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.1267C>T (p.Pro423Ser)

CA231163

129237 (ClinVar)

Gene: HNF4A
Condition: monogenic diabetes
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 7a01c79c-6276-4cff-bc47-1cd33751c6a9
Approved on: 2024-12-12
Published on: 2024-12-12

HGVS expressions

NM_175914.5:c.1267C>T
NM_175914.5(HNF4A):c.1267C>T (p.Pro423Ser)
NC_000020.11:g.44429573C>T
CM000682.2:g.44429573C>T
NC_000020.10:g.43058213C>T
CM000682.1:g.43058213C>T
NC_000020.9:g.42491627C>T
NG_009818.1:g.78773C>T
ENST00000316673.9:c.1267C>T
ENST00000316099.10:c.1333C>T
ENST00000316099.9:c.1333C>T
ENST00000316099.8:c.1333C>T
ENST00000316673.8:c.1267C>T
ENST00000372920.1:c.*1100C>T
ENST00000415691.2:c.1303C>T
ENST00000457232.5:c.1237C>T
ENST00000619550.4:c.1258C>T
NM_000457.4:c.1333C>T
NM_001030003.2:c.1237C>T
NM_001258355.1:c.1312C>T
NM_001287182.1:c.1228C>T
NM_001287183.1:c.1258C>T
NM_175914.4:c.1267C>T
NM_178849.2:c.1303C>T
NM_001030003.3:c.1237C>T
NM_001258355.2:c.1312C>T
NM_001287182.2:c.1228C>T
NM_178849.3:c.1303C>T
NM_000457.5:c.1333C>T
NM_000457.6:c.1333C>T
NM_001287183.2:c.1258C>T
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Uncertain Significance

Met criteria codes 1
BP4
Not Met criteria codes 4
PS3 PP4 PM2 BS3

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.1267C>T variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of proline to serine at codon 423 (p.(Pro423Ser)) of NM_175914.5. This variant has a gnomAD v2.1.1 Grpmax filtering allele frequency of 0.000002920 (below the MDEP threshold of 0.000003), however, it has > 2 copies observed in the European non-Finnish population and other subpopulations; therefore, this variant does not meet the ClinGen MDEP-established cutoff for PM2_Supporting. This variant is predicted to be benign by computational evidence, with a REVEL score of 0.059, which is less than or equal to the MDEP threshold of 0.15 (BP4). While studies exploring the effect of this variant on protein function have been performed, these studies do not meet the criteria set forth by the MDEP for the application of PS3 or BS3 (PMID: 22308320). This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50% (PMID: 15111529 ). In summary, c.1267C>T meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 2.0.0, approved 10/11/2023): BP4.
Met criteria codes
BP4
This variant is predicted to be benign by computational evidence, with a REVEL score of 0.059, which is less than or equal to the MDEP threshold of 0.15 (BP4).
Not Met criteria codes
PS3
While studies exploring the effect of this variant on protein function have been performed, these studies do not meet the criteria set forth by the MDEP for the application of PS3 or BS3 (PMID: 22308320).
PP4
This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50% (PMID: 15111529 ).
PM2
This variant has a gnomAD v2.1.1 Grpmax filtering allele frequency of 0.000002920 (below the MDEP threshold of 0.000003), however, it has > 2 copies observed in the European non-Finnish population and other subpopulations; therefore, this variant does not meet the ClinGen MDEP-established cutoff for PM2_Supporting. gnomAD v4.1.0 Grpmax minor filtering allele frequency=0.00002743
BS3
While studies exploring the effect of this variant on protein function have been performed, these studies do not meet the criteria set forth by the MDEP for the application of PS3 or BS3 (PMID: 22308320).
Curation History
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