The c.1406G>A variant in BRAF is a missense variant predicted to cause substitution of glycine by glutamic acid at amino acid 469 (p.Gly469Glu). This variant is absent from gnomAD v4 (PM2_Supporting). 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). The REVEL computational prediction analysis tool produced a score of 0.921, which is above the threshold necessary to apply PP3 (PP3). Furthermore, this variant is in a location which has been defined by the ClinGen RASopathy Expert Panel functional domain of BRAF (PM1). This variant has been reported in the literature in at least 12 patients with clinical features of RASopathy (PS4, PMIDs: 18042262, 16474404, 30141192, 29907801, 35418823), out of which 3 patients were reported as a confirmed de novo occurrence (PS2_VeryStrong; PMIDs: 18042262, 16474404). Luciferase assays showed that p.Gly469Glu did not enhance ELK-dependent transcription indicating that this variant impacts protein function (PS3_Supporting; 16474404). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2_VeryStrong, PS4, PM1, PS3_Supporting, PM2_Supporting, PP2, PP3 (Specification Version 2.1, 9/17/2024)
ClinVar Genomic variation as it relates to human health
NM_004333.6(BRAF):c.1406G>A (p.Gly469Glu)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Pathogenic
for
RASopathy
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_004333.6(BRAF):c.1406G>A (p.Gly469Glu)
Variation ID: 13974 Accession: VCV000013974.44
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7q34 7: 140781602 (GRCh38) [ NCBI UCSC ] 7: 140481402 (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 Jan 16, 2015 Oct 13, 2024 Sep 17, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004333.6:c.1406G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004324.2:p.Gly469Glu missense NM_001374258.1:c.1526G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001361187.1:p.Gly509Glu missense NM_001354609.2:c.1406G>A NP_001341538.1:p.Gly469Glu missense NM_001374244.1:c.1526G>A NP_001361173.1:p.Gly509Glu missense NM_001378467.1:c.1415G>A NP_001365396.1:p.Gly472Glu missense NM_001378468.1:c.1406G>A NP_001365397.1:p.Gly469Glu missense NM_001378469.1:c.1340G>A NP_001365398.1:p.Gly447Glu missense NM_001378470.1:c.1304G>A NP_001365399.1:p.Gly435Glu missense NM_001378471.1:c.1295G>A NP_001365400.1:p.Gly432Glu missense NM_001378472.1:c.1250G>A NP_001365401.1:p.Gly417Glu missense NM_001378473.1:c.1250G>A NP_001365402.1:p.Gly417Glu missense NM_001378474.1:c.1406G>A NP_001365403.1:p.Gly469Glu missense NM_001378475.1:c.1142G>A NP_001365404.1:p.Gly381Glu missense NC_000007.14:g.140781602C>T NC_000007.13:g.140481402C>T NG_007873.3:g.148163G>A LRG_299:g.148163G>A LRG_299t1:c.1406G>A P15056:p.Gly469Glu - Protein change
- G469E, G381E, G447E, G417E, G432E, G472E, G435E, G509E
- Other names
-
p.G469E:GGA>GAA
NM_004333.5(BRAF):c.1406G>A
NM_004333.6(BRAF):c.1406G>A
- Canonical SPDI
- NC_000007.14:140781601:C:T
-
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.
-
Exome Aggregation Consortium (ExAC) 0.00001
- 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 |
1250 | 1364 | |
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 (4) |
criteria provided, multiple submitters, no conflicts
|
Mar 17, 2024 | RCV000015008.35 | |
| Pathogenic (3) |
reviewed by expert panel
|
Sep 17, 2024 | RCV000033307.17 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jun 13, 2022 | RCV000212152.13 | |
| Pathogenic (3) |
reviewed by expert panel
|
Dec 9, 2019 | RCV000211748.9 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000419576.1 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000419555.1 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000427006.1 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Jul 14, 2015 | RCV000427215.1 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000437869.1 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000434590.1 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000443381.1 | |
| Pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000424773.1 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 31, 2016 | RCV000436804.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 10, 2017 | RCV000506575.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 5, 2021 | RCV001813209.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
- | RCV002287336.2 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV003450641.1 | |
| click to load more click to collapse | ||||
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
(Sep 17, 2024)
|
reviewed by expert panel
Method: curation
|
RASopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen RASopathy Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV000616361.5 First in ClinVar: Dec 19, 2017 Last updated: Oct 13, 2024 |
Comment:
The c.1406G>A variant in BRAF is a missense variant predicted to cause substitution of glycine by glutamic acid at amino acid 469 (p.Gly469Glu). This variant … (more)
The c.1406G>A variant in BRAF is a missense variant predicted to cause substitution of glycine by glutamic acid at amino acid 469 (p.Gly469Glu). This variant is absent from gnomAD v4 (PM2_Supporting). 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). The REVEL computational prediction analysis tool produced a score of 0.921, which is above the threshold necessary to apply PP3 (PP3). Furthermore, this variant is in a location which has been defined by the ClinGen RASopathy Expert Panel functional domain of BRAF (PM1). This variant has been reported in the literature in at least 12 patients with clinical features of RASopathy (PS4, PMIDs: 18042262, 16474404, 30141192, 29907801, 35418823), out of which 3 patients were reported as a confirmed de novo occurrence (PS2_VeryStrong; PMIDs: 18042262, 16474404). Luciferase assays showed that p.Gly469Glu did not enhance ELK-dependent transcription indicating that this variant impacts protein function (PS3_Supporting; 16474404). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2_VeryStrong, PS4, PM1, PS3_Supporting, PM2_Supporting, PP2, PP3 (Specification Version 2.1, 9/17/2024) (less)
|
|
|
Pathogenic
(Mar 10, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000602657.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
|
|
|
Pathogenic
(Jul 27, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000225337.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Pathogenic
(Jul 26, 2011)
|
criteria provided, single submitter
Method: clinical testing
|
Cardio-facio-cutaneous syndrome
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000061581.5
First in ClinVar: May 03, 2013 Last updated: Dec 19, 2017 |
Comment:
The Gly469Glu variant has been reported in the literature in several individuals with clinical features of Cardio-facio-cutaneous syndrome (Niihori 2006, Schulz 2008). In addition, this … (more)
The Gly469Glu variant has been reported in the literature in several individuals with clinical features of Cardio-facio-cutaneous syndrome (Niihori 2006, Schulz 2008). In addition, this variant was reported to have occurred de novo in three of those individuals. Therefore, this variant is highly likely to be pathogenic . (less)
Number of individuals with the variant: 5
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiofaciocutaneous syndrome 1
Affected status: yes
Allele origin:
unknown
|
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn
Accession: SCV000999285.1
First in ClinVar: Nov 30, 2019 Last updated: Nov 30, 2019 |
Number of individuals with the variant: 1
Clinical Features:
Hypertelorism (present) , Global developmental delay (present) , Absent eyelashes (present) , Dry skin (present) , Cryptorchidism (present) , Absent eyebrow (present) , Low-set ears … (more)
Hypertelorism (present) , Global developmental delay (present) , Absent eyelashes (present) , Dry skin (present) , Cryptorchidism (present) , Absent eyebrow (present) , Low-set ears (present) (less)
|
|
|
Pathogenic
(Dec 09, 2019)
|
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: SCV001363181.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: BRAF c.1406G>A (p.Gly469Glu) results in a non-conservative amino acid change located in the protein kinase domain (IPR000719) of the encoded protein sequence. Five … (more)
Variant summary: BRAF c.1406G>A (p.Gly469Glu) results in a non-conservative amino acid change located in the protein kinase domain (IPR000719) of 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 251520 control chromosomes. c.1406G>A has been reported in the literature as a de-novo variant in multiple individuals affected with Cardiofaciocutaneous Syndrome (example, Nihori_2006, Smalley_2009, Sarkozy_2009, Pandit_2007, Schultz_2008, Greaves_2013, Ciara_2015, Lee_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in an induction of ERK activation by trigerring C-RAF activity as a distinct mechanism of action (Wan_2004). Five clinical diagnostic laboratories and one expert panel (ClinGen RASopathy panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Jun 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001714860.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment:
PP2, PP3, PM1, PM2, PS2_VeryStrong, PS3
Number of individuals with the variant: 1
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: research
|
Noonan syndrome 7
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV002576340.1
First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022 |
|
|
|
Pathogenic
(May 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
RASopathy
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000553832.8
First in ClinVar: May 29, 2016 Last updated: Feb 20, 2024 |
Comment:
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) … (more)
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 BRAF protein function. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 13974). This missense change has been observed in individual(s) with cardiofaciocutaneous syndrome (PMID: 16439621, 16474404, 18042262, 19206169). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 469 of the BRAF protein (p.Gly469Glu). (less)
|
|
|
Pathogenic
(Mar 05, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome and Noonan-related syndrome
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002060539.1
First in ClinVar: Jan 20, 2022 Last updated: Jan 20, 2022 |
|
|
|
Pathogenic
(Jun 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000057212.16
First in ClinVar: Apr 04, 2013 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect on B-Raf activity and MEK and ERK phosphorylation (Rodriguez-Viciana et al., 2006); Missense variants in this gene are … (more)
Published functional studies demonstrate a damaging effect on B-Raf activity and MEK and ERK phosphorylation (Rodriguez-Viciana et al., 2006); Missense variants in this gene are often considered pathogenic (HGMD); 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; This variant is associated with the following publications: (PMID: 23093928, 34573299, 30141192, 34184824, 29907801, 18042262, 16474404, 16439621, 19206169, 24803665, 33040082) (less)
|
|
|
Pathogenic
(Mar 17, 2024)
|
criteria provided, single submitter
Method: research
|
Cardiofaciocutaneous syndrome 1
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004804676.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Rasopathy
Affected status: yes
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV000196670.1
First in ClinVar: Jan 16, 2015 Last updated: Jan 16, 2015 |
Comment:
Variant classified using ACMG guidelines
|
|
|
Pathogenic
(Mar 01, 2006)
|
no assertion criteria provided
Method: literature only
|
CARDIOFACIOCUTANEOUS SYNDROME 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000035264.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
In 4 presumably unrelated individuals with cardiofaciocutaneous syndrome (CFC1; 115150), Niihori et al. (2006) found a heterozygous 1406G-A transition in exon 11 of the BRAF … (more)
In 4 presumably unrelated individuals with cardiofaciocutaneous syndrome (CFC1; 115150), Niihori et al. (2006) found a heterozygous 1406G-A transition in exon 11 of the BRAF gene, predicting a gly469-to-glu (G469E) amino acid change. (less)
|
|
|
Pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Neoplasm of the large intestine
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504335.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Prostate adenocarcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504336.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Multiple myeloma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504337.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Squamous cell carcinoma of the skin
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504339.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(Jul 14, 2015)
|
no assertion criteria provided
Method: literature only
|
Melanoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504338.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Squamous cell lung carcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504341.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Transitional cell carcinoma of the bladder
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504340.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
None
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504342.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 31, 2016)
|
no assertion criteria provided
Method: literature only
|
Malignant melanoma of skin
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504343.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Pathogenic
(Dec 25, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Cardiofaciocutaneous syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV000747832.1
First in ClinVar: Aug 22, 2016 Last updated: Aug 22, 2016 |
Comment:
The observed variant c.1406G>A (p.G469E) is not reported in 1000 Genomes and has a minor allele frequency of 0.000008238 in ExAC databases. The in silico … (more)
The observed variant c.1406G>A (p.G469E) is not reported in 1000 Genomes and has a minor allele frequency of 0.000008238 in ExAC databases. The in silico prediction of the variant is disease causing by MutationTaster2, damaging by SIFT, and probably damaging by PolyPhen2. (less)
Clinical Features:
Dry skin (present) , Macrocephaly (present) , Abnormal involuntary eye movements (present) , Epicanthus (present) , Ptosis (present) , Hypertelorism (present) , Low-set ears (present) … (more)
Dry skin (present) , Macrocephaly (present) , Abnormal involuntary eye movements (present) , Epicanthus (present) , Ptosis (present) , Hypertelorism (present) , Low-set ears (present) , Short nose (present) , Depressed nasal bridge (present) , Wide nasal base (present) , Thin vermilion border (present) , Increased anterioposterior diameter of thorax (present) , Hypertrophic cardiomyopathy (present) , Pulmonic stenosis (present) , Global developmental delay (present) (less)
Age: 0-9 years
Sex: male
Ethnicity/Population group: Muslim
Geographic origin: India
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on Illumina sequencing platform. Sequence obtained were aligned to the human reference genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indications.
