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_175914.5:c.1A>G

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA409109837

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 96663a39-52d8-4c02-ab18-c7b46b58e572

Approved on: 2024-06-09

Published on: 2024-06-09

HGVS expressions

NM_175914.5:c.1A>G

NC_000020.11:g.44355805A>G

CM000682.2:g.44355805A>G

NC_000020.10:g.42984445A>G

CM000682.1:g.42984445A>G

NC_000020.9:g.42417859A>G

NG_009818.1:g.5005A>G

ENST00000316673.9:c.1A>G

ENST00000316673.8:c.1A>G

ENST00000457232.5:c.1A>G

ENST00000609262.5:c.-231A>G

ENST00000609795.5:c.1A>G

ENST00000619550.4:c.-231A>G

NM_001030003.2:c.1A>G

NM_001030004.2:c.1A>G

NM_001287182.1:c.-231A>G

NM_001287183.1:c.-231A>G

NM_001287184.1:c.-231A>G

NM_175914.4:c.1A>G

NM_001030003.3:c.1A>G

NM_001030004.3:c.1A>G

NM_001287182.2:c.-231A>G

NM_001287184.2:c.-231A>G

NM_001287183.2:c.-231A>G

Pathogenic

PVS1_Strong PS4_Moderate PM2_Supporting PP4_Moderate PP1_Strong

PM1

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 HNF4A Version 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1A>G variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, results in the loss of the initiation codon (p.Met1?) of NM_175914.5. By altering the start codon of the coding sequence, this variant may cause a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1_Strong; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in four unrelated individuals with non-autoimmune or absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; Internal lab contributors). One of these individuals had a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and antibody negative) (PP4_Moderate; Internal lab contributor). This variant segregated with diabetes, with six informative meioses in two families with MODY (PP1_Strong; Internal lab contributors). 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 2.0.0, approved 10/11/2023): PP1_Strong, PVS1_Strong, PP4_Moderate, PS4_Moderate, PM2_Supporting.

PVS1_Strong

By altering the start codon of the coding sequence, this variant may cause a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1_Strong; PMID: 23348805).

PS4_Moderate

This variant was identified in four unrelated individuals with non-autoimmune or absolute/near-absolute insulin-deficient diabetes (PS4; Internal lab contributors).

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

PP4_Moderate

This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and antibody negative) (PP4_Moderate; Internal lab contributor).

PP1_Strong

This variant segregated with diabetes, with six informative meioses in two families with MODY (PP1_Strong; Internal lab contributors).

PM1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Curation History

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