HNF1B

protein-coding

HNF1 homeobox B, the group of HNF class homeoboxes

Gene summary

This gene encodes a member of the homeodomain-containing superfamily of transcription factors. The protein binds to DNA as either a homodimer, or a heterodimer with the related protein hepatocyte nuclear factor 1-alpha. The gene has been shown to function in nephron development, and regulates development of the embryonic pancreas. Mutations in this gene result in renal cysts and diabetes syndrome and noninsulin-dependent diabetes mellitus, and expression of this gene is altered in some types of cancer. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]

Previous symbols:

TCF2

MANE transcript

NM_000458.4

Inheritance

ClinVar variants

P:312U:313B:170

Top phenotype

Renal cell carcinoma, nonpapillary chromophobe

Max pathogenic AF

—

Genomic locus

chr17:37,686,431-37,745,059

External References & Databases

Ensembl (ENSG00000275410)

Transcript & Mutation Effects

hg38 • Region Span ~58.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

renal cysts and diabetes syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007669

Submitter: G2P

renal cysts and diabetes syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007669

Submitter: PanelApp Australia

renal dysplasia, unilateralSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019644

Submitter: Orphanet

permanent neonatal diabetes mellitusSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100164

Submitter: Genomics England PanelApp

transient neonatal diabetes mellitusSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0020525

Submitter: Genomics England PanelApp

renal cysts and diabetes syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007669

Submitter: Genomics England PanelApp

diabetes mellitus, noninsulin-dependentSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007455

Submitter: Genomics England PanelApp

renal cysts and diabetes syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007669

Submitter: ClinGen

HNF1B was first reported in relation to autosomal dominant Renal Cysts and Diabetes Syndrome in 1997 (Horikawa et al., PMID: 9398836). An alternative description is Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD) – HNF1B. This disease entity consistently includes a primary renal phenotype in which a wide variety of genitourinary developmental malformations may be present, such as renal cysts, interstitial fibrosis, absent or underdeveloped kidney, abnormal nephron development, hypoplastic glomeruli, enlarged renal pelvises, bicornuate uterus, atresia of the vas deferens, rudimentary uterus, vaginal aplasia. Diabetes is typically diagnosed in adolescence or young adulthood, but some families will have carriers who may not have been diagnosed with diabetes but will usually have some evidence of renal pathology that is either congenital or progressive. The disorder has also been referred to as maturity onset diabetes of the young 5 (MODY5) or HNF1B-MODY, as well as Renal Cysts and Diabetes (RCAD; MIM:137920). Treatment for diabetes often includes insulin but optimal management has not been established. Other variable features of the syndrome may include hypomagnesemia, hyperuricemia, pancreatic exocrine insufficiency, hepatic dysfunction such as cholestasis, and intellectual disability (possibly more often when caused by large deletion of 17q12). Numerous variants have been reported in humans per ClinVar, especially whole gene deletions. Evidence supporting this gene-disease relationship includes case-level and experimental data. Summary of case-level and experimental data: 18 points. Variants in this gene have been reported in at least 13 probands in 7 publications (PMIDS: 9398836, 12161522, 25705165, 25754277, 25441779, 15068978, 20378641). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is heterozygous loss of function. This gene-disease association is supported by expression studies, animal models, and in vitro functional assays. In summary, HNF1B is definitively associated with autosomal dominant Renal Cysts and Diabetes Syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Monogenic Diabetes Gene Curation Expert Panel (12/10/2019) in collaboration with the ClinGen Kidney Cystic and Ciliopathy Disorders Gene Curation Expert Panel (1/19/2021) according to SOP Version 8.

renal cysts and diabetes syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007669

Submitter: Labcorp Genetics (formerly Invitae)

unilateral multicystic dysplastic kidneySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019981

Submitter: Orphanet

renal dysplasia, bilateralSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019645

Submitter: Orphanet

renal cysts and diabetes syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007669

Submitter: Orphanet

medullary sponge kidneySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015268

Submitter: Orphanet

Clinical Genomic Database (CGD)

Renal cell carcinoma, nonpapillary chromophobeAD

Manifestation: Endocrine; Genitourinary; Oncologic; Renal

Intervention: Oncologic

Rationale: Surveillance and early detection of and treatment for malignancy may decrease morbidity and mortality

Refs: 7151342; 2624270; 9398836; 10484768; 11085914; 12161522; 12675839; 15068978; 16249435; 15649945; 21380624; 21617276; 21767339; 22587559; 22269832; 22432796; 22706971

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HNF1B variants in ClinVar

21 Conditions Cataloged

not providedTotal: 492

Renal cysts and diabetes syndromeTotal: 416

Maturity-onset diabetes of the youngTotal: 179

HNF1B-related disorderTotal: 174

Type 2 diabetes mellitusTotal: 118

Nonpapillary renal cell carcinomaTotal: 114

not specifiedTotal: 94

Monogenic diabetesTotal: 7

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000458.4. 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			2 clinvar	146 clinvar		148
missense	17 clinvar	82 clinvar	305 clinvar	21 clinvar	3 clinvar	428
nonsense	36 clinvar	19 clinvar				55
start loss	2 clinvar					2
frameshift	74 clinvar	49 clinvar	2 clinvar			125
splice donor/acceptor (+/-2bp)	23 clinvar	10 clinvar	4 clinvar			37
Total	152	160	313	167	3	795

Highest pathogenic variant AF is 0.000033231376

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 24 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000458.4	RefSeq	NP_000449.1	9	MANE Select
ENST00000617811.5	Ensembl	ENSP00000480291.1	9	MANE Select
NM_001165923.4	RefSeq	NP_001159395.1	9	Standard
NM_001304286.2	RefSeq	NP_001291215.1	7	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
hnf1ba	Danio rerio	Structure: hair cell Quality: mislocalised abnormal

Gene / Model

Organism

Observed Phenotype

hnf1ba

Danio rerio

Structure: hair cell

Quality: mislocalised

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Maturity onset diabetes of the young - Homo sapiens (human)
Anti-diabetic Drug Potassium Channel Inhibitors Pathway, Pharmacodynamics
Endoderm Differentiation

Biological Process

negative regulation of transcription by RNA polymerase II
endodermal cell fate specification
kidney development
inner cell mass cell differentiation
regulation of transcription by RNA polymerase II

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity
protein binding
protein homodimerization activity

Cellular Component

nucleus
nucleoplasm
transcription factor complex

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcription factor, probably binds to the inverted palindrome 5'-GTTAATNATTAAC-3'.;
Disease: DISEASE: Renal cysts and diabetes syndrome (RCAD) [MIM:137920]: An autosomal dominant disorder comprising non-diabetic renal disease resulting from abnormal renal development, and diabetes, which in some cases occurs earlier than age 25 years and is thus consistent with a diagnosis of maturity-onset diabetes of the young (MODY5). The renal disease is highly variable and includes renal cysts, glomerular tufts, aberrant nephrogenesis, primitive tubules, irregular collecting systems, oligomeganephronia, enlarged renal pelves, abnormal calyces, small kidney, single kidney, horseshoe kidney, and hyperuricemic nephropathy. Affected individuals may also have abnormalities of the genital tract. {ECO:0000269|PubMed:10484768, ECO:0000269|PubMed:10672455, ECO:0000269|PubMed:11845238, ECO:0000269|PubMed:11918730, ECO:0000269|PubMed:14583183, ECO:0000269|PubMed:15001636, ECO:0000269|PubMed:15068978, ECO:0000269|PubMed:15181075, ECO:0000269|PubMed:15930087, ECO:0000269|PubMed:16249435}. Note=The disease is caused by mutations affecting the gene represented in this entry.; 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:12161522}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry.; DISEASE: Prostate cancer, hereditary, 11 (HPC11) [MIM:611955]: A condition associated with familial predisposition to cancer of the prostate. Most prostate cancers are adenocarcinomas that develop in the acini of the prostatic ducts. Other rare histopathologic types of prostate cancer that occur in approximately 5% of patients include small cell carcinoma, mucinous carcinoma, prostatic ductal carcinoma, transitional cell carcinoma, squamous cell carcinoma, basal cell carcinoma, adenoid cystic carcinoma (basaloid), signet-ring cell carcinoma and neuroendocrine carcinoma. {ECO:0000269|PubMed:18264097}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.708

Intolerance Scores

LoFtool: 0.0380
RVIS EVS: -0.54
RVIS percentile EVS: 20.26

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.914

Gene Damage Prediction

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