|
|
|
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: SCV004190103.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Number of individuals with the variant: 2
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: SCV001156333.1
First in ClinVar: Feb 06, 2020 Last updated: Feb 06, 2020 |
Comment:
Variant interpreted as Pathogenic and reported on 12-02-2009 by Lab or GTR ID 21766. GenomeConnect-CFC International assertions are reported exactly as they appear on the … (more)
Variant interpreted as Pathogenic and reported on 12-02-2009 by Lab or GTR ID 21766. GenomeConnect-CFC International assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Hypermetropia (present) , Ptosis (present) , Abnormality of cardiovascular system morphology (present) , Morphological abnormality of the central nervous system (present) , Cognitive impairment (present) … (more)
Hypermetropia (present) , Ptosis (present) , Abnormality of cardiovascular system morphology (present) , Morphological abnormality of the central nervous system (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Generalized hypotonia (present) , Seizures (present) , Obesity (present) , Bruising susceptibility (present) , Abnormality of the amniotic fluid (present) , Decreased fetal movement (present) , Anxiety (present) , Autistic behavior (present) (less)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: female
Testing laboratory: Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine
Date variant was reported to submitter: 2009-12-02
Testing laboratory interpretation: Pathogenic
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Comment:
Comment:
The Gly469Glu variant has been reported in the literature in several individuals with clinical features of Cardio-facio-cutaneous syndrome (Niihori 2006, Schulz 2008). In addition, this variant was reported to have occurred de novo in three of those individuals. Therefore, this variant is highly likely to be pathogenic .
Comment:
Variant summary: BRAF c.1406G>A (p.Gly469Glu) results in a non-conservative amino acid change located in the protein kinase domain (IPR000719) of 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 251520 control chromosomes. c.1406G>A has been reported in the literature as a de-novo variant in multiple individuals affected with Cardiofaciocutaneous Syndrome (example, Nihori_2006, Smalley_2009, Sarkozy_2009, Pandit_2007, Schultz_2008, Greaves_2013, Ciara_2015, Lee_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in an induction of ERK activation by trigerring C-RAF activity as a distinct mechanism of action (Wan_2004). Five clinical diagnostic laboratories and one expert panel (ClinGen RASopathy panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
PP2, PP3, PM1, PM2, PS2_VeryStrong, PS3
Comment:
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 BRAF protein function. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 13974). This missense change has been observed in individual(s) with cardiofaciocutaneous syndrome (PMID: 16439621, 16474404, 18042262, 19206169). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 469 of the BRAF protein (p.Gly469Glu).
Comment:
Published functional studies demonstrate a damaging effect on B-Raf activity and MEK and ERK phosphorylation (Rodriguez-Viciana et al., 2006); Missense variants in this gene are often considered pathogenic (HGMD); 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; This variant is associated with the following publications: (PMID: 23093928, 34573299, 30141192, 34184824, 29907801, 18042262, 16474404, 16439621, 19206169, 24803665, 33040082)
Comment:
Variant classified using ACMG guidelines
Comment:
The observed variant c.1406G>A (p.G469E) is not reported in 1000 Genomes and has a minor allele frequency of 0.000008238 in ExAC databases. The in silico prediction of the variant is disease causing by MutationTaster2, damaging by SIFT, and probably damaging by PolyPhen2.
Comment:
Variant interpreted as Pathogenic and reported on 12-02-2009 by Lab or GTR ID 21766. GenomeConnect-CFC International assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant.
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.1406G>A variant in BRAF is a missense variant predicted to cause substitution of glycine by glutamic acid at amino acid 469 (p.Gly469Glu). This variant is absent from gnomAD v4 (PM2_Supporting). 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). The REVEL computational prediction analysis tool produced a score of 0.921, which is above the threshold necessary to apply PP3 (PP3). Furthermore, this variant is in a location which has been defined by the ClinGen RASopathy Expert Panel functional domain of BRAF (PM1). This variant has been reported in the literature in at least 12 patients with clinical features of RASopathy (PS4, PMIDs: 18042262, 16474404, 30141192, 29907801, 35418823), out of which 3 patients were reported as a confirmed de novo occurrence (PS2_VeryStrong; PMIDs: 18042262, 16474404). Luciferase assays showed that p.Gly469Glu did not enhance ELK-dependent transcription indicating that this variant impacts protein function (PS3_Supporting; 16474404). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2_VeryStrong, PS4, PM1, PS3_Supporting, PM2_Supporting, PP2, PP3 (Specification Version 2.1, 9/17/2024)
Comment:
The Gly469Glu variant has been reported in the literature in several individuals with clinical features of Cardio-facio-cutaneous syndrome (Niihori 2006, Schulz 2008). In addition, this variant was reported to have occurred de novo in three of those individuals. Therefore, this variant is highly likely to be pathogenic .
Comment:
Variant summary: BRAF c.1406G>A (p.Gly469Glu) results in a non-conservative amino acid change located in the protein kinase domain (IPR000719) of 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 251520 control chromosomes. c.1406G>A has been reported in the literature as a de-novo variant in multiple individuals affected with Cardiofaciocutaneous Syndrome (example, Nihori_2006, Smalley_2009, Sarkozy_2009, Pandit_2007, Schultz_2008, Greaves_2013, Ciara_2015, Lee_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in an induction of ERK activation by trigerring C-RAF activity as a distinct mechanism of action (Wan_2004). Five clinical diagnostic laboratories and one expert panel (ClinGen RASopathy panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
PP2, PP3, PM1, PM2, PS2_VeryStrong, PS3
Comment:
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 BRAF protein function. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 13974). This missense change has been observed in individual(s) with cardiofaciocutaneous syndrome (PMID: 16439621, 16474404, 18042262, 19206169). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 469 of the BRAF protein (p.Gly469Glu).
Comment:
Published functional studies demonstrate a damaging effect on B-Raf activity and MEK and ERK phosphorylation (Rodriguez-Viciana et al., 2006); Missense variants in this gene are often considered pathogenic (HGMD); 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; This variant is associated with the following publications: (PMID: 23093928, 34573299, 30141192, 34184824, 29907801, 18042262, 16474404, 16439621, 19206169, 24803665, 33040082)
Comment:
Variant classified using ACMG guidelines
Comment:
The observed variant c.1406G>A (p.G469E) is not reported in 1000 Genomes and has a minor allele frequency of 0.000008238 in ExAC databases. The in silico prediction of the variant is disease causing by MutationTaster2, damaging by SIFT, and probably damaging by PolyPhen2.
Comment:
Variant interpreted as Pathogenic and reported on 12-02-2009 by Lab or GTR ID 21766. GenomeConnect-CFC International assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| SeqTailor: a user-friendly webserver for the extraction of DNA or protein sequences from next-generation sequencing data. | Zhang P | Nucleic acids research | 2019 | PMID: 31045209 |
| Comparative assessment of gene-specific variant distribution in prenatal and postnatal cohorts tested for Noonan syndrome and related conditions. | Leach NT | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 29907801 |
| Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity. | Chang MT | Nature biotechnology | 2016 | PMID: 26619011 |
| 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 |
| Prospective enterprise-level molecular genotyping of a cohort of cancer patients. | MacConaill LE | The Journal of molecular diagnostics : JMD | 2014 | PMID: 25157968 |
| Frequency and spectrum of BRAF mutations in a retrospective, single-institution study of 1112 cases of melanoma. | Greaves WO | The Journal of molecular diagnostics : JMD | 2013 | PMID: 23273605 |
| The road to resistance: EGFR mutation and cetuximab. | Bardelli A | Nature medicine | 2012 | PMID: 22310681 |
| Spectrum of mutations in Noonan syndrome and their correlation with phenotypes. | Lee BH | The Journal of pediatrics | 2011 | PMID: 21784453 |
| Prognostic vs predictive molecular biomarkers in colorectal cancer: is KRAS and BRAF wild type status required for anti-EGFR therapy? | Rizzo S | Cancer treatment reviews | 2010 | PMID: 21129611 |
| Prognostic and predictive biomarkers in resected colon cancer: current status and future perspectives for integrating genomics into biomarker discovery. | Tejpar S | The oncologist | 2010 | PMID: 20350999 |
| Clinical biomarkers in oncology: focus on colorectal cancer. | De Roock W | Molecular diagnosis & therapy | 2009 | PMID: 19537845 |
| Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum. | Sarkozy A | Human mutation | 2009 | PMID: 19206169 |
| CRAF inhibition induces apoptosis in melanoma cells with non-V600E BRAF mutations. | Smalley KS | Oncogene | 2009 | PMID: 18794803 |
| Rapid identification of somatic mutations in colorectal and breast cancer tissues using mismatch repair detection (MRD). | Bentivegna S | Human mutation | 2008 | PMID: 18186519 |
| Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome. | Schulz AL | Clinical genetics | 2008 | PMID: 18042262 |
| Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. | Pandit B | Nature genetics | 2007 | PMID: 17603483 |
| 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 |
| Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. | Wan PT | Cell | 2004 | PMID: 15035987 |
| Mutations of the BRAF gene in human cancer. | Davies H | Nature | 2002 | PMID: 12068308 |
| http://docm.genome.wustl.edu/variants/ENST00000288602:c.1406G>A | - | - | - | - |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BRAF | - | - | - | - |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/f75f3f8b-6c9c-41a1-9cee-4716d67229dd | - | - | - | - |
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Text-mined citations for rs121913355 ...
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Record last updated Nov 03, 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.