ClinVar Genomic variation as it relates to human health
NM_000754.4(COMT):c.472G>A (p.Val158Met)
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_000754.4(COMT):c.472G>A (p.Val158Met)
Variation ID: 17591 Accession: VCV000017591.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q11.21 22: 19963748 (GRCh38) [ NCBI UCSC ] 22: 19951271 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Feb 25, 2014 Feb 20, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000754.4:c.472G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000745.1:p.Val158Met missense NM_001135161.2:c.472G>A NP_001128633.1:p.Val158Met missense NM_001135162.2:c.472G>A NP_001128634.1:p.Val158Met missense NM_001362828.2:c.472G>A NP_001349757.1:p.Val158Met missense NM_007310.3:c.322G>A NP_009294.1:p.Val108Met missense NC_000022.11:g.19963748G>A NC_000022.10:g.19951271G>A NG_011526.1:g.27009G>A LRG_1010:g.27009G>A LRG_1010t1:c.472G>A LRG_1010p1:p.Val158Met P21964:p.Val158Met - Protein change
- V158M, V108M
- Other names
- COMT, VAL158MET (rs4680)
- Canonical SPDI
- NC_000022.11:19963747:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.36921 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.36921
1000 Genomes Project 30x 0.37008
Trans-Omics for Precision Medicine (TOPMed) 0.42039
The Genome Aggregation Database (gnomAD) 0.44044
The Genome Aggregation Database (gnomAD), exomes 0.46109
Exome Aggregation Consortium (ExAC) 0.47275
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
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. |
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COMT | - | - |
GRCh38 GRCh37 |
88 | 611 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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CATECHOL-O-METHYLTRANSFERASE POLYMORPHISM
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Benign (1) |
no assertion criteria provided
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Jan 1, 2011 | RCV000019156.13 |
Benign (5) |
criteria provided, single submitter
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- | RCV000244083.19 | |
drug response (1) |
no assertion criteria provided
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Apr 28, 2018 | RCV001028880.10 | |
Benign (1) |
criteria provided, single submitter
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- | RCV003633481.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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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: SCV000305505.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
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Benign
(-)
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criteria provided, single submitter
Method: case-control
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Schizophrenia
Affected status: no
Allele origin:
germline
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Center for Forensic Mental Health, Chiba University
Accession: SCV004543740.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Age: 16-80 years
Sex: mixed
Ethnicity/Population group: EastAsia
Geographic origin: Japan
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001809012.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001970895.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Benign
(Jan 01, 2011)
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no assertion criteria provided
Method: literature only
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CATECHOL-O-METHYLTRANSFERASE POLYMORPHISM
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000039444.3
First in ClinVar: Apr 04, 2013 Last updated: Jul 09, 2022 |
Comment on evidence:
COMT inactivates catecholamines and catechol drugs such as L-DOPA. Weinshilboum and Raymond (1977), Spielman and Weinshilboum (1981), and others demonstrated that the level of COMT … (more)
COMT inactivates catecholamines and catechol drugs such as L-DOPA. Weinshilboum and Raymond (1977), Spielman and Weinshilboum (1981), and others demonstrated that the level of COMT enzyme activity is genetically polymorphic in human red blood cells (RBCs) and liver, with a trimodal distribution of low, intermediate, and high levels of activity. This genetic polymorphism results in a 3- to 4-fold difference in COMT activity in RBCs and liver. Segregation analysis of data from family studies demonstrated that the pattern of inheritance is consistent with the presence of autosomal codominant alleles. The polymorphism was also associated with individual variation in COMT thermal instability. Lachman et al. (1996) showed that this polymorphism is due to a G-to-A transition at codon 158 of the COMT gene, resulting in a valine-to-methionine (V158M) substitution. The 2 alleles could be identified with a PCR-based restriction fragment