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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Variant: NM_175914.5(HNF4A):c.931C>T (p.Arg311Cys)

CA214003

36365 (ClinVar)

Gene: HNF4A
Condition: monogenic diabetes
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 41fb915d-b7cd-4a67-8200-96c520087be0
Approved on: 2024-07-28
Published on: 2024-07-29

HGVS expressions

NM_175914.5:c.931C>T
NM_175914.5(HNF4A):c.931C>T (p.Arg311Cys)
NC_000020.11:g.44424122C>T
CM000682.2:g.44424122C>T
NC_000020.10:g.43052762C>T
CM000682.1:g.43052762C>T
NC_000020.9:g.42486176C>T
NG_009818.1:g.73322C>T
ENST00000316673.9:c.931C>T
ENST00000316099.10:c.997C>T
ENST00000619550.5:c.971C>T
ENST00000316099.9:c.997C>T
ENST00000316099.8:c.997C>T
ENST00000316673.8:c.931C>T
ENST00000372920.1:c.*764C>T
ENST00000415691.2:c.997C>T
ENST00000443598.6:c.997C>T
ENST00000457232.5:c.931C>T
ENST00000609795.5:c.931C>T
ENST00000619550.4:c.922C>T
NM_000457.4:c.997C>T
NM_001030003.2:c.931C>T
NM_001030004.2:c.931C>T
NM_001258355.1:c.976C>T
NM_001287182.1:c.922C>T
NM_001287183.1:c.922C>T
NM_001287184.1:c.922C>T
NM_175914.4:c.931C>T
NM_178849.2:c.997C>T
NM_178850.2:c.997C>T
NM_001030003.3:c.931C>T
NM_001030004.3:c.931C>T
NM_001258355.2:c.976C>T
NM_001287182.2:c.922C>T
NM_001287184.2:c.922C>T
NM_178849.3:c.997C>T
NM_178850.3:c.997C>T
NM_000457.5:c.997C>T
NM_000457.6:c.997C>T
NM_001287183.2:c.922C>T

Pathogenic

Met criteria codes 6
PS4 PM2_Supporting PP3 PP4_Moderate PS2_Moderate PM1_Supporting

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 2.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Monogenic Diabetes VCEP
The c.931C>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to cysteine at codon 311 (p.(Arg311Cys)) of NM_175914.5. 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 is predicted to be deleterious by computational evidence, with a REVEL score of 0.976, 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 13 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDS: 29417725, 28862987, 36257325, 35089870, internal lab contributors). This variant was identified in 2 individuals with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative antibodies) (PP4_Moderate; PMID: 28862987, internal lab contributors). One of these 2 cases was a a de novo occurrence with unconfirmed parental relationships (PS2_Moderate; PMID: 28862987). In summary, c.931C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0 approved 10/11/2023): PS4, PP4_Moderate, PS2_Moderate, PP3, PM1_Supporting, PM2_Supporting.
Met criteria codes
PS4
This variant was identified in at least 13 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDS: 29417725, 28862987, 36257325, 35089870, internal lab contributors).
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 0.976, which is greater than the MDEP VCEP threshold of 0.70 (PP3).
PP4_Moderate
This variant was identified in 2 individuals with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative antibodies) (PP4_Moderate; PMID: 28862987, internal lab contributors).
PS2_Moderate
This variant was identified as a de novo occurrence with unconfirmed parental relationships in an individual(s) with a clinical picture highly specific for HNF4A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF1A) (PS2_Moderate; PMID: 28862987).
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).
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