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]
Link to SEPIO compliant JSON-LD document
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!

Variant: NM_175914.5(HNF4A):c.334C>T (p.Arg112Trp)

CA9870226

995121 (ClinVar)

Gene: HNF4A
Condition: monogenic diabetes
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 4cf5740f-27ec-496d-ae49-2dfa3e110ba0

HGVS expressions

NM_175914.5:c.334C>T
NM_175914.5(HNF4A):c.334C>T (p.Arg112Trp)
NC_000020.11:g.44413708C>T
CM000682.2:g.44413708C>T
NC_000020.10:g.43042348C>T
CM000682.1:g.43042348C>T
NC_000020.9:g.42475762C>T
NG_009818.1:g.62908C>T
ENST00000316673.9:c.334C>T
ENST00000316099.10:c.400C>T
ENST00000619550.5:c.374C>T
ENST00000683148.1:n.376C>T
ENST00000683657.1:n.1524C>T
ENST00000316099.9:c.400C>T
ENST00000316099.8:c.400C>T
ENST00000316673.8:c.334C>T
ENST00000372920.1:c.*167C>T
ENST00000415691.2:c.400C>T
ENST00000443598.6:c.400C>T
ENST00000457232.5:c.334C>T
ENST00000609795.5:c.334C>T
ENST00000619550.4:c.325C>T
NM_000457.4:c.400C>T
NM_001030003.2:c.334C>T
NM_001030004.2:c.334C>T
NM_001258355.1:c.379C>T
NM_001287182.1:c.325C>T
NM_001287183.1:c.325C>T
NM_001287184.1:c.325C>T
NM_175914.4:c.334C>T
NM_178849.2:c.400C>T
NM_178850.2:c.400C>T
NM_001030003.3:c.334C>T
NM_001030004.3:c.334C>T
NM_001258355.2:c.379C>T
NM_001287182.2:c.325C>T
NM_001287184.2:c.325C>T
NM_178849.3:c.400C>T
NM_178850.3:c.400C>T
NM_000457.5:c.400C>T
NM_000457.6:c.400C>T
NM_001287183.2:c.325C>T

Pathogenic

Met criteria codes 7
PS4 PP3 PM1 PM5 PM2_Supporting PP4_Moderate PP1_Strong

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.334C>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to tryptophan at codon 112 (p.Arg112Trp)) of NM_175914.5. This variant has an incomputable gnomAD v2.1.1 Popmax filtering allele frequency due to zero copies in the European non-Finnish subpopulation and one copy in the Latino subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). It was identified in 8 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:29207974, 12627330, internal lab contributors). At least two of these individuals have a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and responsive to low-dose sulfonylureas) (PP4_Moderate; internal lab contributor). Additionally, this variant segregated with diabetes, with 7 informative meioses in two families (PP1_Strong; PMID:12627330, internal lab contributor). This variant resides in an amino acid within the HNF4α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). It is also predicted to be deleterious by computational evidence, with a REVEL score of 0.95, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Another missense variant, c.335G>A (p.Arg112Gln) has been interpreted as pathogenic by the ClinGen MDEP, and p.Arg112Trp has a greater Grantham distance (PM5). In summary, c.334C>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 10/11/23): PP1_strong, PS4, PP4_Moderate, PM1, PM5, PP3, PM2_Supporting.
Met criteria codes
PS4
This variant was identified in 8 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:29207974, 12627330, internal lab contributors).
PP3
This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.95, which is greater than the MDEP VCEP threshold of 0.70 (PP3).
PM1
This variant resides in an amino acid within the HNF4α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1).
PM5
Another missense variant, c.335G>A (p.Arg112Gln) has been interpreted as pathogenic by the ClinGen MDEP, and p.Arg112Trp has an equal or greater Grantham distance (PM5).
PM2_Supporting
This variant has an incomputable gnomAD v2.1.1 Popmax filtering allele frequency due to zero copies in the European non-Finnish subpopulation and one copy in the Latino subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting).
PP4_Moderate
This variant was identified in at least two individuals with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and responsive to low-dose sulfonylureas) (PP4_Moderate; internal lab contributor).
PP1_Strong
This variant segregated with diabetes, with 7 informative meioses in two families (PP1_Strong; PMID:12627330, internal lab contributor).
Approved on: 2024-04-06
Published on: 2024-04-06
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.