length polymorphism analysis using the restriction enzyme NlaIII. Lachman et al. (1996) studied patients with velocardiofacial syndrome (VCFS; 192430), a relatively common congenital disorder associated with typical facial appearance, cleft palate, cardiac defects, and learning disabilities. Most patients have an interstitial deletion on 22q11. In addition to physical abnormalities, a variety of psychiatric illnesses have been reported in patients with VCFS, including schizophrenia (181500), bipolar disorder (125480), and attention deficit hyperactivity disorder. The psychiatric manifestations of VCFS could be due to haploinsufficiency of a gene or genes within 22q11, and since the COMT gene maps to this region, it is a candidate. Homozygosity for 158met leads to a 3- to 4-fold reduction in enzymatic activity, compared with homozygosity for 158val. Lachman et al. (1996) reported that in the population of patients with VCFS, there was an apparent association between the low-activity allele, 158met, and the development of bipolar spectrum disorder and, in particular, a rapid-cycling form. Comorbid panic disorder may define a subtype of bipolar disorder and may influence the strength of association between bipolar disorder and candidate genes involved in monoamine neurotransmission. Rotondo et al. (2002) studied the frequency of the V158M polymorphism, the 5-HTTLPR polymorphism of the serotonin transporter SLC6A4 (182138.0001), and a splice site polymorphism (IVS7+218C-A) of tryptophan hydroxylase (TPH; 191060) in a case-control association study of bipolar disorder patients with or without lifetime panic disorder. They compared results from DNA extracted from blood leukocytes of 111 unrelated subjects of Italian descent meeting DSM-III-R criteria for bipolar disorder, including 49 with and 62 without comorbid lifetime panic disorder, with those of 127 healthy subjects. Relative to the comparison subjects, subjects with bipolar disorder without panic disorder, but not those with comorbid bipolar disorder and panic disorder, showed significantly higher frequencies of the COMT met158 and the short 5-HTTLPR alleles. No statistical significance was found between the bipolar disorder groups and the TPH polymorphism. Rotondo et al. (2002) concluded that bipolar disorder without panic disorder may represent a more homogeneous form of illness and that variants of the COMT and SLC6A4 genes may influence clinical features of bipolar disorder. Graf et al. (2001) treated 5 patients with the 22q11.2 deletion syndrome, the 158met polymorphism, and neuropsychiatric illness with a trial of metyrosine. They suggested that the presence of the 158met variant on the nondeleted allele, known to be associated with decreased enzyme activity, leads to increased catecholamine levels and could contribute to neuropsychiatric manifestations. Metyrosine, a competitive inhibitor of tyrosine hydroxylase, lowers the concentration of homovanillic acid, presumably by decreasing brain dopamine. Four of the 5 patients treated experienced subjective improvements in overall well-being. Hoda et al. (1996) found no relationship between this common polymorphism and susceptibility to idiopathic Parkinson disease. Syvanen et al. (1997) likewise demonstrated a val158-to-met change as the basis for the high-activity thermostable and low-activity thermolabile forms of the COMT gene. In the Finnish population, they found that the 2 COMT alleles are equally distributed. No statistically significant difference in the frequencies of the COMT alleles were found when comparing the normal population with a sample of 158 Finnish patients with Parkinson disease. Alcoholism (103780) has been classified into 2 subtypes. Type 2 alcoholism is associated with early onset, high novelty seeking, and impulsive antisocial behavior. Most alcoholics can be classified as type 1, which is characterized by late onset (over 25 years) and no prominent antisocial behavior (Cloninger, 1995). In vivo brain imaging studies in humans have indicated that a dysfunction in dopaminergic neurotransmission occurs in type 1 but not type 2 alcoholics. Since COMT has a crucial role in the metabolism of dopamine, it was suggested that the common functional genetic polymorphism in the COMT gene, which results in 3- to 4-fold difference in COMT enzyme activity (Lachman et al., 1996; Syvanen et al., 1997), may contribute to the etiology of alcoholism. Since ethanol-induced euphoria is associated with the rapid release of dopamine in limbic areas, it was considered conceivable that subjects who inherited the allele encoding the low-activity COMT variant would have a relatively low dopamine inactivation rate, and therefore would be more vulnerable to the development of ethanol dependence. Tiihonen et