ClinVar Genomic variation as it relates to human health
NM_001367943.1(TCF7L2):c.450+33966C>T
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_001367943.1(TCF7L2):c.450+33966C>T
Variation ID: 7413 Accession: VCV000007413.6
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q25.2 10: 112998590 (GRCh38) [ NCBI UCSC ] 10: 114758349 (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 Dec 4, 2021 Dec 4, 2021 Sep 1, 2011 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001367943.1:c.450+33966C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001146274.2:c.450+33966C>T intron variant NM_001146283.2:c.382-41435C>T intron variant NM_001146284.2:c.382-41435C>T intron variant NM_001146285.2:c.382-41435C>T intron variant NM_001146286.2:c.382-41435C>T intron variant NM_001198525.2:c.382-41435C>T intron variant NM_001198526.2:c.382-41435C>T intron variant NM_001198527.2:c.382-41435C>T intron variant NM_001198528.2:c.382-41435C>T intron variant NM_001198529.2:c.382-41435C>T intron variant NM_001198530.2:c.381+46983C>T intron variant NM_001198531.2:c.450+33966C>T intron variant NM_001363501.2:c.450+33966C>T intron variant NM_030756.5:c.382-41435C>T intron variant NC_000010.11:g.112998590C>T NC_000010.10:g.114758349C>T NG_012631.1:g.53341C>T NG_054085.1:g.746C>T - Protein change
- Other names
- IVS3, C-T (rs7903146)
- Canonical SPDI
- NC_000010.11:112998589: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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0.22784 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.22784
1000 Genomes Project 30x 0.23111
The Genome Aggregation Database (gnomAD) 0.27534
Trans-Omics for Precision Medicine (TOPMed) 0.27654
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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TCF7L2 | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
134 | 166 | |
LOC110121472 | - | - | - | GRCh38 | - | 12 |
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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risk factor (1) |
no assertion criteria provided
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Sep 1, 2011 | RCV000007838.14 |
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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risk factor
(Sep 01, 2011)
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no assertion criteria provided
Method: literature only
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TYPE 2 DIABETES MELLITUS, SUSCEPTIBILITY TO
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000028043.5
First in ClinVar: Apr 04, 2013 Last updated: Dec 04, 2021 |
Comment on evidence:
In an Icelandic population, Grant et al. (2006) found strong linkage disequilibrium between a SNP in the TCF7L2 gene, rs7903146, and a microsatellite marker in … (more)
In an Icelandic population, Grant et al. (2006) found strong linkage disequilibrium between a SNP in the TCF7L2 gene, rs7903146, and a microsatellite marker in intron 3, DG10S478, associated with type 2 diabetes (T2D; 125853) (p = 2.1 x 10(-9)). Helgason et al. (2007) refined the definition of the TCF7L2 type 2 diabetes risk variant, HapB(T2D), to the ancestral T allele of the SNP rs7903146 through replication in West African and Danish type 2 diabetes case-control studies and an expanded Icelandic study. They also identified another variant of the same gene, HapA, that shows evidence of positive selection in East Asian, European, and West African populations. Notably, HapA shows a suggestive association with body mass index (BMI) and altered concentrations of the hunger-satiety hormones ghrelin (GHRL; 605353) and leptin (LEP; 164160) in males, indicating that the selective advantage of HapA may have been mediated through effects on energy metabolism. Type 2 diabetes genes may influence birthweight through maternal genotype, by increasing maternal glycemia in pregnancy, or through fetal genotype, by altering fetal insulin secretion. Freathy et al. (2007) assessed the role of the TCF7L2 gene in birthweight. They genotyped the polymorphism rs7903146 in 15,709 individuals whose birthweight was available from 6 studies and in 8,344 mothers from 3 studies. Each fetal copy of the predisposing allele was associated with an 18-gram increase in birthweight (p = 0.001) and each maternal copy with a 30-gram increase in offspring birthweight (p = 2.8 x 10(-5)).. Stratification by fetal genotype suggested that the association was driven by maternal genotype. Analysis of diabetes-related traits in 10,314 nondiabetic individuals suggested that the most likely mechanism is that the risk allele reduces maternal insulin secretion, which results in increased maternal glycemia in pregnancy and hence increased offspring birthweight. Freathy et al. (2007) combined information from the other common variant known to alter fetal growth, the -30G-A polymorphism of glucokinase (138079). The 4% of offspring born to mothers carrying 3 or 4 risk alleles were 119 grams heavier than were the 32% born to mothers with none, comparable to the impact of maternal smoking during pregnancy. Freathy et al. (2007) concluded that this was the first type 2 diabetes susceptibility allele to be reproducibly associated with birthweight. Thus, common gene variants can substantially influence normal birthweight variation. In a study of 286 Mexican patients with type 2 diabetes mellitus and 275 controls, Parra et al. (2007) did not find a significant association between rs7903146 and the disease. In genomewide association studies of type 2 diabetes, The Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes for BioMedical Research (2007), Zeggini et al. (2007), and Scott et al. (2007) confirmed association of the SNP rs7903146 with diabetes susceptibility. Scott et al. (2007) obtained an OR of 1.37, p = 1.0 x 10(-48) for rs7903146 in a metaanalysis of data from international consortia. In a genomewide association study for type 2 diabetes in 1,399 Icelandic cases and 5,275 controls, Steinthorsdottir et al. (2007) found that rs7903146 conferred the most significant risk, with an OR of 1.38 and p = 1.82 x 10(-10) in all individuals with type 2 diabetes. Mayans et al. (2007) genotyped 4 SNPs in the TCF7L2 gene in 872 Swedish patients with type 2 diabetes and 857 age-, sex-, and geographically-matched controls and replicated the previously identified association between rs7093146 and disease (p = 0.00002). In 2 cohorts of Scandinavian subjects followed for 22 years, Lyssenko et al. (2007) found that the CT/TT genotypes of rs7903146 strongly predicted future type 2 diabetes. Extensive metabolic studies in a subset of Swedish and Finnish individuals from the cohort showed that the risk T allele was associated with impaired insulin secretion, incretin effects, and an enhanced rate of hepatic glucose production. TCF7L2 expression in human islets was increased 5-fold in type 2 diabetes, particularly in carriers of the TT genotype; overexpression of TCF7L2 in human islets reduced glucose-stimulated insulin secretion. Ng et al. (2007) examined 22 SNPs spanning the TCF7L2 gene in 433 Hong Kong Chinese hospitalized with early-onset type 2 diabetes and 419 controls and did not find a significant association with rs7903146. Miyake et al. (2008) analyzed 5 SNPs in the TCF7L2 gene in 2,214 Japanese individuals with type 2 diabetes and 1,873 controls and confirmed significant association with the minor allele of rs7903146 (OR, 1.48; p = 2.7 x 10(-4)). The association remained significant after adjustment for age, sex, and BMI (adjusted p = 0.0011). To identify regulatory DNA active in human pancreatic islets, Gaulton et al. (2010) profiled chromatin by formaldehyde-assisted isolation of regulatory elements coupled with high-throughput sequencing (FAIRE-seq). By mapping sequence variants to open chromatin sites, they found that rs7903146 is located in islet-selective open chromatin. In addition, human islet samples heterozygous for rs7903146 showed allelic imbalance in islet FAIRE signals, with the chromatin state more open in chromosomes carrying the risk 'T' allele. Using allele-specific luciferase reporter constructs in islet beta-cell lines, Gaulton et al. (2010) demonstrated that the rs7903146 variant alters enhancer activity, indicating that genetic variation at this locus acts in cis with local chromatin and regulatory changes. Prokunina-Olsson et al. (2009) stated that rs7903146 in intron 3 and rs12255372 (602228.0002) in intron 4 are 50 kb apart and within a 92-kb block of linkage disequilibrium. Savic et al. (2011) found that the 92-kb region containing rs7903146 had strong enhancer activity when expressed in transgenic mice. (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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Alterations in TCF7L2 expression define its role as a key regulator of glucose metabolism. | Savic D | Genome research | 2011 | PMID: 21673050 |
A map of open chromatin in human pancreatic islets. | Gaulton KJ | Nature genetics | 2010 | PMID: 20118932 |
Tissue-specific alternative splicing of TCF7L2. | Prokunina-Olsson L | Human molecular genetics | 2009 | PMID: 19602480 |
Association of TCF7L2 polymorphisms with susceptibility to type 2 diabetes in 4,087 Japanese subjects. | Miyake K | Journal of human genetics | 2008 | PMID: 18097733 |
Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. | Lyssenko V | The Journal of clinical investigation | 2007 | PMID: 17671651 |
Replication and identification of novel variants at TCF7L2 associated with type 2 diabetes in Hong Kong Chinese. | Ng MC | The Journal of clinical endocrinology and metabolism | 2007 | PMID: 17609304 |
Type 2 diabetes TCF7L2 risk genotypes alter birth weight: a study of 24,053 individuals. | Freathy RM | American journal of human genetics | 2007 | PMID: 17503332 |
Association of TCF7L2 polymorphisms with type 2 diabetes in Mexico City. | Parra EJ | Clinical genetics | 2007 | PMID: 17470138 |
Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. | Zeggini E | Science (New York, N.Y.) | 2007 | PMID: 17463249 |
A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. | Scott LJ | Science (New York, N.Y.) | 2007 | PMID: 17463248 |
Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. | Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes of BioMedical Research | Science (New York, N.Y.) | 2007 | PMID: 17463246 |
A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. | Steinthorsdottir V | Nature genetics | 2007 | PMID: 17460697 |
TCF7L2 polymorphisms are associated with type 2 diabetes in northern Sweden. | Mayans S | European journal of human genetics : EJHG | 2007 | PMID: 17245407 |
Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution. | Helgason A | Nature genetics | 2007 | PMID: 17206141 |
Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. | Grant SF | Nature genetics | 2006 | PMID: 16415884 |
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Text-mined citations for rs7903146 ...
HelpRecord last updated Jun 10, 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.