Variant: NM_175914.5(HNF4A):c.335G>A (p.Arg112Gln)

CA409105430

427034 (ClinVar)

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 9374a449-3776-451d-b6e1-4eb50bcbc616

Approved on: 2023-09-29

Published on: 2023-09-29

HGVS expressions

NM_175914.5:c.335G>A
NM_175914.5(HNF4A):c.335G>A (p.Arg112Gln)
NC_000020.11:g.44413709G>A
CM000682.2:g.44413709G>A
NC_000020.10:g.43042349G>A
CM000682.1:g.43042349G>A
NC_000020.9:g.42475763G>A
NG_009818.1:g.62909G>A
ENST00000316099.10:c.401G>A
ENST00000619550.5:c.375G>A
ENST00000683148.1:n.377G>A
ENST00000683657.1:n.1525G>A
ENST00000316099.9:c.401G>A
ENST00000316099.8:c.401G>A
ENST00000316673.8:c.335G>A
ENST00000372920.1:c.*168G>A
ENST00000415691.2:c.401G>A
ENST00000443598.6:c.401G>A
ENST00000457232.5:c.335G>A
ENST00000609795.5:c.335G>A
ENST00000619550.4:c.326G>A
NM_000457.4:c.401G>A
NM_001030003.2:c.335G>A
NM_001030004.2:c.335G>A
NM_001258355.1:c.380G>A
NM_001287182.1:c.326G>A
NM_001287183.1:c.326G>A
NM_001287184.1:c.326G>A
NM_175914.4:c.335G>A
NM_178849.2:c.401G>A
NM_178850.2:c.401G>A
NM_001030003.3:c.335G>A
NM_001030004.3:c.335G>A
NM_001258355.2:c.380G>A
NM_001287182.2:c.326G>A
NM_001287184.2:c.326G>A
NM_178849.3:c.401G>A
NM_178850.3:c.401G>A
NM_000457.5:c.401G>A
NM_000457.6:c.401G>A
NM_001287183.2:c.326G>A

Pathogenic

• Met criteria codes: PS4 PP3 PM1 PP1_Strong PP4_Moderate PM2_Supporting PM5_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 1.1.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.335G>A variant in the hepatic nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to glutamine at codon 112 (p.(Arg112Gln)) of NM_175914.5. This variant resides in an amino acid within the HNF4A DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.959, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in at least 17 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 36257325, 25306193, 26552609, 18356407, internal lab contributors). At least one of these individuals had a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and sulfonylurea-responsive) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes, with 12 informative meioses in 11 families (PP1_Strong; PMID: 18356407, internal lab contributors). Another missense variant, c.334C>T p.Arg112Trp, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg112Gln (PM5_Supporting). In summary, c.335A>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1.0, approved 8/11/2023): PS4, PP1_Strong, PM1, PP4_Moderate, PP3, PM2_Supporting, PM5_Supporting.

Met criteria codes

• PS4: This variant was identified in at least 17 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 36257325, 25306193, 26552609, 18356407, internal lab contributors).
• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.959, which is greater than the MDEP VCEP threshold of 0.70 (PP3).
• PM1: This variant resides in an amino acid within the HNF4A DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1).
• PP1_Strong: This variant segregated with diabetes, with 12 informative meioses in 11 families (PP1_Strong; PMID: 18356407, internal lab contributors).
• PP4_Moderate: This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and sulfonylrea-responsive) (PP4_Moderate; internal lab contributors).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
• PM5_Supporting: Another missense variant, c.334C>T p.Arg112Trp, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg112Gln (PM5_Supporting).