al. (1999) tested this hypothesis among type 1 (late-onset) alcoholics. Two independent Finnish populations were studied, 1 in Turku (67) and 1 in Kuopio (56). The high (H)- and low (L)-activity COMT genotype and allele frequencies were compared with previously published data from Finnish blood donors and race- and gender-matched controls. The frequency of the L allele was markedly higher among the patients in both groups when compared with the general population. The L allele frequency was significantly higher among alcoholics when compared with controls (P = 0.009). The estimate for population etiologic (attributable) fraction for the LL genotype in alcoholism was 13.3% (95% CI = 2.3-25.7%). Egan et al. (2001) examined the relationship of this COMT polymorphism (which they referred to as VAL108/158MET), which accounts for a 4-fold variation in enzyme activity and dopamine catabolism, with both prefrontally mediated cognition and prefrontal cortical physiology. In 175 patients with schizophrenia, 219 unaffected sibs, and 55 controls, COMT genotype was related in allele dosage fashion to performance on the Wisconsin Card Sorting Test of executive cognition and explained 4% of variance in frequency of perseverative errors. The load of the low activity met allele predicted enhanced cognitive performance. Egan et al. (2001) then examined the effect of COMT genotype on prefrontal physiology during a working memory task in 3 separate subgroups assayed with functional MRI. The met allele load consistently predicted a more efficient physiologic response in prefrontal cortex. In transmission disequilibrium test of 104 trios, Egan et al. (2001) found a significant increase in transmission of the val allele to the schizophrenic offspring. Egan et al. (2001) concluded that the COMT val allele, because it increases prefrontal dopamine catabolism, impairs prefrontal cognition and physiology and by this mechanism slightly increases risk for schizophrenia. Shifman et al. (2002) reported the results of a study of COMT as a candidate gene for schizophrenia, using a large sample size (the largest case-control study performed to that time); a relatively well-defined and homogeneous population (Ashkenazi Jews); and a stepwise procedure in which several single nucleotide polymorphisms (SNPs) were scanned in DNA pools, followed by individual genotyping and haplotype analysis of the relevant SNPs. They found a highly significant association between schizophrenia and a COMT haplotype; P = 9.5 x 10(-8). Glatt et al. (2003) evaluated the collective evidence for an association between the val158/108met polymorphism (codon 158 of the membrane-bound form; codon 108 of the soluble form) of the COMT gene and schizophrenia by performing a separate metaanalysis of 14 case-control and 5 family-based studies published between 1996 and 2002. Overall, the case-control studies showed no indication of an association between either allele and schizophrenia, but the family-based studies found modest evidence implicating the val allele in schizophrenia risk. Glatt et al. (2003) concluded that the family-based studies might be more accurate since this method avoids the pitfalls of population stratification. They suggested that the val allele may be a small but reliable risk factor for schizophrenia for people of European ancestry but that its role in Asian populations remained unclear. Fan et al. (2005) conducted a large-scale association study plus metaanalysis of the COMT val/met polymorphism and risk of schizophrenia in 862 patients and 928 healthy control subjects from a Han Chinese population. No significant differences were found in allele or genotype frequencies between patients and normal control subjects, although a nonsignificant overrepresentation of the val allele in schizophrenia patients (OR = 1.09, 95% CI = 0.94-1.26) was suggested. The metaanalysis provided no significant evidence for an association between schizophrenia and the val allele in Asian or European populations. Malhotra et al. (2002) studied 73 healthy individuals who took the Wisconsin Card Sorting Test and were genotyped for the val158-to-met polymorphism. ANOVA analysis revealed that the met/met group made significantly fewer perseverative errors than either the met/val group (p = 0.02) or the val/val group (p = 0.02). There were no significant differences between the performances of the met/val and val/val groups. The findings provided evidence that reduced COMT function is associated with improved cognitive performance. To determine if the V158M polymorphism influences prefrontal cognitive function and increases the risk for schizophrenia, Rosa et al. (2004) genotyped 89 sib pairs discordant for psychosis for this polymorphism and assessed the sib pairs with the Wisconsin Card Sorting