HNF1B

Chr 17

HNF1 homeobox B

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

NCBI Gene: 6928 ENSG00000275410 UniProt: P35680

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 ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.17

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

290 unique Pathogenic / Likely Pathogenic· 276 VUS of 901 total submissions

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Clinical Trials

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

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GeneReview available — HNF1B

Authoritative clinical overview · Recommended first read

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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 OE?0.04 (0.01–0.17)

0≤0.351.4

Missense OE?0.72 (0.65–0.81)

0≤0.61.4

Synonymous OE?1.11

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

This gene — mechanism propensity

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 · 65% of P/LP variants are LoF · LOEUF 0.17 · ClinGen HI: Sufficient evidence for dosage pathogenicity

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.1

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.2

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.3

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

References

ClinVar Variant Classifications

901 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic161

Likely Pathogenic129

VUS276

Likely Benign188

Benign47

Conflicting97

161

Pathogenic

129

Likely Pathogenic

276

VUS

188

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	127	20	14	0	161
Likely Pathogenic	61	64	4	0	129
VUS	4	247	23	2	276
Likely Benign	2	7	68	111	188
Benign	0	2	44	1	47
Conflicting	—				97
Total	194	340	153	114	898

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

138 pathogenic / likely-pathogenic (of 149) ClinVar copy-number / structural variants overlap HNF1B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →