Variant: NM_175914.5(HNF4A):c.1052T>G (p.Met351Arg)

CA120226

9216 (ClinVar)

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 947a4531-75a8-43fd-b583-c67188936101

Approved on: 2024-11-21

Published on: 2024-11-21

HGVS expressions

NM_175914.5:c.1052T>G
NM_175914.5(HNF4A):c.1052T>G (p.Met351Arg)
NC_000020.11:g.44424243T>G
CM000682.2:g.44424243T>G
NC_000020.10:g.43052883T>G
CM000682.1:g.43052883T>G
NC_000020.9:g.42486297T>G
NG_009818.1:g.73443T>G
ENST00000316673.9:c.1052T>G
ENST00000316099.10:c.1118T>G
ENST00000619550.5:c.1092T>G
ENST00000316099.9:c.1118T>G
ENST00000316099.8:c.1118T>G
ENST00000316673.8:c.1052T>G
ENST00000372920.1:c.*885T>G
ENST00000415691.2:c.1118T>G
ENST00000443598.6:c.1118T>G
ENST00000457232.5:c.1052T>G
ENST00000609795.5:c.1052T>G
ENST00000619550.4:c.1043T>G
NM_000457.4:c.1118T>G
NM_001030003.2:c.1052T>G
NM_001030004.2:c.1052T>G
NM_001258355.1:c.1097T>G
NM_001287182.1:c.1043T>G
NM_001287183.1:c.1043T>G
NM_001287184.1:c.1043T>G
NM_175914.4:c.1052T>G
NM_178849.2:c.1118T>G
NM_178850.2:c.1118T>G
NM_001030003.3:c.1052T>G
NM_001030004.3:c.1052T>G
NM_001258355.2:c.1097T>G
NM_001287182.2:c.1043T>G
NM_001287184.2:c.1043T>G
NM_178849.3:c.1118T>G
NM_178850.3:c.1118T>G
NM_000457.5:c.1118T>G
NM_000457.6:c.1118T>G
NM_001287183.2:c.1043T>G

Likely Pathogenic

• Met criteria codes: PS3_Supporting PP3 PP4_Moderate PP1_Moderate PM2_Supporting

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 1052T>G variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of methionine to arginine at codon 351 (p.(Met351Arg)) of NM_175914.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.903, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant segregated with diabetes, with four informative meioses in one family (PP1_Moderate; PMID: 17407387). PP4_moderate was met even without MPC or ABCC8 testing because multiple family members are diazoxide-responsive and would have to be a unique ABCC8 situation. (PP4_Moderate; PMID: 17407387). Functional studies demonstrated the p.Met351Arg protein has transactivation below 40% of wildtype but retains the same DNA binding activity as WT HNF4A, indicating that this variant impacts protein function (PMID: 21323639). In summary, c.1052T>G 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): PS3_supporting, PP1_moderate, PP4_moderate, PM2_supporting, PP3.

Met criteria codes

• PS3_Supporting: Functional studies demonstrated the p.Met351Arg protein has transactivation below 40% of wildtype but retain the same DNA binding activity as WT HNF4A, indicating that this variant impacts protein function (PMID: 21323639)
• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.903, which is greater than the MDEP VCEP threshold of 0.70 (PP3).
• PP4_Moderate: PP4_moderate was met even without MPC or ABCC8 testing because multiple family members are diazoxide-responsive and would have to be a unique ABCC8 situation. (PP4_Moderate; PMID: 17407387).
• PP1_Moderate: This variant segregated with diabetes, with four informative meioses in one family (PP1_Moderate; PMID: 17407387).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting). gnomAD v4.1.0, absent