ClinVar Genomic variation as it relates to human health
NM_000025.3(ADRB3):c.190T>C (p.Trp64Arg)
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_000025.3(ADRB3):c.190T>C (p.Trp64Arg)
Variation ID: 17741 Accession: VCV000017741.2
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 8p11.23 8: 37966280 (GRCh38) [ NCBI UCSC ] 8: 37823798 (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 Apr 4, 2013 Sep 26, 2021 Jun 9, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000025.3:c.190T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000016.1:p.Trp64Arg missense NC_000008.11:g.37966280A>G NC_000008.10:g.37823798A>G NG_011936.1:g.5387T>C P13945:p.Trp64Arg - Protein change
- W64R
- Other names
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- Canonical SPDI
- NC_000008.11:37966279:A:G
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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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0.11502 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.09116
Trans-Omics for Precision Medicine (TOPMed) 0.09917
Exome Aggregation Consortium (ExAC) 0.10568
The Genome Aggregation Database (gnomAD), exomes 0.10617
1000 Genomes Project 30x 0.11165
1000 Genomes Project 0.11502
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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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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ADRB3 | - | - |
GRCh38 GRCh37 |
25 | 88 |
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
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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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Oct 1, 2004 | RCV000033197.2 | |
Benign (1) |
criteria provided, single submitter
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Jun 9, 2021 | RCV001707510.1 |
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
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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
(Jun 09, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001935767.1
First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
Comment:
This variant is associated with the following publications: (PMID: 9080262, 29670643, 22774474, 11380082, 21529759, 23729572, 21289629, 21358132, 20008926, 20069060, 11564599, 17225053, 19553224, 22550477, 19133996, 21285172, … (more)
This variant is associated with the following publications: (PMID: 9080262, 29670643, 22774474, 11380082, 21529759, 23729572, 21289629, 21358132, 20008926, 20069060, 11564599, 17225053, 19553224, 22550477, 19133996, 21285172, 21034552, 19080138, 7487991, 28456594, 23968135, 20078877, 23032405) (less)
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risk factor
(Oct 01, 2004)
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no assertion criteria provided
Method: literature only
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OBESITY, SUSCEPTIBILITY TO
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000057043.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
Using a candidate gene approach to study the genetics of obesity (601665), Clement et al. (1995) found evidence suggesting that the trp64-to-arg (W64R) variant of … (more)
Using a candidate gene approach to study the genetics of obesity (601665), Clement et al. (1995) found evidence suggesting that the trp64-to-arg (W64R) variant of the ADRB3 gene increases the capacity to gain weight. Gagnon et al. (1996) failed to find an association between W64R and obesity in studies in 2 cohorts: the Quebec Family Study (QFS) and the Swedish Obese Subjects (SOS). Walston et al. (1995) found that Pima Indians homozygous for the W64R ADRB3 mutation had an earlier onset of noninsulin-dependent diabetes mellitus (NIDDM; 125853) and tended to have a lower resting metabolic rate. The authors suggested that the mutation may accelerate the onset of NIDDM by altering the balance of energy metabolism in visceral adipose tissue. Elbein et al. (1996) tested the hypothesis that the beta-3-adrenergic receptor locus affects diabetes susceptibility, obesity as measured by body mass index (BMI), and components of the insulin (176730) resistance syndrome, by examining ADRB3 allele sharing in families ascertained for 2 or more sibs with NIDDM. They found no evidence for linkage to NIDDM as a dichotomous trait and no evidence for linkage to BMI, waist/hip ratio, insulin levels, or glucose levels as quantitative traits or to reported age of onset among NIDDM individuals. The W64R mutation present in 11% of the population also did not show linkage or association. They concluded that the beta-3-adrenergic receptor locus does not play an important role in NIDDM susceptibility or in the insulin resistance syndrome among members of families with a strong predisposition to NIDDM. Kim-Motoyama et al. (1997) examined the frequency of the W64R variant in 278 Japanese men in relation to visceral obesity assessed by computerized tomography. They found that the mutation was more frequent in subjects with higher BMI. In subjects with a moderate degree of obesity, the mutation (homozygotes and heterozygotes) was associated with visceral obesity (higher ratio of visceral to subcutaneous fat area). Furthermore, the W64R variant was more frequent in subjects with lower serum