Variant: NM_175914.5:c.337G>T

CA409105441

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: eb06cffd-4920-4549-b807-cf7d878b92e5

Approved on: 2024-02-25

Published on: 2024-02-25

HGVS expressions

NM_175914.5:c.337G>T
NC_000020.11:g.44413711G>T
CM000682.2:g.44413711G>T
NC_000020.10:g.43042351G>T
CM000682.1:g.43042351G>T
NC_000020.9:g.42475765G>T
NG_009818.1:g.62911G>T
ENST00000316673.9:c.337G>T
ENST00000316099.10:c.403G>T
ENST00000619550.5:c.377G>T
ENST00000683148.1:n.379G>T
ENST00000683657.1:n.1527G>T
ENST00000316099.9:c.403G>T
ENST00000316099.8:c.403G>T
ENST00000316673.8:c.337G>T
ENST00000372920.1:c.*170G>T
ENST00000415691.2:c.403G>T
ENST00000443598.6:c.403G>T
ENST00000457232.5:c.337G>T
ENST00000609795.5:c.337G>T
ENST00000619550.4:c.328G>T
NM_000457.4:c.403G>T
NM_001030003.2:c.337G>T
NM_001030004.2:c.337G>T
NM_001258355.1:c.382G>T
NM_001287182.1:c.328G>T
NM_001287183.1:c.328G>T
NM_001287184.1:c.328G>T
NM_175914.4:c.337G>T
NM_178849.2:c.403G>T
NM_178850.2:c.403G>T
NM_001030003.3:c.337G>T
NM_001030004.3:c.337G>T
NM_001258355.2:c.382G>T
NM_001287182.2:c.328G>T
NM_001287184.2:c.328G>T
NM_178849.3:c.403G>T
NM_178850.3:c.403G>T
NM_000457.5:c.403G>T
NM_000457.6:c.403G>T
NM_001287183.2:c.328G>T

Uncertain Significance

• Met criteria codes: PM2_Supporting PS3_Supporting PM1 PP3

• Not Met criteria codes: 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 1.0.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.337G>T variant in the hepatocyte nuclear factor-4 alpha gene, HNF4A, causes an amino acid change of aspartic acid to tyrosine at codon 113 (p.(Asp113Tyr)) of NM_175914.5. This variant resides in an amino acid within the HNF-4α DNA binding domain that directly binds DNA and is necessary for homodimer formation, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1; PMID: 18829458). Functional studies demonstrated the p.Asp113Tyr protein has DNA binding below 60% of wild type, indicating that this variant impacts protein function (PS3_supporting; PMID: 12110948). 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 0.955, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50%, HNF1A was not tested, and the individual had positive anti-GAD antibodies; thus, PP4 criteria was not applied (PMID: 11232004). In summary, c.337G>T meets the criteria to be classified as a VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0.0, approved 11/16/2022): PS3_suppporting, PM1, PM2_supporting, PP3.

Met criteria codes

• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
• PS3_Supporting: Functional studies demonstrated the p.Asp113Tyr protein has DNA binding below 60% of wild type, indicating that this variant impacts protein function (PS3_supporting; PMID: 12110948).
• PM1: This variant resides in an amino acid within the HNF-4α DNA binding domain that directly binds DNA and is necessary for homodimer formation, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1; PMID: 18829458).
• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.955, which is greater than the MDEP VCEP threshold of 0.70 (PP3).

Not Met criteria codes

• PP4: This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50%, HNF1A was not tested, and the individual had positive anti-GAD antibodies; thus, PP4 criteria was not applied (PMID: 11232004).