HNF1B

Chr 17AD

HNF1 homeobox B

Also known as: ADTKD3, FJHN, HNF-1-beta, HNF-1B, HNF1beta, HNF2, HPC11, LF-B3

NCBI Gene: 6928 ENSG00000275410 UniProt: P35680 OMIM: 189907

This transcription factor binds DNA as a homodimer or heterodimer with hepatocyte nuclear factor 1-alpha and regulates nephron development and embryonic pancreas development. Loss-of-function mutations cause renal cysts and diabetes syndrome and type 2 diabetes mellitus through autosomal dominant inheritance. The gene is highly intolerant to loss-of-function variants, consistent with haploinsufficiency as the underlying disease mechanism.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

LOFmechanismADLOEUF 0.173 OMIM phenotypes

Clinical Summary— HNF1B

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Gene-Disease Validity (ClinGen)

renal cysts and diabetes syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

161 unique Pathogenic / Likely Pathogenic· 174 VUS of 499 total submissions

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Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — HNF1B

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.17LOEUF

pLI 1.000

Z-score 4.75

OE 0.04 (0.01–0.17)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

1.73Z-score

OE missense 0.72 (0.65–0.81)

225 obs / 311.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.04 (0.01–0.17)

0≤0.351.4

Missense OE0.72 (0.65–0.81)

0≤0.61.4

Synonymous OE1.11

0≤1.21.6

LoF obs/exp: 1 / 28.3Missense obs/exp: 225 / 311.1Syn Z: -1.03

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveHNF1B-related renal cysts and diabetes syndromeLOFAD

0.3594th %ile

GOF

0.2796th %ile

LOF

0.82top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 51% of P/LP variants are LoF · LOEUF 0.17

DN1 literature citation

GOF1 literature citation

Literature Evidence

DNTruncation mutations, retaining the dimerization domain, displayed defective nuclear localization and weak dominant-negative activity when coexpressed with the wildtype protein.PMID:15509593

GOFTransfection experiments showed that the 5-bp deletion was associated with nephron agenesis and acted as a gain-of-function mutation with increased transactivation potential.PMID:10720943

LOFOur results show that lack of HNF1B blocks specification of pancreatic fate from the foregut progenitor (FP) stage, but HNF1B haploinsufficiency allows differentiation of multipotent pancreatic progenitor cells (MPCs) and insulin-secreting ÃÅ½ÃÂ²-like cells.PMID:34450036

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.