TCF7L2

protein-coding

transcription factor 7 like 2, the group of TCF/LEF transcription factor family|Wnt enhanceosome complex

Gene summary

This gene encodes a high mobility group (HMG) box-containing transcription factor that plays a key role in the Wnt signaling pathway. The protein has been implicated in blood glucose homeostasis. Genetic variants of this gene are associated with increased risk of type 2 diabetes. Several transcript variants encoding multiple different isoforms have been found for this gene.[provided by RefSeq, Oct 2010]

Previous symbols:

TCF4

MANE transcript

NM_001367943.1

Inheritance

ClinVar variants

P:20U:113B:46

Top phenotype

neurodevelopmental disorder

gnomAD constraint

pLI —, LoF o/e 0.12

Max pathogenic AF

—

Genomic locus

chr10:112,950,247-113,167,678

External References & Databases

Ensembl (ENSG00000148737)

Transcript & Mutation Effects

hg38 • Region Span ~217.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital glaucomaLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0020366

Submitter: Ambry Genetics

neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: G2P

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*TCF7L2* encodes a transcription factor involved in the Wnt/β-catenin signaling pathway. Although de novo variants in *TCF7L2* had been observed in large-scale sequencing studies in autism spectrum disorder and intellectual disability between 2014 and 2020 (PMIDs: 25363768, 27479843, 28135719, 33057194 ), the first report focusing on *TCF7L2* variants as a cause of autosomal dominant complex neurodevelopmental disorder and describing the clinical and genotypic spectrum was published in 2021 (Dias et al., PMID: 34003604). Numerous variants in *TCF7L2*, including nonsense, frameshift, splicing site and missense variants, have been reported, with most variants occurring de novo. Missense variants cluster in the DNA binding high mobility group (HMG) box domain, a region highly constrained for missense variants. Affected individuals presented with developmental delays in childhood; some ultimately achieved normal intelligence while others had mild to moderate intellectual disability (PMID: 34003604). Other variable features included myopia in half of the individuals, dysmorphic craniofacial features, orthopedic abnormalities, and behavioral disorders including autism and attention-deficit/hyperactivity disorder. Variants in the *TCF7L2* gene have been reported in at least 22 probands in 5 publications (PMIDs: 25363768, 25533962, 27479843, 33004838, 34003604), including 10 truncating variants (frameshift, stop gain, splice site), and 4 missense variants in the HMG domain. No clear phenotypic differences were observed between individuals with missense and truncating variants, suggesting the disease mechanism is haploinsufficiency (PMID: 34003604). This gene-disease association is also supported by mouse models indicating a role for Tcfl2 in neurogenesis, neuron identity and connectivity (PMID: 29751817). In summary, *TCF7L2* is definitively associated with autosomal dominant complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 12/15/2021 (SOP Version 8).

intellectual disabilityMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0001071

Submitter: Ambry Genetics

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TCF7L2 variants in ClinVar

15 Conditions Cataloged

not providedTotal: 90

Inborn genetic diseasesTotal: 78

TCF7L2-related disorderTotal: 15

not specifiedTotal: 12

Type 2 diabetes mellitusTotal: 5

Complex neurodevelopmental disorderTotal: 2

TCF7L2-related neurodevelopmental disorderTotal: 2

Neurodevelopmental abnormalityTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001367943.1. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	32 clinvar	2 clinvar	35
missense	1 clinvar	4 clinvar	102 clinvar	9 clinvar	3 clinvar	119
nonsense	2 clinvar	2 clinvar	2 clinvar			6
start loss						0
frameshift	3 clinvar	4 clinvar	4 clinvar			11
splice donor/acceptor (+/-2bp)	1 clinvar	3 clinvar	4 clinvar			8
Total	7	13	113	41	5	179

Highest pathogenic variant AF is 0.0000012628591

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 128 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001367943.1	RefSeq	NP_001354872.1	15	MANE Select
ENST00000355995.9	Ensembl	ENSP00000348274.4	15	MANE Select
NM_001146274.2	RefSeq	NP_001139746.1	14	Standard
NM_001146283.2	RefSeq	NP_001139755.1	13	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
tcf7l2	Danio rerio	Structure: pancreatic B cell Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

tcf7l2

Danio rerio

Structure: pancreatic B cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Gastric cancer - Homo sapiens (human)
Adherens junction - Homo sapiens (human)
Cushing,s syndrome - Homo sapiens (human)
Arrhythmogenic right ventricular cardiomyopathy (ARVC) - Homo sapiens (human)
Acute myeloid leukemia - Homo sapiens (human)

Biological Process

negative regulation of transcription by RNA polymerase II
blood vessel development
regulation of transcription, DNA-templated
regulation of transcription by RNA polymerase II
cell cycle arrest

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
RNA polymerase II repressing transcription factor binding
chromatin binding
DNA-binding transcription factor activity

Cellular Component

nuclear chromatin
nucleus
nucleoplasm
transcription factor complex
PML body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000543371
Coding exons: 14
Length: 217429
Individuals with no LoFs: 125725
Homozygous LoFs: 0
Heterozygous LoFs: 23
Defined: 125748
p: 0.0000915

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.40	227	354	0.641	0.0000209	3834
Missense (PolyPhen)		97	220.13	0.44065		2350
Synonymous	-2.11	203	168	1.21	0.0000119	1223
Loss of Function	4.73	4	33.5	0.119	0.00000179	368

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000088	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00012	0.00011	rare
South Asian	0.000066	0.000065	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Participates in the Wnt signaling pathway and modulates MYC expression by binding to its promoter in a sequence-specific manner. Acts as repressor in the absence of CTNNB1, and as activator in its presence. Activates transcription from promoters with several copies of the Tcf motif 5'-CCTTTGATC-3' in the presence of CTNNB1. TLE1, TLE2, TLE3 and TLE4 repress transactivation mediated by TCF7L2/TCF4 and CTNNB1. Expression of dominant-negative mutants results in cell-cycle arrest in G1. Necessary for the maintenance of the epithelial stem-cell compartment of the small intestine. {ECO:0000269|PubMed:12408868, ECO:0000269|PubMed:12727872, ECO:0000269|PubMed:19443654, ECO:0000269|PubMed:22699938, ECO:0000269|PubMed:9727977}.;
Disease: DISEASE: Note=Constitutive activation and subsequent transactivation of target genes may lead to the maintenance of stem-cell characteristics (cycling and longevity) in cells that should normally undergo terminal differentiation and constitute the primary transforming event in colorectal cancer (CRC).; DISEASE: Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:16415884, ECO:0000269|PubMed:24390345}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.485

Intolerance Scores

LoFtool: 0.0268
RVIS EVS: -0.22
RVIS percentile EVS: 37.54

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 1.00

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium