ClinVar Genomic variation as it relates to human health
NM_001709.5(BDNF):c.196G>A (p.Val66Met)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001709.5(BDNF):c.196G>A (p.Val66Met)
Variation ID: 17697 Accession: VCV000017697.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p14.1 11: 27658369 (GRCh38) [ NCBI UCSC ] 11: 27679916 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 2, 2016 Feb 20, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001709.5:c.196G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001700.2:p.Val66Met missense NM_001143805.1:c.196G>A NP_001137277.1:p.Val66Met missense NM_001143806.1:c.196G>A NP_001137278.1:p.Val66Met missense NM_001143807.2:c.196G>A NP_001137279.1:p.Val66Met missense NM_001143808.2:c.196G>A NP_001137280.1:p.Val66Met missense NM_001143809.2:c.283G>A NP_001137281.1:p.Val95Met missense NM_001143810.2:c.442G>A NP_001137282.1:p.Val148Met missense NM_001143811.2:c.196G>A NP_001137283.1:p.Val66Met missense NM_001143812.2:c.196G>A NP_001137284.1:p.Val66Met missense NM_001143813.2:c.196G>A NP_001137285.1:p.Val66Met missense NM_001143814.2:c.196G>A NP_001137286.1:p.Val66Met missense NM_001143816.2:c.196G>A NP_001137288.1:p.Val66Met missense NM_170731.5:c.220G>A NP_733927.1:p.Val74Met missense NM_170732.4:c.196G>A NP_733928.1:p.Val66Met missense NM_170733.4:c.196G>A NP_733929.1:p.Val66Met missense NM_170734.4:c.241G>A NP_733930.1:p.Val81Met missense NM_170735.6:c.196G>A NP_733931.1:p.Val66Met missense NR_002832.2:n.503C>T non-coding transcript variant NR_033312.1:n.434C>T non-coding transcript variant NR_033313.1:n.434C>T non-coding transcript variant NR_033314.1:n.503C>T non-coding transcript variant NR_033315.1:n.434C>T non-coding transcript variant NC_000011.10:g.27658369C>T NC_000011.9:g.27679916C>T NG_011794.1:g.68690G>A P23560:p.Val66Met - Protein change
- V66M, V74M, V81M, V148M, V95M
- Other names
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- Canonical SPDI
- NC_000011.10:27658368:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.20128 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.14533
Trans-Omics for Precision Medicine (TOPMed) 0.15105
Exome Aggregation Consortium (ExAC) 0.19375
The Genome Aggregation Database (gnomAD), exomes 0.19488
1000 Genomes Project 30x 0.19550
1000 Genomes Project 0.20128
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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. |
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BDNF | - | - |
GRCh38 GRCh37 |
7 | 97 | |
BDNF-AS | - | - |
GRCh38 GRCh37 |
- | 92 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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risk factor (1) |
no assertion criteria provided
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Dec 13, 2022 | RCV000019267.8 | |
Benign (2) |
criteria provided, multiple submitters, no conflicts
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Jun 18, 2013 | RCV000155463.10 | |
Benign (1) |
criteria provided, single submitter
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Jan 31, 2024 | RCV002054446.6 |
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
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Benign
(-)
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criteria provided, single submitter
Method: clinical testing
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NOT SPECIFIED
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV000316419.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
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Benign
(Jun 18, 2013)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000205154.4
First in ClinVar: Jan 31, 2015 Last updated: Oct 02, 2016 |
Comment:
Benign with respect to pulmonary disease based on high population frequency, Th is variant has been proposed to be associated with a rnage of psychiatric … (more)
Benign with respect to pulmonary disease based on high population frequency, Th is variant has been proposed to be associated with a rnage of psychiatric manife stations though the data is not solid and more recent meta-analyses argue agains t a risk effect. (less)
Number of individuals with the variant: 28
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Benign
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002355196.3
First in ClinVar: Apr 08, 2022 Last updated: Feb 20, 2024 |
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risk factor
(Dec 13, 2022)
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no assertion criteria provided
Method: literature only
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RECLASSIFIED - BRAIN-DERIVED NEUROTROPHIC FACTOR POLYMORPHISM
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000039555.5
First in ClinVar: Apr 04, 2013 Last updated: Dec 17, 2022 |
Comment on evidence:
This variant, formerly associated with several phenotypes, has been reclassified as a polymorphism based on a review of the ExAC database by Hamosh (2018). The … (more)
This variant, formerly associated with several phenotypes, has been reclassified as a polymorphism based on a review of the ExAC database by Hamosh (2018). The variant was present in 23,500 of 121,350 alleles and in 2,879 homozygotes, with an allele frequency of 0.1937 (April 24, 2018). Memory Impairment, Susceptibility To Egan et al. (2003) identified a single-nucleotide polymorphism (rs6265), 196G-A, in the BDNF gene that results in a val66-to-met (V66M) change in the 5-prime pro-region of the protein. They examined the effects of this polymorphism in a cohort of 641 human subjects. The M66 allele was associated with poorer episodic memory, abnormal hippocampal activation assayed with fMRI, and lower hippocampal N-acetyl aspartate assayed with MRI spectroscopy. Obsessive-Compulsive Disorder, Protection Against In a study of 164 proband-parent trios with obsessive-compulsive disorder (see 164230), Hall et al. (2003) found significant evidence of association between OCD and all BDNF gene markers tested, including the V66M polymorphism. Haplotype transmission comparisons in this and previous studies pointed to a functionally distinct BDNF haplotype uniquely marked by the rare M66 allele, which is undertransmitted and likely confers a protective effect in OCD and other psychiatric disorders. Anorxia Nervosa or Bulimia Nervosa, Susceptibility To Ribases et al. (2003) reported a strong association of the met66 allele with restricting anorexia nervosa (see 610269) and low minimum body mass index in Spanish patients. Ribases et al. (2004) performed a case-control study in 1,142 European patients with eating disorders. They found that the met66 variant of BDNF was strongly associated with all eating disorder subtypes (anorexia nervosa, restricting anorexia nervosa, binge-eating/purging anorexia nervosa, and bulimia nervosa; see 610269). Bipolar Affective Disorder Geller et al. (2004) noted that Sklar et al. (2002) and Neves-Pereira et al. (2002), using family-based methods, had found that the val66 allele was preferentially transmitted to predominantly Caucasian adult probands with bipolar disorder (se 125480). Geller et al. (2004) reported that the val66 allele was also preferentially transmitted in children with bipolar disorder. Lohoff et al. (2005) studied the BDNF val66 allele in 621 European patients with bipolar I disorder and positive family histories of affective disorder and 998 European controls. The frequency of the val66 allele was significantly increased in the bipolar I patients when compared to controls (p = 0.028; OR of 1.22). Rybakowski et al. (2006) studied the performance of 111 patients with bipolar disorder, 129 schizophrenia patients, and 92 healthy controls on the Wisconsin Card Sorting Test in the context of the BDNF V66M polymorphism. Bipolar patients with the val/val genotype made significantly fewer perseverative errors and had more correctly completed categories and conceptual level responses compared to bipolar patients with the val/met or met/met genotypes. No differences were observed in schizophrenia patients or controls. Rosa et al. (2006) studied the V66M polymorphism in a sample of 94 nuclear families (94 probands with schizophrenia-spectrum disorders and 282 family members). The results indicated that the val66 polymorphism plays a significant role in the phenotype of psychosis. No association was found with prefrontal cognitive functions as assessed on the Wisconsin Card Sorting Test and Trail Making Test. Parkinson Disease In a metaanalysis of 6 published association studies, Zintzaras and Hadjigeorgiou (2005) found no association between the 196G-A polymorphism and the development of Parkinson disease. In a study of 597 patients from 322 families with PD, Karamohamed et al. (2005) found that homozygosity for the met66 allele was associated with a 5.4-year older age at disease onset. The findings were significant only under an autosomal recessive model (see, e.g., PARK2, 600116). Anxiety Disorder Soliman et al. (2010) identified parallel phenotypes in mice and humans resulting from the common V66M SNP in BDNF, which is involved in anxiety-related behavior (see 607834). An inbred genetic knockin mouse strain expressing the variant BDNF recapitulated the phenotypic effects of the human polymorphism. Both were impaired in extinguishing a conditioned fear response, which was paralleled by atypical frontoamygdala activity in humans. Soliman et al. (2010) concluded that this variant BDNF allele may play a role in anxiety disorders showing impaired learning of cues that signal safety versus threat and in the efficacy of treatments that rely on extinction mechanisms, such as exposure therapy. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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A genetic variant BDNF polymorphism alters extinction learning in both mouse and human. | Soliman F | Science (New York, N.Y.) | 2010 | PMID: 20075215 |
The Val66Met polymorphism of the brain-derived neurotrophic factor gene is associated with risk for psychosis: evidence from a family-based association study. | Rosa A | American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics | 2006 | PMID: 16389585 |
Illness-specific association of val66met BDNF polymorphism with performance on Wisconsin Card Sorting Test in bipolar mood disorder. | Rybakowski JK | Molecular psychiatry | 2006 | PMID: 16222333 |
BDNF genetic variants are associated with onset age of familial Parkinson disease: GenePD Study. | Karamohamed S | Neurology | 2005 | PMID: 16344533 |
The role of G196A polymorphism in the brain-derived neurotrophic factor gene in the cause of Parkinson's disease: a meta-analysis. | Zintzaras E | Journal of human genetics | 2005 | PMID: 16172806 |
Confirmation of association between the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene and bipolar I disorder. | Lohoff FW | American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics | 2005 | PMID: 16152572 |
Linkage disequilibrium of the brain-derived neurotrophic factor Val66Met polymorphism in children with a prepubertal and early adolescent bipolar disorder phenotype. | Geller B | The American journal of psychiatry | 2004 | PMID: 15337662 |
Association of BDNF with anorexia, bulimia and age of onset of weight loss in six European populations. | Ribasés M | Human molecular genetics | 2004 | PMID: 15115760 |
Met66 in the brain-derived neurotrophic factor (BDNF) precursor is associated with anorexia nervosa restrictive type. | Ribasés M | Molecular psychiatry | 2003 | PMID: 12888803 |
Sequence variants of the brain-derived neurotrophic factor (BDNF) gene are strongly associated with obsessive-compulsive disorder. | Hall D | American journal of human genetics | 2003 | PMID: 12836135 |
The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. | Egan MF | Cell | 2003 | PMID: 12553913 |
The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: evidence from a family-based association study. | Neves-Pereira M | American journal of human genetics | 2002 | PMID: 12161822 |
Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Brain-derived neutrophic factor. | Sklar P | Molecular psychiatry | 2002 | PMID: 12140781 |
Hamosh, A. Personal Communication. 2018. Baltimore, Md. | - | - | - | - |
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Text-mined citations for rs6265 ...
HelpRecord last updated Mar 11, 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.