Test. In healthy sibs, a linear relationship was seen in which performance on the Wisconsin Card Sorting Test was associated in an allele dosage fashion with COMT genotype (val/val vs other genotypes, p = 0.007); however, this association was not observed in patients with schizophrenia. Furthermore, there was no evidence of genetic association with psychosis. In a case-control study of 320 Korean patients with schizophrenia and 379 controls, Lee et al. (2005) found that the val/met polymorphism was not associated with an increased risk of schizophrenia (OR = 0.88, 95% CI = 0.64-1.21, p = 0.43). Tsai et al. (2006) studied the transmission of the COMT val/met polymorphism in 223 trios consisting of Chinese patients with schizophrenia and their biologic parents. Using the transmission disequilibrium test, they found no significant difference between transmitted and nontransmitted allele frequencies for this polymorphism. To study the association of the COMT val/met polymorphism with schizophrenia, Williams et al. (2005) studied 2,800 individuals including nearly 1,200 individuals with schizophrenia from case-control and family-based European association samples. No support was found for the hypotheses that the polymorphism influences susceptibility to schizophrenia in general or in Ashkenazi or Irish subjects. Munafo et al. (2005) studied the association of the COMT val108/158met allele with schizophrenia by conducting a metaanalysis of 18 studies published between 1996 and 2003. When all studies were included in a metaregression, there was evidence for a significant association of the COMT val allele frequency with schizophrenia case status and a significant main effect of ancestry. However, the interaction of the COMT val allele frequency and ancestry was also significant. When Munafo et al. (2005) included only studies that reported allele frequencies that did not depart significantly from Hardy-Weinberg equilibrium among controls, these effects were no longer significant. Thus, the results of the metaanalysis did not support an association between the COMT val allele and schizophrenia case status and did not indicate that an association may be moderated by ancestry. Woo et al. (2002) studied 51 patients meeting DSM-IV criteria for panic disorder and 45 healthy comparison subjects for the V158M polymorphism. The frequency of the met/met genotype was significantly higher in patients with panic disorder than in healthy subjects (19.6% vs 2.2%). Furthermore, panic disorder was significantly associated with the met allele (38.2% vs 18.9%). Patients with panic disorder who had the met/met genotype had a poorer treatment response than those with other genotypes. Woo et al. (2002) concluded that COMT activity might be related to susceptibility to panic disorder and treatment response to medications. Wu et al. (2001) analyzed 224 Taiwanese patients with Parkinson disease (168600) for MAOB intron 13 G (309860) and COMT L (V158M) polymorphisms and found that the MAOB G genotype (G in men, G/G in women) was associated with a 2.07-fold increased relative risk for PD, an association which was stronger for men than for women. Although COMT polymorphism alone was not associated with an increased risk for PD, when it was considered in conjunction with the MAOB G genotype, there was a 2.4-fold increased relative risk for PD. In men, the combined alleles, MAOB G and COMT L, increased the relative risk for PD to 7.24. Wu et al. (2001) suggested that, in Taiwanese, the development of PD may be related to the interaction of 2 or more genes involved in dopamine metabolism. The functional V158M variant represents an exon 4 SNP that is detected as an NlaIII restriction site polymorphism. It is polymorphic in populations around the world (Palmatier et al., 1999). DeMille et al. (2002) described a 4-site haplotype spanning 28 kb and effectively encompassing the COMT gene. Avramopoulos et al. (2002) genotyped 379 healthy 18- to 24-year-old male individuals who had completed the Perceptual Aberration Scale (PAS), Schizotypal Personality Questionnaire (SPQ), and Aggression Questionnaire (AQ). Self-reported schizotypy scores were significantly related to the COMT val158-to-met polymorphism (P = 0.028 for the PAS and P = 0.015 for the SPQ). Individuals homozygous for the high activity allele showed the highest scores. No significant findings were seen using the AQ. Suicidal behavior is often correlated with other-directed aggression, which is believed to be partially mediated by catecholaminergic neurotransmission. Rujescu et al. (2003) examined the influence of the V158M polymorphism on suicidal behavior and anger-related traits. By Taq polymerase digestion of PCR products, they genotyped 149 German suicide attempters and 328 German control