NM_175914.5:c.734G>A

CA315411422

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 7a6d322f-2dac-433e-9598-cf312f83caf3

HGVS expressions

NM_175914.5:c.734G>A
NC_000020.11:g.44419784G>A
CM000682.2:g.44419784G>A
NC_000020.10:g.43048424G>A
CM000682.1:g.43048424G>A
NC_000020.9:g.42481838G>A
NG_009818.1:g.68984G>A
ENST00000316099.10:c.800G>A
ENST00000619550.5:c.774G>A
ENST00000683148.1:n.776G>A
ENST00000683657.1:n.1924G>A
ENST00000316099.9:c.800G>A
ENST00000316099.8:c.800G>A
ENST00000316673.8:c.734G>A
ENST00000372920.1:c.*567G>A
ENST00000415691.2:c.800G>A
ENST00000443598.6:c.800G>A
ENST00000457232.5:c.734G>A
ENST00000609795.5:c.734G>A
ENST00000619550.4:c.725G>A
NM_000457.4:c.800G>A
NM_001030003.2:c.734G>A
NM_001030004.2:c.734G>A
NM_001258355.1:c.779G>A
NM_001287182.1:c.725G>A
NM_001287183.1:c.725G>A
NM_001287184.1:c.725G>A
NM_175914.4:c.734G>A
NM_178849.2:c.800G>A
NM_178850.2:c.800G>A
NM_001030003.3:c.734G>A
NM_001030004.3:c.734G>A
NM_001258355.2:c.779G>A
NM_001287182.2:c.725G>A
NM_001287184.2:c.725G>A
NM_178849.3:c.800G>A
NM_178850.3:c.800G>A
NM_000457.5:c.800G>A
NM_000457.6:c.800G>A
NM_001287183.2:c.725G>A

Pathogenic

• Met criteria codes: PS4 PP4_Moderate PP3 PM5_Supporting PM2_Supporting PS3_Supporting PP1_Strong

• Not Met criteria codes: BA1 PM1 BS1 BP4

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 1.0.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.734G>A variant in the HNF4A gene causes an amino acid change of arginine to histidine at codon 245 (p.Arg254His) of NM_175914.4. Functional studies demonstrated the p.Arg254His protein has transactivation below 60% of wildtype, indicating that this variant impacts protein function (PS3_Supporting; PMID: 30325586). This variant was identified in 7 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; internal lab collaborators, PMIDs: 30325586, 21922456). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.733C>T p.Arg245Cys, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg345His (PM5_Supporting). This variant segregated with diabetes, with at least 4 informative meioses in 3 families (PP1_Strong; internal lab collaborators). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.92, which is greater than the MDEP VCEP threshold of 0.70 (PP3). 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 personal history of being large for gestational age) (PP4_Moderate; internal lab collaborators). In summary, c.734G>A 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): PS3_Supporting, PS4, PM2_Supporting, PM5_Supporting, PP1_Strong, PP3, PP4_Moderate.

Met criteria codes

• PS4: This variant was identified in 7 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; internal lab collaborators, PMIDs: 30325586, 21922456).
• 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 personal history of being large for gestational age) (PP4_Moderate; internal lab collaborators).
• PP3: REVEL score above 0.7.
• PM5_Supporting: R245C is P, R-C Grantham distance: 180, greater than R245H (GD 29).
• PM2_Supporting: This variant is absent from gnomAD.
• PS3_Supporting: Functional studies demonstrated the p.Arg254His protein has transactivation below 60% of wildtype, indicating that this variant impacts protein function (PMID: 30325586).
• PP1_Strong: This variant segregated with diabetes, with at least 4 informative meioses in 3 families with MODY (PP1_Strong; internal lab collaborators).

Not Met criteria codes

• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: This variant is outside of the region defined as critical for the protein’s function by the ClinGen MDEP (codons 37-113, 180-220 and 300-350).
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2023-09-15

Published on: 2023-09-15