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 PP4_Moderate PVS1

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.

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.

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.

Curation History

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