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 computed assertion could be determined for this classification!

Variant: NM_175914.5(HNF4A):c.232C>T (p.Arg78Trp)

CA409104106

447515 (ClinVar)

Gene: HNF4A
Condition: monogenic diabetes
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: f7720b28-0ee7-4086-a4d7-6b8ae0f9cc5a
Approved on: 2025-08-12
Published on: 2025-08-29

HGVS expressions

NM_175914.5:c.232C>T
NM_175914.5(HNF4A):c.232C>T (p.Arg78Trp)
NC_000020.11:g.44407388C>T
CM000682.2:g.44407388C>T
NC_000020.10:g.43036028C>T
CM000682.1:g.43036028C>T
NC_000020.9:g.42469442C>T
NG_009818.1:g.56588C>T
ENST00000316673.9:c.232C>T
ENST00000316099.10:c.298C>T
ENST00000619550.5:c.272C>T
ENST00000681977.1:c.274C>T
ENST00000682169.1:c.251C>T
ENST00000683148.1:n.274C>T
ENST00000683657.1:n.1422C>T
ENST00000684046.1:c.274C>T
ENST00000684136.1:c.284C>T
ENST00000684476.1:c.255C>T
ENST00000316099.9:c.298C>T
ENST00000316099.8:c.298C>T
ENST00000316673.8:c.232C>T
ENST00000372920.1:c.*65C>T
ENST00000415691.2:c.298C>T
ENST00000443598.6:c.298C>T
ENST00000457232.5:c.232C>T
ENST00000609262.5:c.223C>T
ENST00000609795.5:c.232C>T
ENST00000619550.4:c.223C>T
NM_000457.4:c.298C>T
NM_001030003.2:c.232C>T
NM_001030004.2:c.232C>T
NM_001258355.1:c.277C>T
NM_001287182.1:c.223C>T
NM_001287183.1:c.223C>T
NM_001287184.1:c.223C>T
NM_175914.4:c.232C>T
NM_178849.2:c.298C>T
NM_178850.2:c.298C>T
NM_001030003.3:c.232C>T
NM_001030004.3:c.232C>T
NM_001258355.2:c.277C>T
NM_001287182.2:c.223C>T
NM_001287184.2:c.223C>T
NM_178849.3:c.298C>T
NM_178850.3:c.298C>T
NM_000457.5:c.298C>T
NM_000457.6:c.298C>T
NM_001287183.2:c.223C>T
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Uncertain Significance

Met criteria codes 2
PP3 PM1_Supporting
Not Met criteria codes 4
BS1 PS4 PP4 PM2

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 3.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Monogenic Diabetes VCEP
The c.232C>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to tryptophan at codon 78 (p.Arg78Trp) of NM_175914.5. This variant has a Grpmax filtering allele frequency of 0.0000069 in gnomAD v4.1.0, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant was identified in 2 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because the number of cases is less the MDEP threshold for PS4_Moderate and the variant does not meet PM2_Supporting (PMID: 21105941, internal lab contributors). This variant is located within the DNA binding domain (codons 37-113) 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 0.832, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information and age of diagnosis over 35 (internal lab contributors). In summary, c.232C>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM1_Supporting, PP3.
Met criteria codes
PP3
This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.832, which is greater than the MDEP VCEP threshold of 0.70 (PP3).
PM1_Supporting
This variant is located within the DNA binding domain (codons 37-113) which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).
Not Met criteria codes
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
This variant was identified in 2 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because the number of cases is less the MDEP threshold of 4 cases for PS4_Moderate.
PP4
This variant was identified in an individual with diabetes; however, the MODY probability is unable to be calculated due to lack of clinical information and age of diagnosis over 35 (internal lab contributors).
PM2
This variant has a Grpmax filtering allele frequency of 0.0000069 in gnomAD v4.1.0, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied.
Curation History
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