581Asp) variant involves the alteration of a conserved nucleotide and is located in the catalytic loop of the protein kinase domain (InterPro, Niihori_2006). 3/4 in silico tools predict a damaging outcome for this variant. This variant is absent in approximately 121424 control chromosomes. In literature, this variant is reported as a pathogenic variant found in several patients with cardio-facio-cutaneous syndrome, including reported de novo occurrences (Niihori_2006, Rodriguez-Viciana_2006, Narumi_2007, Nava_2007, Schulz_2008, Pierpont _2010, Hazan_2012, Quaio_2013). In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Functional studies in zebra fish have shown that the N581D variant results in developmental defects that can be rescued by FGF-MAPK pathway inhibitors (Anastasaki_2009). Taken together, this variant is classified as Pathogenic. (less)
|
|
|
Pathogenic
(Nov 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiofaciocutaneous syndrome 1
Affected status: yes
Allele origin:
germline
|
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000781086.1
First in ClinVar: Aug 22, 2016 Last updated: Aug 22, 2016 |
|
|
|
Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446714.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Global developmental delay (present) , Birth length greater than 97th percentile (present) , Cryptorchidism (present) , Hypotonia (present)
Sex: male
|
|
|
Pathogenic
(Oct 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiofaciocutaneous syndrome 1
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV002012143.1
First in ClinVar: Nov 11, 2021 Last updated: Nov 11, 2021 |
Comment:
The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novoo in at least two similarly affected unrelated individuals (PMID:25463315, … (more)
The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novoo in at least two similarly affected unrelated individuals (PMID:25463315, PM6_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 19376813, 16474404). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Asn621Lys) has been reported as pathogenic (ClinVar ID: VCV000044811.2, PM5). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.932, 3Cnet: 0.999, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Strabismus (present) , Global developmental delay (present) , Abnormal facial shape (present) , Ptosis (present) , Pes planus (present) , Delayed speech and language development … (more)
Strabismus (present) , Global developmental delay (present) , Abnormal facial shape (present) , Ptosis (present) , Pes planus (present) , Delayed speech and language development (present) , Delayed gross motor development (present) , Delayed fine motor development (present) , Intellectual disability (present) (less)
|
|
|
Pathogenic
(Mar 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000057234.15
First in ClinVar: Apr 04, 2013 Last updated: Mar 18, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate N581D shows impaired ability to induce phosphorylation of ERK and MEK … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate N581D shows impaired ability to induce phosphorylation of ERK and MEK (Niihori et al., 2006); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 23093928, 16439621, 34573299, 30141192, 33040082, 22876591, 19376813, 24803665, 30050098, 29907801, 33967092, 34643321, 16474404, 25463315) (less)
|
|
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Pathogenic
(May 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000742141.5
First in ClinVar: Apr 15, 2018 Last updated: May 01, 2024 |
Comment:
The c.1741A>G (p.N581D) alteration is located in exon 14 (coding exon 14) of the BRAF gene. This alteration results from an A to G substitution … (more)
The c.1741A>G (p.N581D) alteration is located in exon 14 (coding exon 14) of the BRAF gene. This alteration results from an A to G substitution at nucleotide position 1741. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in multiple individuals with features consistent with BRAF-related RASopathy, including multiple cases with reported de novo occurrences (Niihori, 2006; Rodriguez-Viciana, 2006; Yoon, 2007; Hazan, 2012; Ciara, 2014; Battaglia, 2021; Pierpont, 2022). Another alteration at the same codon, c.1741A>C (p.N581H), has been reported de novo in an individual with features of BRAF-related RASopathy (Sparks, 2020). This amino acid position is highly conserved in available vertebrate species. The p.N581D amino acid is located in the catalytic loop of BRAF (Niihori, 2006). Experimental studies on the effect of cardiofaciocutaneous syndrome mutant alleles in an in vivo zebrafish model system showed that the p.N581D alteration can result in developmental abnormalities in zebrafish when expressed during early development. The mutant embryos were shown to respond to treatment with inhibitors of the FGF-MAPK pathway (Anastasaki, 2009). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. (less)
|
|
