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.925C>A (p.Arg309Ser)

CA409108243

586022 (ClinVar)

Gene: HNF4A
Condition: monogenic diabetes
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 44496cb6-8b2e-48e5-a86b-7744bf194280
Approved on: 2024-09-26
Published on: 2024-09-26

HGVS expressions

NM_175914.5:c.925C>A
NM_175914.5(HNF4A):c.925C>A (p.Arg309Ser)
NC_000020.11:g.44424116C>A
CM000682.2:g.44424116C>A
NC_000020.10:g.43052756C>A
CM000682.1:g.43052756C>A
NC_000020.9:g.42486170C>A
NG_009818.1:g.73316C>A
ENST00000316673.9:c.925C>A
ENST00000316099.10:c.991C>A
ENST00000619550.5:c.965C>A
ENST00000316099.9:c.991C>A
ENST00000316099.8:c.991C>A
ENST00000316673.8:c.925C>A
ENST00000372920.1:c.*758C>A
ENST00000415691.2:c.991C>A
ENST00000443598.6:c.991C>A
ENST00000457232.5:c.925C>A
ENST00000609795.5:c.925C>A
ENST00000619550.4:c.916C>A
NM_000457.4:c.991C>A
NM_001030003.2:c.925C>A
NM_001030004.2:c.925C>A
NM_001258355.1:c.970C>A
NM_001287182.1:c.916C>A
NM_001287183.1:c.916C>A
NM_001287184.1:c.916C>A
NM_175914.4:c.925C>A
NM_178849.2:c.991C>A
NM_178850.2:c.991C>A
NM_001030003.3:c.925C>A
NM_001030004.3:c.925C>A
NM_001258355.2:c.970C>A
NM_001287182.2:c.916C>A
NM_001287184.2:c.916C>A
NM_178849.3:c.991C>A
NM_178850.3:c.991C>A
NM_000457.5:c.991C>A
NM_000457.6:c.991C>A
NM_001287183.2:c.916C>A
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Uncertain Significance

Met criteria codes 4
PM5_Supporting PP3 PM2_Supporting 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.925C>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of arginine to serine at codon 309 (p.(Arg309Ser)) of NM_175914.5. 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 0.737, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is located within the ligand-binding domain (codons 300-350) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Another missense variant, c.c.925C>T, p.Arg309Cys, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg309Ser (PM5_Supporting). In summary, c.778G>T meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PM2_supporting, PP3, PM1_supporting, PM5_supporting.
Met criteria codes
PM5_Supporting
Another missense variant, c.c.925C>T, p.Arg309Cys, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg309Ser (PM5_Supporting).
PP3
This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.737, which is greater than the MDEP VCEP threshold of 0.70 (PP3).
PM2_Supporting
This variant is absent from gnomAD v2.1.1 (PM2_Supporting). gnomAD v4.1.0: 1 copy in European non-Finnish population
PM1_Supporting
This variant is located within the ligand-binding domain (codons 300-350) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).
Curation History
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