subjects. There was no overall difference in allele/genotype frequency between patients and control subjects. However, the low activity L allele was overrepresented in violent suicide attempters (62% vs 51%). LL carriers expressed their anger more outwardly versus HH carriers who expressed it more inwardly, and they reported more state anger, as assessed by the State-Trait Anger Expression Inventory. Rujescu et al. (2003) interpreted these findings as supporting the hypothesis that this functional polymorphism may modify the phenotype of suicide attempts and anger-related traits. Zubieta et al. (2003) examined the influence of the V158M polymorphism, which affects the metabolism of catecholamines, on the modulation of responses to sustained pain in humans. Individuals homozygous for the M158 allele showed diminished regional mu-opioid system (see 600018) responses to pain compared with heterozygotes. These effects were accompanied by higher sensory and affective ratings of pain and a more negative internal affective state. Opposite effects were observed in V158 homozygotes. Zubieta et al. (2003) concluded that the COMT V158M polymorphism influences the human experience of pain and may underlie interindividual differences in the adaptation and responses to pain and other stressful stimuli. The clinical effects of amphetamine are quite variable, from positive effects on mood and cognition in some individuals, to negative responses in others, perhaps related to individual variations in monoaminergic and monoamine system genes. Mattay et al. (2003) found that amphetamine enhanced the efficiency of prefrontal cortex function assayed with functional MRI during a working memory task in subjects with the high enzyme activity val/val genotype, who presumably have relatively less prefrontal synaptic dopamine. In contrast, in subjects with the low activity met/met genotype who tend to have superior baseline prefrontal function, the drug had no effect on cortical efficiency at low-to-moderate working memory load and caused deterioration at high working memory load. The data illustrated an application of functional neuroimaging and extended basic evidence of an inverted-'U' functional-response curve to increasing dopamine signaling in the prefrontal cortex. Further, individuals with the met/met catechol O-methyltransferase genotype appeared to be at increased risk for an adverse response to amphetamine. In COS-1 and HEK293 cells, Shield et al. (2004) transiently expressed wildtype and thr52 and met108 variants of COMT. The thr52 variant had no significant change in level of COMT activity, but there was a 40% decrease in the level of activity in cells transfected with the met108 variant. The met108 variant displayed a 70 to 90% decrease in immunoreactive protein when compared with wildtype, but there was no significant change in the level of immunoreactive protein for thr52. A significant decrease in the level of immunoreactive protein was also found in hepatic biopsy samples from patients homozygous for the met108 allele. Shield et al. (2004) concluded that the decreased level of activity of the met108 allele appeared to be due to a reduced COMT protein level. In a large sample (n = 108) of postmortem human prefrontal cortex tissue, which expresses predominantly the membrane-bound isoform of COMT, Chen et al. (2004) studied the effects of several single-nucleotide polymorphisms (SNPs) within COMT on mRNA expression levels (using RT-PCR analysis), protein levels (using Western blot analysis), and enzyme activity (using catechol methylation). They found that the common coding SNP V158M significantly affected protein abundance and enzyme activity but not mRNA expression levels, suggesting that differences in protein integrity account for the difference in enzyme activity between alleles. Using site-directed mutagenesis of mouse COMT cDNA followed by in vitro translation, they found that the conversion of leu at the homologous position into met or val progressively and significantly diminished enzyme activity. Thus, although Chen et al. (2004) could not exclude a more complex genetic basis for functional effects of COMT, val158 appeared to be a predominant factor that determines higher COMT activity in the prefrontal cortex, which presumably leads to lower synaptic dopamine levels and relatively deleterious prefrontal function. Using multimodal neuroimaging techniques to analyze 24 healthy individuals, Meyer-Lindenberg et al. (2005) found that 11 carriers of the val108/158 allele had significantly higher midbrain F-DOPA uptake rates compared to 13 homozygous met108/158 carriers, indicating decreased dopamine synthesis in met carriers. During a working memory challenge test, the 2 genotypes were associated with inverse differences in regional