triglyceride levels, and homozygotes, but not heterozygotes, exhibited lower triglyceride levels. Kim-Motoyama et al. (1997) suggested that the mutation may describe a subset of subjects characterized by decreased lipolysis in visceral adipose tissue. To examine the effect of W64R on body weight during adult life, the ADRB3 genotypes of 186 unselected Japanese men, most of whom had records of body weight measured yearly from 25 to 53 years of age, were determined by Nagase et al. (1997). Of these subjects, 26 were diagnosed as having noninsulin-dependent diabetes mellitus (NIDDM) and 41 as having impaired glucose tolerance. The results suggested that ADRB3 is not a major contributing factor to obesity or NIDDM in Japanese men. Buettner et al. (1998) examined the prevalence of the 2 ADRB3 alleles in Germany and looked for associations between the ADRB3 genotype and obesity and NIDDM. The frequencies of the different genotypes in the examined cohort were as follows: trp64/trp64, 88.3%; trp64/arg64, 10.8%; and arg64/arg64, 0.8%. The authors found no significant differences between the different genotypes when comparing age, BMI, weight, total and high density lipoprotein, cholesterol, fasting insulin, HbA1c, and blood pressure. They concluded that the NIDDM phenotype did not differ significantly between the different genotype groups in terms of age of diabetes onset or HbA1c. Using hyperinsulinemic/euglycemic clamp methodology, Garcia-Rubi et al. (1998) measured insulin sensitivity in 13 obese women heterozygous for the W64R ADRB3 variant and in 14 women homozygous for the normal gene. Exogenous glucose infusion during the clamp was significantly lower (P = 0.03) in W64R heterozygotes (241 +/- 135 mg/min) compared with normal homozygotes (379 +/- 172 mg/min). They concluded that obese postmenopausal women who are heterozygous for the W64R variant have greater insulin resistance than women homozygous for the normal gene matched for age, body composition, and physical activity. Mitchell et al. (1998) detected an effect of the W64R variant on obesity in a Mexican-American population. They had previously identified a major quantitative trait locus (QTL) influencing the serum concentrations of leptin on 2p in a Mexican-American population in south Texas (Comuzzie et al., 1997). They studied 45 sib pairs who were concordant (identical by descent) for this locus on chromosome 2, which had been shown previously to be tightly linked to obesity in this population. The W64R variant, detected by PCR-RFLP analysis, was present in 1 sib within each of the 45 sib pairs. Presence of the variant was associated with a significantly higher values in body mass index, fat mass, and waist circumference. The paired-sib design enhanced their ability to detect the effects of this variant by allowing them to account for variation attributable to another obesity susceptibility locus and to background genes. Since ADRB3 plays a significant role in the control of lipolysis and thermogenesis in brown adipose tissue through autonomic nervous system (ANS) activity, Shihara et al. (1999) investigated the association of the W64R polymorphism with ANS activity. Subjects with the polymorphism did not differ from subjects without it in BMI, plasma glucose, plasma insulin, or family history of diabetes or obesity. The total power of heterozygotes at supine rest was lower than that of normal subjects (1,124.6 +/- 191.6 vs 3,029.8 +/- 758.8 ms2; mean +/- SE). With a postural change to standing, the parasympathetic and sympathetic nervous system activity indexes of heterozygotes showed a higher response than those of normal subjects (parasympathetic nervous system index, 0.10 +/- 0.02 vs 0.17 +/- 0.02; sympathetic nervous system index, 10.55 +/- 1.47 vs 6.26 +/- 1.09) and the difference in total power disappeared. The authors concluded that subjects with the polymorphism, even heterozygotes, had lower resting ANS activity than did normal subjects. Hoffstedt et al. (1999) studied 208 healthy Swedish subjects. Twenty-two percent of those with a high BMI (defined as greater than 31 kg/m(2)) carried the W64R ADRB3 variant, compared with 11% of those who had a lower BMI. Furthermore, BMI was approximately 2 kg/m(2) higher in arg carriers compared with subjects who were trp homozygous in the lower BMI group. No association of the W64R haplotype with metabolic parameters or blood pressure was identified. When comparing sensitivity for CPG12177, a selective beta-3-receptor agonist, Hoffstedt et al. (1999) observed a 10-fold decrease in beta-3-arg compared with beta-3-trp subjects. Festa et al. (1999) studied the relationship between ADRB3 genotype and glucose tolerance during pregnancy, a state of physiologic insulin resistance. The frequency of the W64R allele was 9.15% in 179 pregnant women. In 70 women with mild gestational diabetes, as defined by 60-minute postload glucose values, the W64R genotype was more frequent than in 109 women with normal glucose tolerance (26% vs 11%; P of 0.01). Furthermore, the W64R genotype was associated with increased weight gain during pregnancy (baseline to gestational weeks 20 to 31) and increased postload glucose, insulin, and C peptide values during the oral glucose tolerance test. This apparent association with mild gestational diabetes suggested to the authors that the impact of the