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(HNF4A):c.221G>A (p.Cys74Tyr)

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Curation History
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CA409104024

520895 (ClinVar)

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: f2739226-2eea-4b90-933d-6a5411fe0a64

Approved on: 2024-04-06

Published on: 2024-04-06

HGVS expressions

NM_175914.5:c.221G>A

NM_175914.5(HNF4A):c.221G>A (p.Cys74Tyr)

NC_000020.11:g.44406229G>A

CM000682.2:g.44406229G>A

NC_000020.10:g.43034869G>A

CM000682.1:g.43034869G>A

NC_000020.9:g.42468283G>A

NG_009818.1:g.55429G>A

ENST00000316673.9:c.221G>A

ENST00000316099.10:c.287G>A

ENST00000619550.5:c.261G>A

ENST00000681977.1:c.263G>A

ENST00000682169.1:c.240G>A

ENST00000683148.1:n.263G>A

ENST00000683657.1:n.263G>A

ENST00000684046.1:c.263G>A

ENST00000684136.1:c.263G>A

ENST00000684476.1:c.244G>A

ENST00000316099.9:c.287G>A

ENST00000316099.8:c.287G>A

ENST00000316673.8:c.221G>A

ENST00000372920.1:c.*54G>A

ENST00000415691.2:c.287G>A

ENST00000443598.6:c.287G>A

ENST00000457232.5:c.221G>A

ENST00000609262.5:c.212G>A

ENST00000609795.5:c.221G>A

ENST00000619550.4:c.212G>A

NM_000457.4:c.287G>A

NM_001030003.2:c.221G>A

NM_001030004.2:c.221G>A

NM_001258355.1:c.266G>A

NM_001287182.1:c.212G>A

NM_001287183.1:c.212G>A

NM_001287184.1:c.212G>A

NM_175914.4:c.221G>A

NM_178849.2:c.287G>A

NM_178850.2:c.287G>A

NM_001030003.3:c.221G>A

NM_001030004.3:c.221G>A

NM_001258355.2:c.266G>A

NM_001287182.2:c.212G>A

NM_001287184.2:c.212G>A

NM_178849.3:c.287G>A

NM_178850.3:c.287G>A

NM_000457.5:c.287G>A

NM_000457.6:c.287G>A

NM_001287183.2:c.212G>A

Likely Pathogenic

PM2_Supporting PP3 PM1 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.221G>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of cysteine to tyrosine at codon 74 (p.(Cys74Tyr)) of NM_175914.5. This variant is absent in gnomAD v2.1.1 (PM2_Supporting). It was identified in an individual with a clinical history highly specific for HNF4A-MODY (neonatal hypoglycemia that is responsive to diazoxide, negative genetic testing for ABCC8 and KCNJ11, and large for gestational age in the absence of sufficient maternal hyperglycemia) (PP4_Moderate; internal lab contributor). This variant resides in an amino acid that is necessary for Zinc-finger formation, which is defined as critical for the protein's function by the ClinGen MDEP (PM1). It is also predicted to be deleterious by computational evidence, with a REVEL score of 0.976, which is greater than the MDEP VCEP threshold of 0.70 (PP3). In summary, c.221G>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): PP4_Moderate, PM1, PP3, PM2_Supporting.

PM2_Supporting

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

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.976, which is greater than the MDEP VCEP threshold of 0.70 (PP3).

PM1

This variant resides in an amino acid that is necessary for Zinc-finger formation, which is defined as critical for the protein's function by the ClinGen MDEP (PM1).

PP4_Moderate

This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (neonatal hypoglycemia that is responsive to diazoxide, negative genetic testing for ABCC8 and KCNJ11, and large for gestational age in the absence of sufficient maternal hyperglycemia) (PP4_Moderate; internal lab contributor).

Curation History

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