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]

Link to SEPIO compliant JSON-LD document

Variant: NM_175914.5:c.421del

CA2573106197

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 9e4cc6c0-7996-4775-8a1c-bd77e372d8de

HGVS expressions

NM_175914.5:c.421del

NC_000020.11:g.44413795del

CM000682.2:g.44413795del

NC_000020.10:g.43042435del

CM000682.1:g.43042435del

NC_000020.9:g.42475849del

NG_009818.1:g.62995del

ENST00000316673.9:c.421del

ENST00000316099.10:c.487del

ENST00000619550.5:c.461del

ENST00000683148.1:n.463del

ENST00000683657.1:n.1611del

ENST00000316099.9:c.487del

ENST00000316099.8:c.487del

ENST00000316673.8:c.421del

ENST00000372920.1:c.*254del

ENST00000415691.2:c.487del

ENST00000443598.6:c.487del

ENST00000457232.5:c.421del

ENST00000609795.5:c.421del

ENST00000619550.4:c.412del

NM_000457.4:c.487del

NM_001030003.2:c.421del

NM_001030004.2:c.421del

NM_001258355.1:c.466del

NM_001287182.1:c.412del

NM_001287183.1:c.412del

NM_001287184.1:c.412del

NM_175914.4:c.421del

NM_178849.2:c.487del

NM_178850.2:c.487del

NM_001030003.3:c.421del

NM_001030004.3:c.421del

NM_001258355.2:c.466del

NM_001287182.2:c.412del

NM_001287184.2:c.412del

NM_178849.3:c.487del

NM_178850.3:c.487del

NM_000457.5:c.487del

NM_000457.6:c.487del

NM_001287183.2:c.412del

Pathogenic

PM2_Supporting PVS1 PP4 PP1

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.421del variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes a frameshift in the protein at codon 141 of NM_175914.5, adding 29 novel amino acids before encountering a stop codon (p.(Arg141AspfsTer29)). 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 in gnomAD v2.1.1 (PM2_Supporting), and was identified in an individual with a clinical history suggestive of HNF4A-MODY (neonatal hyperinsulinemic hypoglycemia that is responsive to diazoxide and negative genetic testing for ABCC8 and KCNJ11)(PP4; PMID: 23796040). This variant segregated with diabetes, with three informative meioses in a single family with MODY (PP1; internal lab contributor). In summary, c.421del 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 10/11/23): PVS1, PP1, PP4, PM2_Supporting.

PM2_Supporting

This variant is absent in 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).

PP4

This variant was identified in an individual with a clinical history suggestive of HNF4A-MODY (neonatal hypoglycemia that is responsive to diazoxide or hyperinsulinemic hypoglycemia and negative genetic testing for ABCC8 and KCNJ11)(PP4; PMID: 23796040).

PP1

This variant segregated with diabetes, with three informative meioses in a single family with MODY (PP1; internal lab contributor).

Approved on: 2024-04-06

Published on: 2024-04-06

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