Variant: NM_175914.5(HNF4A):c.1033G>T (p.Asp345Tyr)

CA409108716

1700658 (ClinVar)

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: b78cff7f-8058-49cb-b96a-9bf51c9c469b

Approved on: 2025-01-29

Published on: 2025-01-29

HGVS expressions

NM_175914.5:c.1033G>T
NM_175914.5(HNF4A):c.1033G>T (p.Asp345Tyr)
NC_000020.11:g.44424224G>T
CM000682.2:g.44424224G>T
NC_000020.10:g.43052864G>T
CM000682.1:g.43052864G>T
NC_000020.9:g.42486278G>T
NG_009818.1:g.73424G>T
ENST00000316673.9:c.1033G>T
ENST00000316099.10:c.1099G>T
ENST00000619550.5:c.1073G>T
ENST00000316099.9:c.1099G>T
ENST00000316099.8:c.1099G>T
ENST00000316673.8:c.1033G>T
ENST00000372920.1:c.*866G>T
ENST00000415691.2:c.1099G>T
ENST00000443598.6:c.1099G>T
ENST00000457232.5:c.1033G>T
ENST00000609795.5:c.1033G>T
ENST00000619550.4:c.1024G>T
NM_000457.4:c.1099G>T
NM_001030003.2:c.1033G>T
NM_001030004.2:c.1033G>T
NM_001258355.1:c.1078G>T
NM_001287182.1:c.1024G>T
NM_001287183.1:c.1024G>T
NM_001287184.1:c.1024G>T
NM_175914.4:c.1033G>T
NM_178849.2:c.1099G>T
NM_178850.2:c.1099G>T
NM_001030003.3:c.1033G>T
NM_001030004.3:c.1033G>T
NM_001258355.2:c.1078G>T
NM_001287182.2:c.1024G>T
NM_001287184.2:c.1024G>T
NM_178849.3:c.1099G>T
NM_178850.3:c.1099G>T
NM_000457.5:c.1099G>T
NM_000457.6:c.1099G>T
NM_001287183.2:c.1024G>T

Likely Pathogenic

• Met criteria codes: PS2_Moderate PM2_Supporting PP4 PP3 PM1_Supporting

• Not Met criteria codes: PS4 PP1

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.1033G>T variant in the HNF4 homeobox A gene, HNF4A, causes an amino acid change of aspartic acid to tyrosine at codon 345 (p.(Asp345Tyr)) 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 0.913, which is greater than the MDEP threshold of 0.70 (PP3).  This variant is located within the ligand-binding domain (codons 180-220 and 300-350) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 32670997, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (including neonatal hypoglycemia, large for gestational age, and negative KCNJ11/ABCC8 germline sequencing) (PP4; PMID: 32670997). In summary, c.1033G>T 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): PM1_Supporting, PM2_Supporting, PP3, PP4, PS2_Moderate.

Met criteria codes

• PS2_Moderate: This variant was identified as a de novo occurrence with unconfirmed parental relationships in an individual with a clinical picture highly specific for HNF4A-monogenic diabetes (antibody-negative pediatric diabetes and a child with neonatal hyperinsulinsim negative for KCNJ11 and ABCC8 variants) (PS2_Moderate; PMID: 32670997).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting). v4.1 1 copy
• PP4: This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (neonatal hyperinsuliemic hypoglycemia, KCNJ11- and ABCC8- negative) (PP4; PMID: 32670997).
• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.913, which is greater than the MDEP VCEP threshold of 0.70 (PP3).
• PM1_Supporting: This variant is located within the ligand-binding domain (codons 180-220 and 300-350) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).

Not Met criteria codes

• PS4: This variant was identified in 2 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 32670997, internal lab contributors).
• PP1: This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMIDs: 27236918, 32670997).