Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000545.8(HNF1A):c.1769-1G>A

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA386940950

1687082 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: d5222a0b-2379-4a72-b324-d71ebc783271

Approved on: 2025-10-03

Published on: 2025-10-03

HGVS expressions

NM_000545.8:c.1769-1G>A

NM_000545.8(HNF1A):c.1769-1G>A

NC_000012.12:g.121001064G>A

CM000674.2:g.121001064G>A

NC_000012.11:g.121438867G>A

CM000674.1:g.121438867G>A

NC_000012.10:g.119923250G>A

NG_011731.2:g.27319G>A

ENST00000560968.6:c.*516-1G>A

ENST00000257555.11:c.1769-1G>A

ENST00000257555.10:c.1769-1G>A

ENST00000288757.7:c.*3089C>T

ENST00000540108.1:c.*1209-1G>A

ENST00000541395.5:c.1862-1G>A

ENST00000543427.5:c.1232-1G>A

ENST00000544413.2:c.1790-1G>A

ENST00000560968.5:c.1586-1G>A

ENST00000615446.4:c.557-1G>A

ENST00000617366.4:c.*178-1G>A

NM_000545.5:c.1769-1G>A

NM_000545.6:c.1769-1G>A

NM_001306179.1:c.1790-1G>A

NM_001286191.2:c.*3089C>T

NM_001286196.2:c.*3089C>T

NM_001306179.2:c.1790-1G>A

NM_022895.3:c.*3089C>T

Uncertain Significance

PM2_Supporting PVS1_Strong

PP1 PP4

Evidence Links 0

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specification: ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HNF1A Version 3.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1769-1G>A variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice acceptor site in intron 10 of NM_000545.8. This variant, located in the donor site of exon 10 of 10, is predicted to disrupt a significant part of the transactivation domain, a functionally important region of the protein. Even though this truncated transcript is predicted to escape nonsense-mediated decay in a gene in which loss-of-function is an established mechanism of disease, there is clinical evidence that variants in this region lead to a monogenic diabetes phenotype. (PVS1_Strong; PMID: 23348805). Additionally, this variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant was identified in an individual with diabetes and negative testing for HNF4A; however, the calculated MODY probability is <50%. Therefore, PP4 could not be applied (Internal lab contributor). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (Internal lab contributor). In summary, c.1769-1G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025: PVS1_Strong, PM2_Supporting.

PM2_Supporting

This variant is absent from gnomAD v4.1.0 (PM2_Supporting).

PVS1_Strong

This variant, located in the splice acceptor site of exon 10 of 10, is predicted to result in the loss of the splice acceptor site and to form new acceptor site nearby, which would change the entire amino acid sequence of exon 10 and add additional 27 amino acids to the C terminus of the protein, thus disrupting a significant part of the transactivation domain, a functionally important region of the protein. Even though this truncated transcript is predicted to escape nonsense mediated decay in a gene in which loss-of-function is an established mechanism of disease, there is clinical evidence that variants in this region lead to a monogenic diabetes phenotype.

PP1

This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors).

PP4

This variant was identified in an individual with diabetes and negative testing for HNF4A; however, the calculated MODY probability is <50% (internal lab contributors).

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.