The L597V variant in the BRAF gene gene has been reported previously as a de novo variant in an individual with Noonan syndrome (Sarkozy et al., 2009). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L597V variant is a conservative amino acid substitution, which occurs at a position that is conserved across species. Functional studies demonstrate that the L597V variant leads to increased protein activity (Sarkozy et al., 2009; Andreadi et al., 2012). Missense variants in nearby residues (F595L, G596V, T599R, V600G, K601Q, K601I, K601T) have been reported in the Human Gene Mutation Database in association with BRAF-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret L597V as a pathogenic variant.
ClinVar Genomic variation as it relates to human health
NM_004333.6(BRAF):c.1789C>G (p.Leu597Val)
Germline
Classification
Help
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.
(16)
Help
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.
Pathogenic
16
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_004333.6(BRAF):c.1789C>G (p.Leu597Val)
Variation ID: 13969 Accession: VCV000013969.45
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 7q34 7: 140753346 (GRCh38) [ NCBI UCSC ] 7: 140453146 (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 Oct 11, 2015 Oct 20, 2024 Mar 14, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_004333.6:c.1789C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004324.2:p.Leu597Val missense NM_001374258.1:c.1909C>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001361187.1:p.Leu637Val missense NM_001354609.2:c.1789C>G NP_001341538.1:p.Leu597Val missense NM_001374244.1:c.1909C>G NP_001361173.1:p.Leu637Val missense NM_001378467.1:c.1798C>G NP_001365396.1:p.Leu600Val missense NM_001378468.1:c.1789C>G NP_001365397.1:p.Leu597Val missense NM_001378469.1:c.1723C>G NP_001365398.1:p.Leu575Val missense NM_001378470.1:c.1687C>G NP_001365399.1:p.Leu563Val missense NM_001378471.1:c.1678C>G NP_001365400.1:p.Leu560Val missense NM_001378472.1:c.1633C>G NP_001365401.1:p.Leu545Val missense NM_001378473.1:c.1633C>G NP_001365402.1:p.Leu545Val missense NM_001378474.1:c.1789C>G NP_001365403.1:p.Leu597Val missense NM_001378475.1:c.1525C>G NP_001365404.1:p.Leu509Val missense NC_000007.14:g.140753346G>C NC_000007.13:g.140453146G>C NG_007873.3:g.176419C>G LRG_299:g.176419C>G LRG_299t1:c.1789C>G P15056:p.Leu597Val - Protein change
- L597V, L509V, L545V, L563V, L600V, L637V, L560V, L575V
- Other names
- -
- Canonical SPDI
- NC_000007.14:140753345:G: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 |
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 (2) |
no assertion criteria provided
|
Apr 21, 2016 | RCV000015003.12 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Jun 10, 2022 | RCV000030948.33 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 21, 2016 | RCV000033333.10 | |
| not provided (1) |
no classification provided
|
- | RCV000208539.4 | |
| Pathogenic (1) |
no assertion criteria provided
|
Oct 2, 2014 | RCV000419516.3 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 13, 2016 | RCV000437189.3 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jul 14, 2015 | RCV000426915.3 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 23, 2020 | RCV000505705.28 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 1, 2020 | RCV001813207.5 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 14, 2024 | RCV002271369.4 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 3, 2022 | RCV002513056.4 | |
| 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
(May 15, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000057238.7
First in ClinVar: Apr 04, 2013 Last updated: Sep 26, 2017 |
Comment:
The L597V variant in the BRAF gene gene has been reported previously as a de novo variant in an individual with Noonan syndrome (Sarkozy et … (more)
The L597V variant in the BRAF gene gene has been reported previously as a de novo variant in an individual with Noonan syndrome (Sarkozy et al., 2009). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L597V variant is a conservative amino acid substitution, which occurs at a position that is conserved across species. Functional studies demonstrate that the L597V variant leads to increased protein activity (Sarkozy et al., 2009; Andreadi et al., 2012). Missense variants in nearby residues (F595L, G596V, T599R, V600G, K601Q, K601I, K601T) have been reported in the Human Gene Mutation Database in association with BRAF-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret L597V as a pathogenic variant. (less)
|
|
|
Pathogenic
(Apr 21, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome
Cardio-facio-cutaneous syndrome
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000204067.4
First in ClinVar: Jan 31, 2015 Last updated: Apr 09, 2018 |
Comment:
The p.Leu597Val variant in BRAF has been previously reported in 4 individuals wi th clinical features of Noonan syndrome and Cardio-facio-cutaneous syndrome, inc luding one … (more)
The p.Leu597Val variant in BRAF has been previously reported in 4 individuals wi th clinical features of Noonan syndrome and Cardio-facio-cutaneous syndrome, inc luding one de novo occurrence (Sarkozy 2009, LMM data). It has not been identifi ed in large population studies. The p.Leu597Val has also been previously reporte d as a somatic mutation in melanomas and non-small cell lung carcinomas (NSCLC)( COSMIC). In vitro functional studies suggest that the p.Leu597Val variant may i mpact protein function (Wan 2004, Andreadi 2012, Sarkozy 2009). In summary, this variant meets the criteria to be classified as pathogenic for Noonan spectrum d isorders in an autosomal dominant manner based upon the de novo occurrence, stat istically significant increase of the allele frequency in affected individuals o ver the general population, and supporting functional evidence. (less)
Number of individuals with the variant: 5
|
|
|
Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447768.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Global developmental delay (present) , Hypotonia (present) , Strabismus (present)
Sex: female
|
|
|
Pathogenic
(Jul 01, 2020)
|
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: SCV002060761.1
First in ClinVar: Jan 20, 2022 Last updated: Jan 20, 2022 |
|
|
|
Pathogenic
(Jun 03, 2022)
|
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: SCV002555623.1
First in ClinVar: Aug 03, 2022 Last updated: Aug 03, 2022 |
Comment:
Variant summary: BRAF c.1789C>G (p.Leu597Val) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four … (more)
Variant summary: BRAF c.1789C>G (p.Leu597Val) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251240 control chromosomes. c.1789C>G has been reported in the literature as a de-novo variant in multiple individuals affected with Noonan/Cardiofaciocutaneous syndrome (example, Sarkozy_2009, Pierpont_2010, Stevenson_2011, Timeus_2013, Wei_2021). These data indicate that the variant is likely to be associated with disease. Ras/MAPK dysregulation in development has been deonstrated to cause a skeletal myopathy in an activating Braf-L597V mouse model for cardio-facio-cutaneous syndrome (Maeda_2021). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Jun 10, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Noonan syndrome 7
Affected status: yes
Allele origin:
germline
|
DASA
Accession: SCV002526401.1
First in ClinVar: Jun 18, 2022 Last updated: Jun 18, 2022 |
Comment:
The c.1909C>G;p.(Leu637Val) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 13969; PMID: 19206169) - PS4.Well-established … (more)
The c.1909C>G;p.(Leu637Val) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 13969; PMID: 19206169) - PS4.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 19206169) - PS3_supporting. The variant is located in a mutational hot spot and/or critical and well-established functional domain (PK_Tyr_Ser-Thr) - PM1. This variant is not present in population databases:rs121913369, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 19206169) PM6. In summary, the currently available evidence indicates that the variant is Pathogenic (less)
Number of individuals with the variant: 1
Sex: male
Geographic origin: Brazil
|
|
|
Pathogenic
(Aug 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
RASopathy
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003440223.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 597 of the BRAF protein (p.Leu597Val). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 597 of the BRAF protein (p.Leu597Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 19206169). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13969). 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. Experimental studies have shown that this missense change affects BRAF function (PMID: 19206169). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 14, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiofaciocutaneous syndrome
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV005038820.1
First in ClinVar: May 07, 2024 Last updated: May 07, 2024 |
|
|
|
Pathogenic
(Jan 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247575.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Aug 15, 2003)
|
no assertion criteria provided
Method: literature only
|
NONSMALL CELL LUNG CANCER, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000035259.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
In a nonsmall cell lung carcinoma (see 211980), Brose et al. (2002) identified a leu596-to-val (L596V) change in exon 15 of the BRAF gene. Based … (more)
In a nonsmall cell lung carcinoma (see 211980), Brose et al. (2002) identified a leu596-to-val (L596V) change in exon 15 of the BRAF gene. Based on the revised numbering system of Kumar et al. (2003), the LEU596VAL mutation has been renumbered as LEU597VAL. (less)
|
|
|
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: SCV000504278.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely pathogenic
(May 13, 2016)
|
no assertion criteria provided
Method: literature only
|
Neoplasm
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504279.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Pathogenic
(Oct 02, 2014)
|
no assertion criteria provided
Method: literature only
|
Lung cancer
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504280.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Pathogenic
(Apr 01, 2009)
|
no assertion criteria provided
Method: literature only
|
NOONAN SYNDROME 7
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000043972.5
First in ClinVar: Apr 04, 2013 Last updated: Feb 02, 2018 |
Comment on evidence:
