Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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  • No ClinVar Id was directly found from the curated document

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

CA409105441

Gene: HNF4A
Condition: monogenic diabetes
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: eb06cffd-4920-4549-b807-cf7d878b92e5

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 4
PM1 PS3_Supporting PM2_Supporting PP3
Not Met criteria codes 1
PP4

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HNF4A Version 1.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
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
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).
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).
PM2_Supporting
This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
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).
Approved on: 2024-02-25
Published on: 2024-02-25
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