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.1541A>G (p.His514Arg)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA6832103

435421 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 16f80b95-4ea3-4440-a3dc-453c6802904d

Approved on: 2025-02-20

Published on: 2025-02-28

HGVS expressions

NM_000545.8:c.1541A>G

NM_000545.8(HNF1A):c.1541A>G (p.His514Arg)

NC_000012.12:g.120999307A>G

CM000674.2:g.120999307A>G

NC_000012.11:g.121437110A>G

CM000674.1:g.121437110A>G

NC_000012.10:g.119921493A>G

NG_011731.2:g.25562A>G

ENST00000560968.6:c.*288A>G

ENST00000257555.11:c.1541A>G

ENST00000257555.10:c.1541A>G

ENST00000540108.1:c.*981A>G

ENST00000541395.5:c.1541A>G

ENST00000543427.5:c.1004A>G

ENST00000544413.2:c.1541A>G

ENST00000560968.5:c.1358A>G

ENST00000615446.4:c.329A>G

ENST00000617366.4:c.658A>G

NM_000545.5:c.1541A>G

NM_000545.6:c.1541A>G

NM_001306179.1:c.1541A>G

NM_001306179.2:c.1541A>G

Benign

BA1 BP5 PP3

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 2.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1541A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of histidine to arginine at codon 514 (p.(His514Arg)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.85, which is greater than the MDEP VCEP threshold of 0.70 (PP3). However, this variant has a Grpmax Filtering allele frequency in gnomAD 2.1.1 of 0.0001150, which is greater than the MDEP threshold for BA1 (0.0001) (BA1). Additionally, this variant was identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributors). In summary, c.1541A>G meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 08/11/2023): BA1, BP5, PP3. While this variant is benign for HNF1A-monogenic diabetes, there is evidence to suggest that this variant may act as a risk allele for type 2 diabetes (PMID: 11692182, 27899486, 36216889, 33046911).

BA1

This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0001150, which is greater than the MDEP threshold for BA1 (0.0001) (BA1).

BP5

This variant was identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributors).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.85, which is greater than the MDEP VCEP threshold of 0.70 (PP3).

Curation History

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