rs193922485 — HNF1B

Rare HNF1B splice-region intronic variant of uncertain significance, found near exon 9 of the HNF1B gene and submitted to ClinVar in the context of renal cysts and diabetes syndrome (MODY5 / HNF1B-related disease)

See your personal result for HNF1B

Upload your DNA data to find out which genotype you carry and what it means for you.

Upload your DNA data

Works with 23andMe, AncestryDNA, and other DNA test exports. Results in under 60 seconds.

HNF1B and the Multisystem Glucose-Kidney Axis

The HNF1B gene (hepatocyte nuclear factor 1-beta) encodes a transcription factor that directs the embryonic development of the kidneys, pancreas, liver, urogenital tract, parathyroid, and parts of the brain. Unlike single-organ transcription factors, HNF1β is a master regulator whose influence spans multiple organ systems simultaneously — which is why HNF1B-related disease produces such a diverse and often confusing clinical picture. Pathogenic HNF1B variants cause renal cysts and diabetes syndrome11 renal cysts and diabetes syndrome
Also called MODY5 (maturity-onset diabetes of the young type 5) or HNF1B-related disorder; OMIM 189907, a dominantly-inherited condition that combines early-onset diabetes with kidney abnormalities and a constellation of other organ-system findings.

The rs193922485 variant sits within intron 8 of HNF1B, four nucleotides upstream of the exon 9 splice acceptor site. Its ClinVar annotation NM_000458.4:c.1654-4G>A22 NM_000458.4:c.1654-4G>A
Plus-strand genomic: NC_000017.11:g.37687396C>T; the HNF1B gene is on the minus strand, so the coding-strand G>A corresponds to the plus-strand C>T reflects a position close enough to the splice junction that it was flagged as potentially significant — but computational splice prediction tools and the observation that this nucleotide is not conserved across vertebrate species have led the most recent high-volume clinical laboratories to classify it as likely benign. Three of six ClinVar submitters classify it as likely benign; three as uncertain significance. No published case series documents clinical HNF1B disease in an individual specifically carrying this variant.

The Mechanism

True pathogenic HNF1B variants disrupt haploinsufficiency — one functional copy of HNF1B is insufficient for normal organ development, causing developmental defects in the branching architecture of the kidneys, the differentiation of pancreatic cells (leading to reduced beta-cell mass and early-onset diabetes), magnesium reabsorption in the renal tubule (causing hypomagnesemia), and hepatocyte differentiation. The full syndrome includes renal cysts, early-onset non-immune diabetes, hypomagnesemia, pancreatic dysplasia, and urogenital malformations — often in combination, but rarely all in one individual.

Whether c.1654-4G>A disrupts splicing depends on whether the adenosine substitution at position -4 of the intron creates a novel splice branch point or weakens the polypyrimidine tract. Current in silico tools predict no significant effect on normal splicing at this position, and the non-conserved nucleotide context supports the likely benign interpretation. However, because the clinical consequence of a true splice disruption here would be significant, the variant warrants awareness, particularly in individuals who present with characteristic features of HNF1B-related disease.

The Evidence

HNF1B-related disease is well characterized at the gene level33 well characterized at the gene level
Verhave JC et al. J Am Soc Nephrol 2016, PMID 26319241. A large cohort study of 61 confirmed MODY5 patients Ge Z et al. 202244 Ge Z et al. 2022
Front Endocrinol, PMID 35846334 found: renal cysts in 72%, hypomagnesemia in 92%, pancreatic dysplasia in 72%, median diabetes onset age of 16 years, and lean body habitus (only 8% overweight). Family history of diabetes was present in 66% — consistent with autosomal dominant inheritance. These data apply to confirmed pathogenic HNF1B variants; the clinical impact of this specific intronic variant is unknown.

The most common type of pathogenic HNF1B change (~40-50% of cases) is a recurrent whole-gene deletion at chromosome 17q12. Point mutations (missense, nonsense, and splice-site) account for the remainder. Intronic variants at the splice acceptor can be pathogenic if they disrupt the AG dinucleotide consensus or the polypyrimidine tract, but variants at position -4 (outside the core splice signal of the last two intronic nucleotides) require functional RNA evidence to confirm pathogenicity.

This specific variant has no published case reports linking it to confirmed HNF1B disease. Its clinical significance therefore remains technically unresolved.

Practical Actions

The primary clinical value of knowing about this variant is awareness: if you carry the T allele and have features consistent with HNF1B-related disease (unexplained renal cysts, early-onset non-immune diabetes, low magnesium, urogenital anomalies), this result supports requesting specialist evaluation and clinical-grade HNF1B testing. If you have none of these features, the variant is most likely benign based on current evidence.

Interactions

The HNF1B gene is the central axis for MODY5 / renal cysts and diabetes syndrome. Other MODY-causing genes (HNF1A for MODY3, HNF4A for MODY1, GCK for MODY2) cause clinically distinct subtypes that require different management — differentiating them requires genetic testing because treatment differs substantially. For blood sugar regulation, TCF7L2 rs7903146 and GCK variants operate in different pathways but converge on insulin secretion and glucose homeostasis.

Genotype Interpretations

What each possible genotype means for this variant.

CC Normal HNF1B Sequence Normal

Normal HNF1B sequence at this position

You carry two copies of the reference C allele at rs193922485. This is the case for virtually everyone in the population — the T allele has been observed in fewer than 1 in 20,000 chromosomes in population databases. No specific actions are indicated for this variant.

CT HNF1B Variant Carrier Carrier

One copy of an uncertain-significance HNF1B intronic variant

HNF1B (hepatocyte nuclear factor 1-beta) is a master transcriptional regulator of multiple organ systems. When one copy of the gene is disrupted by a confirmed pathogenic variant, the haploinsufficiency causes a constellation of findings during organ development: bilateral renal cysts (72% of confirmed cases), early-onset diabetes from reduced beta-cell mass (45-88% of cases depending on cohort), profound hypomagnesemia from tubular wasting (up to 92%), pancreatic dysplasia, and congenital urogenital malformations.

The variant you carry (c.1654-4G>A, four nucleotides before the exon 9 splice site) falls in a region that could theoretically affect splicing if it disrupts the polypyrimidine tract. However, the nucleotide is not conserved in vertebrate species and in silico tools predict no splice impact. The most recent and largest-volume laboratories (LabCorp, Labcorp Genetics) classify it as likely benign as of 2025–2026.

If you have none of the features of HNF1B-related disease (no unexplained renal cysts on imaging, no early-onset diabetes, no low magnesium, no urogenital anomalies), this variant is most likely not responsible for any current clinical findings. If you do have some of these features, clinical-grade HNF1B sequencing and deletion analysis would be the next diagnostic step to determine whether a second HNF1B abnormality is present or whether the variant is truly functional.

TT Homozygous HNF1B Variant Homozygous

Two copies of an uncertain-significance HNF1B intronic variant

You appear to carry two copies of the T allele at rs193922485. This genotype combination has essentially never been observed in population databases and almost certainly represents a sequencing artifact or data quality issue rather than true homozygosity. The T allele frequency is approximately 0.00005 in gnomAD, making the expected frequency of TT homozygosity roughly 1 in 400,000,000. Confirm this result with clinical-grade sequencing before drawing any conclusions.