Variant: NM_175914.5(HNF4A):c.881A>G (p.Gln294Arg)

CA409108097

3063964 (ClinVar)

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 4105dd03-df37-4b55-9f4d-8d67cada2212

Approved on: 2025-04-07

Published on: 2025-06-02

HGVS expressions

NM_175914.5:c.881A>G
NM_175914.5(HNF4A):c.881A>G (p.Gln294Arg)
NC_000020.11:g.44424072A>G
CM000682.2:g.44424072A>G
NC_000020.10:g.43052712A>G
CM000682.1:g.43052712A>G
NC_000020.9:g.42486126A>G
NG_009818.1:g.73272A>G
ENST00000316673.9:c.881A>G
ENST00000316099.10:c.947A>G
ENST00000619550.5:c.921A>G
ENST00000316099.9:c.947A>G
ENST00000316099.8:c.947A>G
ENST00000316673.8:c.881A>G
ENST00000372920.1:c.*714A>G
ENST00000415691.2:c.947A>G
ENST00000443598.6:c.947A>G
ENST00000457232.5:c.881A>G
ENST00000609795.5:c.881A>G
ENST00000619550.4:c.872A>G
NM_000457.4:c.947A>G
NM_001030003.2:c.881A>G
NM_001030004.2:c.881A>G
NM_001258355.1:c.926A>G
NM_001287182.1:c.872A>G
NM_001287183.1:c.872A>G
NM_001287184.1:c.872A>G
NM_175914.4:c.881A>G
NM_178849.2:c.947A>G
NM_178850.2:c.947A>G
NM_001030003.3:c.881A>G
NM_001030004.3:c.881A>G
NM_001258355.2:c.926A>G
NM_001287182.2:c.872A>G
NM_001287184.2:c.872A>G
NM_178849.3:c.947A>G
NM_178850.3:c.947A>G
NM_000457.5:c.947A>G
NM_000457.6:c.947A>G
NM_001287183.2:c.872A>G

Uncertain Significance

• Met criteria codes: PP3 PM2_Supporting

• Not Met criteria codes: PM5 PM1 PP4

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

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.881A>G variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of glutamine to arginine at codon 294 (p.(Gln294Arg)) of NM_175914.5. This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.948, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with diabetes; however, MODY probability cannot be calculated due to lack of clinical information (internal lab contributors). Another missense variant at the same codon, c.881A>C (p.Gln294Pro) has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.881A>G 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, PP3.

Met criteria codes

• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.948, which is greater than the MDEP VCEP threshold of 0.70 (PP3).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 and v4.1 (PM2_Supporting).

Not Met criteria codes

• PM5: Another missense variant at the same codon, c.881A>C (p.Gln294Pro) has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied.
• 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, MODY probability cannot be calculated due to lack of clinical information (internal lab contributors).