blood flow in the prefrontal cortex as related to midbrain F-DOPA uptake, reflecting greater cortical extracellular dopamine in met homozygotes. The findings suggested a dopaminergic 'tuning' mechanism in the prefrontal cortex during cognitive processing and indicated a link between cortical and subcortical dopaminergic activity. Thapar et al. (2005) noted that early-onset antisocial behavior accompanied by ADHD is a clinically severe variant of antisocial behavior with a poor outcome. In 240 British children with ADHD or hyperkinetic disorder, they studied the V158M SNP and the effects of birth weight, which is an environmentally influenced index. A comprehensive standardized assessment including measures of antisocial behavior and IQ was conducted. The val/val genotype (P = 0.002) and lower birth weight (P = 0.002) were associated with increased symptoms of conduct disorder and a significant gene-environment interaction (P = 0.006) was also confirmed. Bruder et al. (2005) examined the relation of V158M genotype to performance on a battery of working memory tests that assessed different cognitive operations. A total of 4,002 healthy adults were tested for working memory tasks: Spatial Delayed Response, Word Serial Position Test, N-back, and Letter-Number Sequencing. A subsample of 246 individuals was tested on the Wisconsin Card Sorting Test. Letter-Numbering Sequencing was the only working memory test that showed expected differences with the met/met group showing the best performance and the val/val group reporting the poorest performance. The met/met group also performed better than the val/val group on the Wisconsin Card Sorting Test. Bruder et al. (2005) concluded that COMT genotype was not associated with performance on tests measuring simple storage, maintenance of temporal order, or updating of information in working memory but was associated with higher-order components of processing. Baker et al. (2005) studied 2 hypotheses: first, that individuals with 22q11 deletion syndrome (see 188400 and 192430) would manifest specific cognitive and neurophysiologic abnormalities in common with individuals at high risk for schizophrenia in the general population; and second, that the COMT val108/158met polymorphism would modify the severity of endophenotypic features. Adolescents and young adults with 22q11 deletion syndrome, aged 13-21, were compared with age- and IQ-matched control subjects on measures that were associated with risk for idiopathic schizophrenia. These individuals displayed poorer verbal working memory and expressive language performance than control subjects. Auditory mismatch negativity event-related potentials were reduced at frontal electrodes but intact at temporal sites. The presence of the COMT val108/158met allele on the single intact chromosome 22 was associated with more marked auditory mismatch negativity amplitude reduction and poorer neuropsychologic performance. Neither allele influenced psychiatric symptoms. Patients with DiGeorge syndrome (188400) are hemizygous for the COMT gene. In a study of 21 nonpsychotic DiGeorge syndrome patients aged 7 to 16 years, Shashi et al. (2006) found that those carrying the met158 allele performed better on tests of general cognitive ability and on a specific test of prefrontal cognition compared to those with the val158 allele. Glaser et al. (2006) tested measures of executive function, IQ, and memory in 34 children and young adults with the 22q11.2 microdeletion (14 hemizygous for val158 and 30 for met158). No significant differences were detected between met- and val-hemizygous participants on measures of executive function. The groups did not differ on full-scale, performance, and verbal IQ or on verbal and visual memory. Glaser et al. (2006) suggested that either the COMT polymorphism has a small effect on executive function in 22q11.2 deletion syndrome or no effect exists at all. Stolk et al. (2007) determined the genotype of the val158-to-met polymorphism in 2,515 men and 3,554 women from the Rotterdam Study, a population-based cohort study of individuals aged 55 and older. Male carriers of the met158 allele had an increased risk for osteoporotic fractures (hazard ratio = 1.6; 95% CI, 1.0-2.4) and for fragility fractures (hazard ratio = 2.7; 95% CI, 1.3-5.9), with evidence for a dominant effect. Adjustments for age, height, weight, and bone mineral density (BMD) did not change the risk estimates. Stolk et al. (2007) concluded that the COMT V158M polymorphism is associated with fracture risk in elderly men, through a mechanism independent of BMD. Zalsman et al. (2005) studied the relationship of MAOA promoter (uVNTR; 309850.0002) and COMT missense (V158M) polymorphisms to CSF monoamine metabolite levels in a psychiatric sample of 98 Caucasians who were assessed for axis I and II diagnoses. CSF was obtained by lumbar puncture and the relationships of the 2 polymorphisms to monoamine metabolites (HVA, 5-HIAA, and MHPG) were examined. The higher-expressing MAOA-uVNTR genotype was associated with higher CSF-HVA levels in males (N = 46) (195.80 pmol/ml, SD = 61.64 vs 161.13, SD = 50.23, respectively; p = 0.042). No association was found with the diagnosis. The COMT V158M polymorphism was not associated with CSF monoamine metabolite levels. L-DOPA, used to treat Parkinson disease (PD; 168600) is predominantly metabolized to the inactive 3-O-methyldopa by COMT. Entacapone is a COMT inhibitor that acts to prolong the half-life of L-DOPA and yields prolonged therapeutic benefits. The val158-to-met (V158M) polymorphism in the COMT gene confers increased (val) or decreased (met) COMT activity. In a randomized control trial of 33 PD patients, Corvol et al. (2011) found that those homozygous for the high-activity val158 allele had significantly increased COMT inhibition by entacapone and significantly better bioavailability of and clinical response to L-DOPA compared to patients homozygous for the low-activity met158 allele. The findings indicated that homozygosity for the val158 allele in PD patients enhances the effect of entacapone on the pharmacodynamics and pharmacokinetics of levodopa. The response to entacapone in heterozygous patients was not studied. (less)
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drug response
(Apr 28, 2018)
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no assertion criteria provided
Method: research
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Tramadol response
Affected status: yes
Allele origin:
somatic
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Bruce Budowle Laboratory, University of North Texas Health Science Center
Accession: SCV001191666.1
First in ClinVar: Mar 29, 2020 Last updated: Mar 29, 2020 |
Number of individuals with the variant: 202
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001743194.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Benign
(-)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001955267.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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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The COMT Val158Met polymorphism affects the response to entacapone in Parkinson's disease: a randomized crossover clinical trial. | Corvol JC | Annals of neurology | 2011 | PMID: 21280081 |
The catechol-O-methyltransferase Met158 low-activity allele and association with nonvertebral fracture risk in elderly men. | Stolk L | The Journal of clinical endocrinology and metabolism | 2007 | PMID: 17504906 |
Cognitive correlates of a functional COMT polymorphism in children with 22q11.2 deletion syndrome. | Shashi V | Clinical genetics | 2006 | PMID: 16542388 |
No evidence for an effect of COMT Val158Met genotype on executive function in patients with 22q11 deletion syndrome. | Glaser B | The American journal of psychiatry | 2006 | PMID: 16513880 |
Lack of association of catechol-O-methyltransferase gene Val108/158Met polymorphism with schizophrenia: a family-based association study in a Chinese population. | Tsai SJ | Molecular psychiatry | 2006 | PMID: 16130008 |
Catechol O-methyltransferase gene variant and birth weight predict early-onset antisocial behavior in children with attention-deficit/hyperactivity disorder. | Thapar A | Archives of general psychiatry | 2005 | PMID: 16275815 |
No association between schizophrenia and polymorphisms in COMT in two large samples. | Williams HJ | The American journal of psychiatry | 2005 | PMID: 16135635 |
Catechol-O-methyltransferase (COMT) genotypes and working memory: associations with differing cognitive operations. | Bruder GE | Biological psychiatry | 2005 | PMID: 16043133 |
COMT Val108/158 Met modifies mismatch negativity and cognitive function in 22q11 deletion syndrome. | Baker K | Biological psychiatry | 2005 | PMID: 15935994 |
Lack of association of the COMT (Val158/108 Met) gene and schizophrenia: a meta-analysis of case-control studies. | Munafò MR | Molecular psychiatry | 2005 | PMID: 15824744 |
Midbrain dopamine and prefrontal function in humans: interaction and modulation by COMT genotype. | Meyer-Lindenberg A | Nature neuroscience | 2005 | PMID: 15821730 |
Catechol-O-methyltransferase gene Val/Met functional polymorphism and risk of schizophrenia: a large-scale association study plus meta-analysis. | Fan JB | Biological psychiatry | 2005 | PMID: 15652872 |
Association of Ala72Ser polymorphism with COMT enzyme activity and the risk of schizophrenia in Koreans. | Lee SG | Human genetics | 2005 | PMID: 15645182 |
Relationship of MAO-A promoter (u-VNTR) and COMT (V158M) gene polymorphisms to CSF monoamine metabolites levels in a psychiatric sample of caucasians: A preliminary report. | Zalsman G | American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics | 2005 | PMID: 15457497 |
Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. | Chen J | American journal of human genetics | 2004 | PMID: 15457404 |
New evidence of association between COMT gene and prefrontal neurocognitive function in healthy individuals from sibling pairs discordant for psychosis. | Rosa A | The American journal of psychiatry | 2004 | PMID: 15169701 |
Human catechol O-methyltransferase genetic variation: gene resequencing and functional characterization of variant allozymes. | Shield AJ | Molecular psychiatry | 2004 | PMID: 14966473 |
A functional single nucleotide polymorphism (V158M) in the COMT gene is associated with aggressive personality traits. | Rujescu D | Biological psychiatry | 2003 | PMID: 12842306 |
Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. | Mattay VS | Proceedings of the National Academy of Sciences of the United States of America | 2003 | PMID: 12716966 |
Association between a functional catechol O-methyltransferase gene polymorphism and schizophrenia: meta-analysis of case-control and family-based studies. | Glatt SJ | The American journal of psychiatry | 2003 | PMID: 12611827 |
COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor. | Zubieta JK | Science (New York, N.Y.) | 2003 | PMID: 12595695 |
Population variation in linkage disequilibrium across the COMT gene considering promoter region and coding region variation. | DeMille MM | Human genetics | 2002 | PMID: 12436243 |
A highly significant association between a COMT haplotype and schizophrenia. | Shifman S | American journal of human genetics | 2002 | PMID: 12402217 |
Catechol O-methyltransferase genetic polymorphism in panic disorder. | Woo JM | The American journal of psychiatry | 2002 | PMID: 12359690 |
Higher scores of self reported schizotypy in healthy young males carrying the COMT high activity allele. | Avramopoulos D | Molecular psychiatry | 2002 | PMID: 12192614 |
A functional polymorphism in the COMT gene and performance on a test of prefrontal cognition. | Malhotra AK | The American journal of psychiatry | 2002 | PMID: 11925305 |
Catechol o-methyltransferase, serotonin transporter, and tryptophan hydroxylase gene polymorphisms in bipolar disorder patients with and without comorbid panic disorder. | Rotondo A | The American journal of psychiatry | 2002 | PMID: 11772685 |
Catecholamines in patients with 22q11.2 deletion syndrome and the low-activity COMT polymorphism. | Graf WD | Neurology | 2001 | PMID: 11502905 |
Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. | Egan MF | Proceedings of the National Academy of Sciences of the United States of America | 2001 | PMID: 11381111 |
The COMT L allele modifies the association between MAOB polymorphism and PD in Taiwanese. | Wu RM | Neurology | 2001 | PMID: 11171904 |
Global variation in the frequencies of functionally different catechol-O-methyltransferase alleles. | Palmatier MA | Biological psychiatry | 1999 | PMID: 10459407 |
Association between the functional variant of the catechol-O-methyltransferase (COMT) gene and type 1 alcoholism. | Tiihonen J | Molecular psychiatry | 1999 | PMID: 10395222 |
Genetic polymorphism of catechol-O-methyltransferase (COMT): correlation of genotype with individual variation of S-COMT activity and comparison of the allele frequencies in the normal population and parkinsonian patients in Finland. | Syvänen AC | Pharmacogenetics | 1997 | PMID: 9110364 |
No association between Parkinson's disease and low-activity alleles of catechol O-methyltransferase. | Hoda F | Biochemical and biophysical research communications | 1996 | PMID: 8941353 |
Association of codon 108/158 catechol-O-methyltransferase gene polymorphism with the psychiatric manifestations of velo-cardio-facial syndrome. | Lachman HM | American journal of medical genetics | 1996 | PMID: 8886163 |
Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. | Lachman HM | Pharmacogenetics | 1996 | PMID: 8807664 |
The psychobiological regulation of social cooperation. | Cloninger CR | Nature medicine | 1995 | PMID: 7585135 |
Genetics of red cell COMT activity: analysis of thermal stability and family data. | Spielman RS | American journal of medical genetics | 1981 | PMID: 7304673 |
Weinshilboum, R. M. Catecholamine biochemical genetics in human populations. In: Breakefield, X. O. Neurogenetics: Genetic Approaches to the Nervous System. New York: Elsevier/North Holland (pub.) 257-282, 1979. | - | - | - | - |
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Text-mined citations for rs4680 ...
HelpRecord last updated Jul 29, 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.