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.2T>A

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA409109839

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 6b4c0a27-9d3a-40d5-8947-f07cfe75a70f

Approved on: 2024-06-09

Published on: 2024-06-09

HGVS expressions

NM_175914.5:c.2T>A

NC_000020.11:g.44355806T>A

CM000682.2:g.44355806T>A

NC_000020.10:g.42984446T>A

CM000682.1:g.42984446T>A

NC_000020.9:g.42417860T>A

NG_009818.1:g.5006T>A

ENST00000316673.9:c.2T>A

ENST00000316673.8:c.2T>A

ENST00000457232.5:c.2T>A

ENST00000609262.5:c.-230T>A

ENST00000609795.5:c.2T>A

ENST00000619550.4:c.-230T>A

NM_001030003.2:c.2T>A

NM_001030004.2:c.2T>A

NM_001287182.1:c.-230T>A

NM_001287183.1:c.-230T>A

NM_001287184.1:c.-230T>A

NM_175914.4:c.2T>A

NM_001030003.3:c.2T>A

NM_001030004.3:c.2T>A

NM_001287182.2:c.-230T>A

NM_001287184.2:c.-230T>A

NM_001287183.2:c.-230T>A

Likely Pathogenic

PVS1_Strong PM2_Supporting 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 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.2T>A 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 an individual with a phenotype highly specific for HNF4A-monogenic diabetes (MPC > 50% and had a macrosomic infant with the variant with diazoxide-responsive hyperinsulinemic hypoglycemia (PP4_Moderate; Internal lab contributor). In summary, c.2T>A meets the criteria to be classified as Likely Pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PVS1_Strong, PP4_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 (PMID: 23348805).

PM2_Supporting

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

PP4_Moderate

This variant was identified Identified in an individual with a phenotype highly specific for HNF4A-monogenic diabetes (MPC > 50% and had a macrosomic infant with the variant with diazoxide-responsive hyperinsulinemic hypoglycemia (PP4_Moderate; Internal lab contributor).

Curation History

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