polymorphism may be clinically important during pregnancy. The study of Urhammer et al. (2000) failed to demonstrate an additive or synergistic effect of the W64R variant of the ADRB3 gene and the -3826 A-G variant of the UCP1 gene (113730.0001) on the development of obesity and insulin resistance among randomly recruited Danish Caucasian subjects. Walston et al. (2000) found that arg64/arg64 homozygotes secrete significantly less insulin in response to a glucose infusion, have higher fasting glucose levels, and have lower glucose effectiveness compared with trp64/trp64 homozygotes. They concluded that their data may help explain the earlier onset of type 2 diabetes mellitus (NIDDM) observed in several populations of individuals with the arg64 ADRB3 variant allele. Wang et al. (2004) evaluated whether the W64R polymorphism in the ADRB3 gene is associated with decreased birth weight and might account for some of the association between birth weight and impaired insulin sensitivity. Frequency of the W64R allele was similar in groups of neonates classified as appropriate for gestational age (AGA) and small for gestational age (SGA) (0.15 and 0.17, respectively). Moreover, after adjustment for sex and gestational age, there was no significant difference in birth weight, fasting glucose, insulin levels, or insulin-to-glucose ratio between those with and without the mutation. However, in the SGA group, carriers of the W64R allele had significantly higher fasting insulin levels and insulin-to-glucose ratios than noncarriers, whereas no association was detected for this polymorphism in the AGA group. (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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Effects of the Trp64Arg polymorphism in the beta3-adrenergic receptor gene on insulin sensitivity in small for gestational age neonates. | Wang X | The Journal of clinical endocrinology and metabolism | 2004 | PMID: 15472194 |
Insulin response to glucose is lower in individuals homozygous for the Arg 64 variant of the beta-3-adrenergic receptor. | Walston J | The Journal of clinical endocrinology and metabolism | 2000 | PMID: 11095426 |
Studies of the synergistic effect of the Trp/Arg64 polymorphism of the beta3-adrenergic receptor gene and the -3826 A-->G variant of the uncoupling protein-1 gene on features of obesity and insulin resistance in a population-based sample of 379 young Danish subjects. | Urhammer SA | The Journal of clinical endocrinology and metabolism | 2000 | PMID: 10999801 |
Trp64Arg polymorphism of the beta3-adrenergic receptor gene in pregnancy: association with mild gestational diabetes mellitus. | Festa A | The Journal of clinical endocrinology and metabolism | 1999 | PMID: 10323402 |
The association between Trp64Arg polymorphism of the beta3-adrenergic receptor and autonomic nervous system activity. | Shihara N | The Journal of clinical endocrinology and metabolism | 1999 | PMID: 10323390 |
Polymorphism of the human beta3-adrenoceptor gene forms a well-conserved haplotype that is associated with moderate obesity and altered receptor function. | Hoffstedt J | Diabetes | 1999 | PMID: 9892244 |
Trp64Arg variant of the beta3-adrenoceptor and insulin resistance in obese postmenopausal women. | García-Rubi E | The Journal of clinical endocrinology and metabolism | 1998 | PMID: 9814483 |
The Trp64Arg polymorphism of the beta 3-adrenergic receptor gene is not associated with obesity or type 2 diabetes mellitus in a large population-based Caucasian cohort. | Büettner R | The Journal of clinical endocrinology and metabolism | 1998 | PMID: 9709965 |
A paired sibling analysis of the beta-3 adrenergic receptor and obesity in Mexican Americans. | Mitchell BD | The Journal of clinical investigation | 1998 | PMID: 9449691 |
A mutation of the beta 3-adrenergic receptor is associated with visceral obesity but decreased serum triglyceride. | Kim-Motoyama H | Diabetologia | 1997 | PMID: 9112025 |
Lack of association between the Trp64 Arg mutation in the beta 3-adrenergic receptor gene and obesity in Japanese men: a longitudinal analysis. | Nagase T | The Journal of clinical endocrinology and metabolism | 1997 | PMID: 9100608 |
A major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2. | Comuzzie AG | Nature genetics | 1997 | PMID: 9054940 |
Role of the beta 3-adrenergic receptor locus in obesity and noninsulin-dependent diabetes among members of Caucasian families with a diabetic sibling pair. | Elbein SC | The Journal of clinical endocrinology and metabolism | 1996 | PMID: 8954053 |
The Trp64Arg mutation of the beta3 adrenergic receptor gene has no effect on obesity phenotypes in the Québec Family Study and Swedish Obese Subjects cohorts. | Gagnon J | The Journal of clinical investigation | 1996 | PMID: 8903328 |
Genetic variation in the beta 3-adrenergic receptor and an increased capacity to gain weight in patients with morbid obesity. | Clément K | The New England journal of medicine | 1995 | PMID: 7609752 |
Time of onset of non-insulin-dependent diabetes mellitus and genetic variation in the beta 3-adrenergic-receptor gene. | Walston J | The New England journal of medicine | 1995 | PMID: 7609750 |
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Text-mined citations for rs4994 ...
HelpRecord last updated Dec 25, 2023
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.