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]

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Variant: NM_175914.5(HNF4A):c.421C>T (p.Arg141Ter)

CA120194

9211 (ClinVar)

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 25c9cb77-d5c3-4fa2-8add-89f6e238bf3a

Approved on: 2024-05-09

Published on: 2024-05-09

HGVS expressions

NM_175914.5:c.421C>T

NM_175914.5(HNF4A):c.421C>T (p.Arg141Ter)

NC_000020.11:g.44413795C>T

CM000682.2:g.44413795C>T

NC_000020.10:g.43042435C>T

CM000682.1:g.43042435C>T

NC_000020.9:g.42475849C>T

NG_009818.1:g.62995C>T

ENST00000316673.9:c.421C>T

ENST00000316099.10:c.487C>T

ENST00000619550.5:c.461C>T

ENST00000683148.1:n.463C>T

ENST00000683657.1:n.1611C>T

ENST00000316099.9:c.487C>T

ENST00000316099.8:c.487C>T

ENST00000316673.8:c.421C>T

ENST00000372920.1:c.*254C>T

ENST00000415691.2:c.487C>T

ENST00000443598.6:c.487C>T

ENST00000457232.5:c.421C>T

ENST00000609795.5:c.421C>T

ENST00000619550.4:c.412C>T

NM_000457.4:c.487C>T

NM_001030003.2:c.421C>T

NM_001030004.2:c.421C>T

NM_001258355.1:c.466C>T

NM_001287182.1:c.412C>T

NM_001287183.1:c.412C>T

NM_001287184.1:c.412C>T

NM_175914.4:c.421C>T

NM_178849.2:c.487C>T

NM_178850.2:c.487C>T

NM_001030003.3:c.421C>T

NM_001030004.3:c.421C>T

NM_001258355.2:c.466C>T

NM_001287182.2:c.412C>T

NM_001287184.2:c.412C>T

NM_178849.3:c.487C>T

NM_178850.3:c.487C>T

NM_000457.5:c.487C>T

NM_000457.6:c.487C>T

NM_001287183.2:c.412C>T

Pathogenic

PS4 PP1_Strong PP4_Moderate PM2_Supporting 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 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.421C>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, results in a premature termination at codon 141 (p.(Arg141Ter)) of NM_175914.5. This variant, located in biologically-relevant exon 4 of 10, is predicted to lead to nonsense mediated decay 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), and was identified in at least 10 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 9294105, internal lab contributors). Three individuals had a clinical history highly specific for HNF4A-MODY monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and response to low-dose sulfonylureas) (PP4_Moderate; internal lab contributors). This variant also segregated with diabetes, with at least seven informative meioses in two families (PP1_Strong; PMID: 9294105, internal lab contributor). In summary, c.421C>T 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): PVS1, PP1_Strong, PS4, PP4_Moderate, PM2_Supporting).

PS4

This variant was identified in at least 10 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 9294105, internal lab contributors).

PP1_Strong

This variant segregated with diabetes, with at least seven informative meioses in two families (PP1_Strong; PMID: 9294105, internal lab contributor).

PP4_Moderate

This variant was identified in least 3 individuals with a clinical history highly specific for HNF4A-MODY monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and response to low-dose sulfonylureas) (PP4_Moderate; internal lab contributors).

PM2_Supporting

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

PVS1

This variant, located in biologically-relevant exon 4 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID:23348805).

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