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Pathogenic
(Mar 01, 2006)
|
no assertion criteria provided
Method: literature only
|
CARDIOFACIOCUTANEOUS SYNDROME 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000035269.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
In 2 presumably unrelated patients with cardiofaciocutaneous syndrome (CFC1; 115150), Niihori et al. (2006) found a heterozygous 1741A-G transition in exon 14 of the BRAF … (more)
In 2 presumably unrelated patients with cardiofaciocutaneous syndrome (CFC1; 115150), Niihori et al. (2006) found a heterozygous 1741A-G transition in exon 14 of the BRAF gene, predicting an asn581-to-asp (N581D) amino acid change. (less)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001807094.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001951112.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Cardiofaciocutaneous syndrome 1
Affected status: yes
Allele origin:
unknown
|
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand
Accession: SCV003840148.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Noonan syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Molecular Genetics, Centre for Human Genetics
Accession: SCV004190104.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Number of individuals with the variant: 1
Secondary finding: no
|
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
Cardio-facio-cutaneous syndrome
Affected status: yes
Allele origin:
unknown
|
GenomeConnect - CFC International
Accession: SCV003761515.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Clinical Features:
Cognitive impairment (present) , Hyperthyroidism (present) , Abnormality of thrombocytes (present) , Abnormal delivery (present) , Pregnancy history (present) , Premature birth (present)
Age: 0-9 years
Sex: male
Method: Partial Gene Sequencing
Testing laboratory: PreventionGenetics,PreventionGenetics
Date variant was reported to submitter: 2006-07-10
Testing laboratory interpretation: Pathogenic
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Comment:
Comment:
The Asn581Asp variant has been reported in the literature in eight individuals w ith clinical features of Cardio-facio-cutaneous syndrome and was absent from at least 180 control chromosomes (Rodriguez-Viciana 2006, Niihori 2006, Schulz 2008 , Yoon 2007, Hazan 2012). This variant was observed to have occurred de novo in at least three of these individuals (Rodriguez-Viciana 2006, Hazan 2012). The As n581Asp variant has also been identified by our laboratory in one individual wit h Cardio-facio-cutaneous syndrome (LMM unpublished data), and was not identified in this individual's parents. Additionally, the Asparagine (Asn) residue at pos ition 581 is highly conserved across evolutionarily distant species, and the var iant was not identified in large population studies. In summary, this variant me ets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based upon segregation studies, de novo occurrence, and absence from controls.
Comment:
This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 581 of the BRAF protein (p.Asn581Asp). This missense change has been observed in individual(s) with features of cardio-facio-cutaneous (CFC) syndrome (PMID: 16439621, 16474404, 17366577, 18042262, 22876591, 24037001, 25463315). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects BRAF function (PMID: 19376813). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 13979).
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with LEOPARD syndrome 3 (MIM#613707), cardiofaciocutaneous syndrome (MIM#115150) and Noonan syndrome 7 (MIM#613706) (PMID: 28783719, PMID: 29540830). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to aspartic acid. (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. This variant has been reported many times as pathogenic, and observed in individuals with cardiofaciocutaneous syndrome. One of these reports is by an expert panel (ClinVar). (SP) 1102 - Strong phenotype match for this individual. (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
Comment:
Variant summary: The BRAF c.1741A>G (p.Asn581Asp) variant involves the alteration of a conserved nucleotide and is located in the catalytic loop of the protein kinase domain (InterPro, Niihori_2006). 3/4 in silico tools predict a damaging outcome for this variant. This variant is absent in approximately 121424 control chromosomes. In literature, this variant is reported as a pathogenic variant found in several patients with cardio-facio-cutaneous syndrome, including reported de novo occurrences (Niihori_2006, Rodriguez-Viciana_2006, Narumi_2007, Nava_2007, Schulz_2008, Pierpont _2010, Hazan_2012, Quaio_2013). In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Functional studies in zebra fish have shown that the N581D variant results in developmental defects that can be rescued by FGF-MAPK pathway inhibitors (Anastasaki_2009). Taken together, this variant is classified as Pathogenic.
