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]
  • 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.187C>T (p.Arg63Trp)

CA170773

156152 (ClinVar)

Gene: HNF4A
Condition: monogenic diabetes
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 35127f40-c453-4957-ab23-eb682d17599f
Approved on: 2024-04-06
Published on: 2024-04-06

HGVS expressions

NM_175914.5:c.187C>T
NM_175914.5(HNF4A):c.187C>T (p.Arg63Trp)
NC_000020.11:g.44406195C>T
CM000682.2:g.44406195C>T
NC_000020.10:g.43034835C>T
CM000682.1:g.43034835C>T
NC_000020.9:g.42468249C>T
NG_009818.1:g.55395C>T
ENST00000316673.9:c.187C>T
ENST00000316099.10:c.253C>T
ENST00000619550.5:c.227C>T
ENST00000681977.1:c.229C>T
ENST00000682169.1:c.206C>T
ENST00000683148.1:n.229C>T
ENST00000683657.1:n.229C>T
ENST00000684046.1:c.229C>T
ENST00000684136.1:c.229C>T
ENST00000684476.1:c.210C>T
ENST00000316099.9:c.253C>T
ENST00000316099.8:c.253C>T
ENST00000316673.8:c.187C>T
ENST00000372920.1:c.*20C>T
ENST00000415691.2:c.253C>T
ENST00000443598.6:c.253C>T
ENST00000457232.5:c.187C>T
ENST00000609262.5:c.178C>T
ENST00000609795.5:c.187C>T
ENST00000619550.4:c.178C>T
NM_000457.4:c.253C>T
NM_001030003.2:c.187C>T
NM_001030004.2:c.187C>T
NM_001258355.1:c.232C>T
NM_001287182.1:c.178C>T
NM_001287183.1:c.178C>T
NM_001287184.1:c.178C>T
NM_175914.4:c.187C>T
NM_178849.2:c.253C>T
NM_178850.2:c.253C>T
NM_001030003.3:c.187C>T
NM_001030004.3:c.187C>T
NM_001258355.2:c.232C>T
NM_001287182.2:c.178C>T
NM_001287184.2:c.178C>T
NM_178849.3:c.253C>T
NM_178850.3:c.253C>T
NM_000457.5:c.253C>T
NM_000457.6:c.253C>T
NM_001287183.2:c.178C>T
More

Pathogenic

Met criteria codes 8
PS4 PP3 PM1 PM5 PM2_Supporting PP1_Strong PS2_Very Strong PP4_Moderate

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.187C>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to tryptophan at codon 63 (p.(Arg63Trp) of NM_175914.5. This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in 21 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 24285859, 25819479, 28693455, internal lab contributors). This variant segregated with diabetes, with at least 7 meioses in 4 families (PP1_Strong, PMID: 24285859, 28693455, internal lab contributors). At least 6 individuals have a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and Fanconi phenotype) (PP4_Moderate; internal lab contributors). Additionally, this variant was identified as a de novo occurrence with both confirmed and unconfirmed parental relationships in 5 individual(s) with a clinical picture consistent with HNF4A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF1A) (PS2_Very Strong; internal lab contributor, PMID: 24285859, 25819479). 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 0.949, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Lastly, another missense variant, c.188G>A (p.Arg63Gln), has been interpreted as pathogenic by the ClinGen MDEP, and p.Arg63Trp has a greater Grantham distance (PM5). In summary, c.187C>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): PS2_Very strong, PP1_Strong, PS4, PP4_Moderate, PM1, PP3, PM2_Supporting, PM5_Supporting.
Met criteria codes
PS4
This variant was identified in 21 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 24285859, 25819479, 28693455, internal lab contributors).
PP3
This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.949, 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.188G>A (p.Arg63Gln), has been interpreted as pathogenic by the ClinGen MDEP, and p.Arg63Trp has an equal or greater Grantham distance (PM5).
PM2_Supporting
This variant is absent in gnomAD v2.1.1 (PM2_Supporting).
PP1_Strong
This variant segregated with diabetes, with at least 7 meioses in 4 families (PP1_Strong, PMID: 24285859, 28693455, internal lab contributors).
PS2_Very Strong
This variant was identified as a de novo occurrence with both confirmed and unconfirmed parental relationships in 5 individual(s) with a clinical picture consistent with HNF4A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF1A) (PS2_Very Strong; internal lab contributor, PMID: 24285859, 25819479).
PP4_Moderate
This variant was identified in at least 6 individuals with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and Fanconi phenotype) (PP4_Moderate; internal lab contributors).
Curation History
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