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_000545.6(HNF1A):c.1A>G (p.Met1Val)

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA214292

36814 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 7c508e24-1f72-4f67-a59e-36cd9ef980bd

Approved on: 2022-03-04

Published on: 2022-07-11

HGVS expressions

NM_000545.6:c.1A>G

NM_000545.6(HNF1A):c.1A>G (p.Met1Val)

NC_000012.12:g.120978769A>G

CM000674.2:g.120978769A>G

NC_000012.11:g.121416572A>G

CM000674.1:g.121416572A>G

NC_000012.10:g.119900955A>G

NG_011731.2:g.5024A>G

ENST00000257555.11:c.1A>G

ENST00000257555.10:c.1A>G

ENST00000400024.6:c.1A>G

ENST00000402929.5:n.136A>G

ENST00000535955.5:n.42+77A>G

ENST00000538626.2:n.119A>G

ENST00000538646.5:c.1A>G

ENST00000540108.1:c.1A>G

ENST00000541395.5:c.1A>G

ENST00000541924.5:c.1A>G

ENST00000543427.5:c.1A>G

ENST00000544413.2:c.1A>G

ENST00000544574.5:c.1A>G

ENST00000560968.5:n.144A>G

ENST00000615446.4:c.-258+58A>G

ENST00000617366.4:c.1A>G

NM_000545.5:c.1A>G

NM_001306179.1:c.1A>G

NM_000545.8:c.1A>G

NM_001306179.2:c.1A>G

NM_000545.8(HNF1A):c.1A>G (p.Met1Val)

Pathogenic

PM2_Supporting PVS1 PP4_Moderate

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 Version 1.1

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1A>G variant in the HNF1 homeobox A gene, HNF1A, results in the loss of the initiation codon (p.Met1Val) of NM_000545.8. By altering the start codon of the coding sequence, this variant is predicted to cause a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, antibody negative) (PP4_Moderate; internal lab contributor). In summary, c.1A>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 9/30/2021): PVS1, PM2_Supporting, PP4_Moderate

PM2_Supporting

This variant is absent from gnomAD database.

PVS1

This variant affects the initiation codon, and is ≥1 pathogenic variant(s) upstream of closest potential in-frame start codon. The closest potential alternative start codon is Met118, which is a whole dimerization domain away and 18 % of the protein would be lost.

PP4_Moderate

This variant was identified in multiple individuals with a clinical history consistent with HNF1A-MODY (MODY probability calculator result greater than 50% and negative genetic testing for HNF4A), who were also antibody negative and demonstrated a response to low dose sulfonylureas.

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.