Comment:
The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novoo in at least two similarly affected unrelated individuals (PMID:25463315, PM6_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 19376813, 16474404). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Asn621Lys) has been reported as pathogenic (ClinVar ID: VCV000044811.2, PM5). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.932, 3Cnet: 0.999, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate N581D shows impaired ability to induce phosphorylation of ERK and MEK (Niihori et al., 2006); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 23093928, 16439621, 34573299, 30141192, 33040082, 22876591, 19376813, 24803665, 30050098, 29907801, 33967092, 34643321, 16474404, 25463315)
Comment:
The c.1741A>G (p.N581D) alteration is located in exon 14 (coding exon 14) of the BRAF gene. This alteration results from an A to G substitution at nucleotide position 1741. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in multiple individuals with features consistent with BRAF-related RASopathy, including multiple cases with reported de novo occurrences (Niihori, 2006; Rodriguez-Viciana, 2006; Yoon, 2007; Hazan, 2012; Ciara, 2014; Battaglia, 2021; Pierpont, 2022). Another alteration at the same codon, c.1741A>C (p.N581H), has been reported de novo in an individual with features of BRAF-related RASopathy (Sparks, 2020). This amino acid position is highly conserved in available vertebrate species. The p.N581D amino acid is located in the catalytic loop of BRAF (Niihori, 2006). Experimental studies on the effect of cardiofaciocutaneous syndrome mutant alleles in an in vivo zebrafish model system showed that the p.N581D alteration can result in developmental abnormalities in zebrafish when expressed during early development. The mutant embryos were shown to respond to treatment with inhibitors of the FGF-MAPK pathway (Anastasaki, 2009). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
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. |
Comment:
The c.1741A>G (p.Asn581Asp) variant in BRAF has been reported in the literature as a non-maternity/paternity confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PM6_Strong; PMID 25463315). In vitro functional studies provide some evidence that the p.Asn581Asp variant may impact protein function (PS3; 19376813, 16474404). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the BRAF 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). Furthermore, this variant is located in the catalytic loop of BRAF (PM1; 16474404, 29493581). Computational prediction tools and conservation analysis suggest that the p.Asn581Asp 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): PP2, PP3, PM1, PM2, PM6_Strong, PS3.
Comment:
The Asn581Asp variant has been reported in the literature in eight individuals w ith clinical features of Cardio-facio-cutaneous syndrome and was absent from at least 180 control chromosomes (Rodriguez-Viciana 2006, Niihori 2006, Schulz 2008 , Yoon 2007, Hazan 2012). This variant was observed to have occurred de novo in at least three of these individuals (Rodriguez-Viciana 2006, Hazan 2012). The As n581Asp variant has also been identified by our laboratory in one individual wit h Cardio-facio-cutaneous syndrome (LMM unpublished data), and was not identified in this individual's parents. Additionally, the Asparagine (Asn) residue at pos ition 581 is highly conserved across evolutionarily distant species, and the var iant was not identified in large population studies. In summary, this variant me ets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based upon segregation studies, de novo occurrence, and absence from controls.
Comment:
This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 581 of the BRAF protein (p.Asn581Asp). This missense change has been observed in individual(s) with features of cardio-facio-cutaneous (CFC) syndrome (PMID: 16439621, 16474404, 17366577, 18042262, 22876591, 24037001, 25463315). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects BRAF function (PMID: 19376813). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 13979).
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with LEOPARD syndrome 3 (MIM#613707), cardiofaciocutaneous syndrome (MIM#115150) and Noonan syndrome 7 (MIM#613706) (PMID: 28783719, PMID: 29540830). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to aspartic acid. (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. This variant has been reported many times as pathogenic, and observed in individuals with cardiofaciocutaneous syndrome. One of these reports is by an expert panel (ClinVar). (SP) 1102 - Strong phenotype match for this individual. (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
Comment:
Variant summary: The BRAF c.1741A>G (p.Asn581Asp) variant involves the alteration of a conserved nucleotide and is located in the catalytic loop of the protein kinase domain (InterPro, Niihori_2006). 3/4 in silico tools predict a damaging outcome for this variant. This variant is absent in approximately 121424 control chromosomes. In literature, this variant is reported as a pathogenic variant found in several patients with cardio-facio-cutaneous syndrome, including reported de novo occurrences (Niihori_2006, Rodriguez-Viciana_2006, Narumi_2007, Nava_2007, Schulz_2008, Pierpont _2010, Hazan_2012, Quaio_2013). In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Functional studies in zebra fish have shown that the N581D variant results in developmental defects that can be rescued by FGF-MAPK pathway inhibitors (Anastasaki_2009). Taken together, this variant is classified as Pathogenic.
Comment:
The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novoo in at least two similarly affected unrelated individuals (PMID:25463315, PM6_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 19376813, 16474404). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Asn621Lys) has been reported as pathogenic (ClinVar ID: VCV000044811.2, PM5). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.932, 3Cnet: 0.999, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate N581D shows impaired ability to induce phosphorylation of ERK and MEK (Niihori et al., 2006); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 23093928, 16439621, 34573299, 30141192, 33040082, 22876591, 19376813, 24803665, 30050098, 29907801, 33967092, 34643321, 16474404, 25463315)
Comment:
The c.1741A>G (p.N581D) alteration is located in exon 14 (coding exon 14) of the BRAF gene. This alteration results from an A to G substitution at nucleotide position 1741. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in multiple individuals with features consistent with BRAF-related RASopathy, including multiple cases with reported de novo occurrences (Niihori, 2006; Rodriguez-Viciana, 2006; Yoon, 2007; Hazan, 2012; Ciara, 2014; Battaglia, 2021; Pierpont, 2022). Another alteration at the same codon, c.1741A>C (p.N581H), has been reported de novo in an individual with features of BRAF-related RASopathy (Sparks, 2020). This amino acid position is highly conserved in available vertebrate species. The p.N581D amino acid is located in the catalytic loop of BRAF (Niihori, 2006). Experimental studies on the effect of cardiofaciocutaneous syndrome mutant alleles in an in vivo zebrafish model system showed that the p.N581D alteration can result in developmental abnormalities in zebrafish when expressed during early development. The mutant embryos were shown to respond to treatment with inhibitors of the FGF-MAPK pathway (Anastasaki, 2009). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Neurologic and neurodevelopmental complications in cardiofaciocutaneous syndrome are associated with genotype: A multinational cohort study. | Pierpont EI | Genetics in medicine : official journal of the American College of Medical Genetics | 2022 | PMID: 35524774 |
| Epilepsy and BRAF Mutations: Phenotypes, Natural History and Genotype-Phenotype Correlations. | Battaglia DI | Genes | 2021 | PMID: 34573299 |
| Exome Sequencing for Prenatal Diagnosis in Nonimmune Hydrops Fetalis. | Sparks TN | The New England journal of medicine | 2020 | PMID: 33027564 |
| Classifying BRAF alterations in cancer: new rational therapeutic strategies for actionable mutations. | Dankner M | Oncogene | 2018 | PMID: 29540830 |
| Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS. | Yao Z | Nature | 2017 | PMID: 28783719 |
| Is diagnosing cardio-facio-cutaneous (CFC) syndrome still a challenge? Delineation of the phenotype in 15 Polish patients with proven mutations, including novel mutations in the BRAF1 gene. | Ciara E | European journal of medical genetics | 2015 | PMID: 25463315 |
| Tegumentary manifestations of Noonan and Noonan-related syndromes. | Quaio CR | Clinics (Sao Paulo, Brazil) | 2013 | PMID: 24037001 |
| A structural systems biology approach for quantifying the systemic consequences of missense mutations in proteins. | Cheng TM | PLoS computational biology | 2012 | PMID: 23093928 |
| A cardio-facio-cutaneous syndrome case with tight Achilles tendons. | Hazan F | Genetic counseling (Geneva, Switzerland) | 2012 | PMID: 22876591 |
| Effects of germline mutations in the Ras/MAPK signaling pathway on adaptive behavior: cardiofaciocutaneous syndrome and Noonan syndrome. | Pierpont EI | American journal of medical genetics. Part A | 2010 | PMID: 20186801 |
| Kinase-activating and kinase-impaired cardio-facio-cutaneous syndrome alleles have activity during zebrafish development and are sensitive to small molecule inhibitors. | Anastasaki C | Human molecular genetics | 2009 | PMID: 19376813 |
| Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum. | Sarkozy A | Human mutation | 2009 | PMID: 19206169 |
| The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. | Aoki Y | Human mutation | 2008 | PMID: 18470943 |
| Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome. | Schulz AL | Clinical genetics | 2008 | PMID: 18042262 |
| Neurological complications of cardio-facio-cutaneous syndrome. | Yoon G | Developmental medicine and child neurology | 2007 | PMID: 18039235 |
| Cardio-facio-cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype-phenotype relationships and overlap with Costello syndrome. | Nava C | Journal of medical genetics | 2007 | PMID: 17704260 |
| Molecular and clinical characterization of cardio-facio-cutaneous (CFC) syndrome: overlapping clinical manifestations with Costello syndrome. | Narumi Y | American journal of medical genetics. Part A | 2007 | PMID: 17366577 |
| Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. | Niihori T | Nature genetics | 2006 | PMID: 16474404 |
| Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. | Rodriguez-Viciana P | Science (New York, N.Y.) | 2006 | PMID: 16439621 |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/f2cf40e6-1706-4a5e-b2f8-b7b396ddbde2 | - | - | - | - |
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Text-mined citations for rs180177040 ...
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Record last updated Nov 19, 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.