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.454G>A (p.Gly152Ser)

Curation Version - 1.0
Curation History
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CA9870282

549554 (ClinVar)

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 0951987b-620c-49a7-a4db-2061752e3205

Approved on: 2024-05-09

Published on: 2024-05-09

HGVS expressions

NM_175914.5:c.454G>A

NM_175914.5(HNF4A):c.454G>A (p.Gly152Ser)

NC_000020.11:g.44414534G>A

CM000682.2:g.44414534G>A

NC_000020.10:g.43043174G>A

CM000682.1:g.43043174G>A

NC_000020.9:g.42476588G>A

NG_009818.1:g.63734G>A

ENST00000316673.9:c.454G>A

ENST00000316099.10:c.520G>A

ENST00000619550.5:c.494G>A

ENST00000683148.1:n.496G>A

ENST00000683657.1:n.1644G>A

ENST00000316099.9:c.520G>A

ENST00000316099.8:c.520G>A

ENST00000316673.8:c.454G>A

ENST00000372920.1:c.*287G>A

ENST00000415691.2:c.520G>A

ENST00000443598.6:c.520G>A

ENST00000457232.5:c.454G>A

ENST00000609795.5:c.454G>A

ENST00000619550.4:c.445G>A

NM_000457.4:c.520G>A

NM_001030003.2:c.454G>A

NM_001030004.2:c.454G>A

NM_001258355.1:c.499G>A

NM_001287182.1:c.445G>A

NM_001287183.1:c.445G>A

NM_001287184.1:c.445G>A

NM_175914.4:c.454G>A

NM_178849.2:c.520G>A

NM_178850.2:c.520G>A

NM_001030003.3:c.454G>A

NM_001030004.3:c.454G>A

NM_001258355.2:c.499G>A

NM_001287182.2:c.445G>A

NM_001287184.2:c.445G>A

NM_178849.3:c.520G>A

NM_178850.3:c.520G>A

NM_000457.5:c.520G>A

NM_000457.6:c.520G>A

NM_001287183.2:c.445G>A

Uncertain Significance

PM2_Supporting

PM1 PP4 PP3

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.454G>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of glycine to serine at codon 152 (p.(Gly152Ser)) of NM_175914.5. This variant has a gnomAD v2.1.1 Grpmax filtering allele frequency of 0.00000292 (below the MDEP threshold of 0.000003) and <=2 copies observed in the European non-Finnish population and <=1 copies in any other subpopulation, thereby meeting the ClinGen MDEP criteria for PM2_Supporting (PM2_Supporting). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to age of diagnosis over 35 (internal lab contributor). Additionally, this variant has a REVEL score of 0.232, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. In summary, c.454G>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PM2_Supporting.

PM2_Supporting

This variant has a gnomAD v2.1.1 Gepmax filtering allele frequency of 0.00000292 (below the MDEP threshold of 0.000003) and <=2 copies observed in the European non-Finnish population and <=1 copies in any other subpopulation, thereby meeting the ClinGen MDEP criteria for PM2_Supporting (PM2_Supporting).

PM1

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

PP4

This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to age of diagnosis over 35 (internal lab contributor).

PP3

This variant has a REVEL score of 0.232, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function.

Curation History

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