In patient with Noonan syndrome-7 (NS7; 613706), Sarkozy et al. (2009) identified a heterozygous de novo 1789C-G transversion in exon 15 of the BRAF gene, … (more)
In patient with Noonan syndrome-7 (NS7; 613706), Sarkozy et al. (2009) identified a heterozygous de novo 1789C-G transversion in exon 15 of the BRAF gene, resulting in a leu597-to-val (L597V) substitution. In vitro functional expression studies showed that the W531C mutant protein did not show transforming ability to cells in vitro, although there was a slight increase in MEK phosphorylation, suggesting activation of the downstream MAPK pathway. (less)
|
|
|
Pathogenic
(Apr 21, 2016)
|
no assertion criteria provided
Method: clinical testing
|
Non-small cell lung carcinoma
Affected status: not provided
Allele origin:
somatic
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000197134.2
First in ClinVar: Jan 31, 2015 Last updated: Oct 11, 2015 |
Number of individuals with the variant: 5
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Noonan syndrome 1
Affected status: yes
Allele origin:
germline
|
GeneReviews
Accession: SCV000264344.2
First in ClinVar: Mar 01, 2016 Last updated: Oct 01, 2022 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
The p.Leu597Val variant in BRAF has been previously reported in 4 individuals wi th clinical features of Noonan syndrome and Cardio-facio-cutaneous syndrome, inc luding one de novo occurrence (Sarkozy 2009, LMM data). It has not been identifi ed in large population studies. The p.Leu597Val has also been previously reporte d as a somatic mutation in melanomas and non-small cell lung carcinomas (NSCLC)( COSMIC). In vitro functional studies suggest that the p.Leu597Val variant may i mpact protein function (Wan 2004, Andreadi 2012, Sarkozy 2009). In summary, this variant meets the criteria to be classified as pathogenic for Noonan spectrum d isorders in an autosomal dominant manner based upon the de novo occurrence, stat istically significant increase of the allele frequency in affected individuals o ver the general population, and supporting functional evidence.
Comment:
Variant summary: BRAF c.1789C>G (p.Leu597Val) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251240 control chromosomes. c.1789C>G has been reported in the literature as a de-novo variant in multiple individuals affected with Noonan/Cardiofaciocutaneous syndrome (example, Sarkozy_2009, Pierpont_2010, Stevenson_2011, Timeus_2013, Wei_2021). These data indicate that the variant is likely to be associated with disease. Ras/MAPK dysregulation in development has been deonstrated to cause a skeletal myopathy in an activating Braf-L597V mouse model for cardio-facio-cutaneous syndrome (Maeda_2021). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The c.1909C>G;p.(Leu637Val) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 13969; PMID: 19206169) - PS4.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 19206169) - PS3_supporting. The variant is located in a mutational hot spot and/or critical and well-established functional domain (PK_Tyr_Ser-Thr) - PM1. This variant is not present in population databases:rs121913369, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 19206169) PM6. In summary, the currently available evidence indicates that the variant is Pathogenic
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 597 of the BRAF protein (p.Leu597Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 19206169). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13969). 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. Experimental studies have shown that this missense change affects BRAF function (PMID: 19206169). For these reasons, this variant has been 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 L597V variant in the BRAF gene gene has been reported previously as a de novo variant in an individual with Noonan syndrome (Sarkozy et al., 2009). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L597V variant is a conservative amino acid substitution, which occurs at a position that is conserved across species. Functional studies demonstrate that the L597V variant leads to increased protein activity (Sarkozy et al., 2009; Andreadi et al., 2012). Missense variants in nearby residues (F595L, G596V, T599R, V600G, K601Q, K601I, K601T) have been reported in the Human Gene Mutation Database in association with BRAF-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret L597V as a pathogenic variant.
Comment:
The p.Leu597Val variant in BRAF has been previously reported in 4 individuals wi th clinical features of Noonan syndrome and Cardio-facio-cutaneous syndrome, inc luding one de novo occurrence (Sarkozy 2009, LMM data). It has not been identifi ed in large population studies. The p.Leu597Val has also been previously reporte d as a somatic mutation in melanomas and non-small cell lung carcinomas (NSCLC)( COSMIC). In vitro functional studies suggest that the p.Leu597Val variant may i mpact protein function (Wan 2004, Andreadi 2012, Sarkozy 2009). In summary, this variant meets the criteria to be classified as pathogenic for Noonan spectrum d isorders in an autosomal dominant manner based upon the de novo occurrence, stat istically significant increase of the allele frequency in affected individuals o ver the general population, and supporting functional evidence.
Comment:
Variant summary: BRAF c.1789C>G (p.Leu597Val) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251240 control chromosomes. c.1789C>G has been reported in the literature as a de-novo variant in multiple individuals affected with Noonan/Cardiofaciocutaneous syndrome (example, Sarkozy_2009, Pierpont_2010, Stevenson_2011, Timeus_2013, Wei_2021). These data indicate that the variant is likely to be associated with disease. Ras/MAPK dysregulation in development has been deonstrated to cause a skeletal myopathy in an activating Braf-L597V mouse model for cardio-facio-cutaneous syndrome (Maeda_2021). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The c.1909C>G;p.(Leu637Val) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 13969; PMID: 19206169) - PS4.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 19206169) - PS3_supporting. The variant is located in a mutational hot spot and/or critical and well-established functional domain (PK_Tyr_Ser-Thr) - PM1. This variant is not present in population databases:rs121913369, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 19206169) PM6. In summary, the currently available evidence indicates that the variant is Pathogenic
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 597 of the BRAF protein (p.Leu597Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 19206169). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13969). 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. Experimental studies have shown that this missense change affects BRAF function (PMID: 19206169). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Noonan Syndrome. | Adam MP | - | 2022 | PMID: 20301303 |
| Ras/MAPK dysregulation in development causes a skeletal myopathy in an activating Braf(L597V) mouse model for cardio-facio-cutaneous syndrome. | Maeda Y | Developmental dynamics : an official publication of the American Association of Anatomists | 2021 | PMID: 33522658 |
| Genetic landscape of congenital disorders in patients from Southeast Asia: results from sequencing using a gene panel for Mendelian phenotypes. | Wei H | Archives of disease in childhood | 2021 | PMID: 32978145 |
| Prospective enterprise-level molecular genotyping of a cohort of cancer patients. | MacConaill LE | The Journal of molecular diagnostics : JMD | 2014 | PMID: 25157968 |
| Clinical, pathologic, and biologic features associated with BRAF mutations in non-small cell lung cancer. | Cardarella S | Clinical cancer research : an official journal of the American Association for Cancer Research | 2013 | PMID: 23833300 |
| Functional evaluation of circulating hematopoietic progenitors in Noonan syndrome. | Timeus F | Oncology reports | 2013 | PMID: 23756559 |
| Major clinical response to a BRAF inhibitor in a patient with a BRAF L597R-mutated melanoma. | Bahadoran P | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2013 | PMID: 23715574 |
| A structural systems biology approach for quantifying the systemic consequences of missense mutations in proteins. | Cheng TM | PLoS computational biology | 2012 | PMID: 23093928 |
| The intermediate-activity (L597V)BRAF mutant acts as an epistatic modifier of oncogenic RAS by enhancing signaling through the RAF/MEK/ERK pathway. | Andreadi C | Genes & development | 2012 | PMID: 22892241 |
| Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. | Falchook GS | The Lancet. Oncology | 2012 | PMID: 22805292 |
| BRAF(L597) mutations in melanoma are associated with sensitivity to MEK inhibitors. | Dahlman KB | Cancer discovery | 2012 | PMID: 22798288 |
| Kinase-impaired BRAF mutations in lung cancer confer sensitivity to dasatinib. | Sen B | Science translational medicine | 2012 | PMID: 22649091 |
| Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. | Paik PK | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2011 | PMID: 21483012 |
| Bone resorption in syndromes of the Ras/MAPK pathway. | Stevenson DA | Clinical genetics | 2011 | PMID: 21204800 |
| 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 |
| Alterations in genes of the EGFR signaling pathway and their relationship to EGFR tyrosine kinase inhibitor sensitivity in lung cancer cell lines. | Gandhi J | PloS one | 2009 | PMID: 19238210 |
| Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum. | Sarkozy A | Human mutation | 2009 | PMID: 19206169 |
| Genetic predictors of MEK dependence in non-small cell lung cancer. | Pratilas CA | Cancer research | 2008 | PMID: 19010912 |
| Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. | Wan PT | Cell | 2004 | PMID: 15035987 |
| BRAF mutations in metastatic melanoma: a possible association with clinical outcome. | Kumar R | Clinical cancer research : an official journal of the American Association for Cancer Research | 2003 | PMID: 12960123 |
| Missense mutations of the BRAF gene in human lung adenocarcinoma. | Naoki K | Cancer research | 2002 | PMID: 12460919 |
| BRAF and RAS mutations in human lung cancer and melanoma. | Brose MS | Cancer research | 2002 | PMID: 12460918 |
| Mutations of the BRAF gene in human cancer. | Davies H | Nature | 2002 | PMID: 12068308 |
| http://docm.genome.wustl.edu/variants/ENST00000288602:c.1789C>G | - | - | - | - |
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Text-mined citations for rs121913369 ...
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Record last updated Oct 20, 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.