Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_175914.5(HNF4A):c.692G>A (p.Arg231Gln)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA409107360

447520 (ClinVar)

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: a47e05a4-6c6b-401c-a56c-913556dba9cd

Approved on: 2024-05-10

Published on: 2024-05-10

HGVS expressions

NM_175914.5:c.692G>A

NM_175914.5(HNF4A):c.692G>A (p.Arg231Gln)

NC_000020.11:g.44419742G>A

CM000682.2:g.44419742G>A

NC_000020.10:g.43048382G>A

CM000682.1:g.43048382G>A

NC_000020.9:g.42481796G>A

NG_009818.1:g.68942G>A

ENST00000316673.9:c.692G>A

ENST00000316099.10:c.758G>A

ENST00000619550.5:c.732G>A

ENST00000683148.1:n.734G>A

ENST00000683657.1:n.1882G>A

ENST00000316099.9:c.758G>A

ENST00000316099.8:c.758G>A

ENST00000316673.8:c.692G>A

ENST00000372920.1:c.*525G>A

ENST00000415691.2:c.758G>A

ENST00000443598.6:c.758G>A

ENST00000457232.5:c.692G>A

ENST00000609795.5:c.692G>A

ENST00000619550.4:c.683G>A

NM_000457.4:c.758G>A

NM_001030003.2:c.692G>A

NM_001030004.2:c.692G>A

NM_001258355.1:c.737G>A

NM_001287182.1:c.683G>A

NM_001287183.1:c.683G>A

NM_001287184.1:c.683G>A

NM_175914.4:c.692G>A

NM_178849.2:c.758G>A

NM_178850.2:c.758G>A

NM_001030003.3:c.692G>A

NM_001030004.3:c.692G>A

NM_001258355.2:c.737G>A

NM_001287182.2:c.683G>A

NM_001287184.2:c.683G>A

NM_178849.3:c.758G>A

NM_178850.3:c.758G>A

NM_000457.5:c.758G>A

NM_000457.6:c.758G>A

NM_001287183.2:c.683G>A

Pathogenic

PP1_Strong PM2_Supporting PP4_Moderate PS4 PP3

Evidence Links 0

Expert Panel

Monogenic Diabetes VCEP

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.692G>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of arginine to glutamine at codon 231 (p.(Arg231Gln)) of NM_175914.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.896, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in 10 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:12413008, PMID:12627330, internal lab contributors). This variant segregated with diabetes, with at least four informative meioses in two families (PP1_Strong; PMID:12413008, internal lab contributor). One individual has a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, negative autoantibodies, and response to low-dose sulfonylureas) (PP4_Moderate; internal lab contributor). In summary, c.692G>A 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): PP1_Strong, PS4, PP4_Moderate, PP3, PM2_Supporting.

PP1_Strong

This variant segregated with diabetes, with at least four informative meioses in two families (PP1_Strong; PMID:12413008, internal lab contributor).

PM2_Supporting

This variant is absent in gnomAD v2.1.1 (PM2_Supporting).

PP4_Moderate

This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, negative autoantibodies, and response to low-dose sulfonylureas) (PP4_Moderate; internal lab contributor).

PS4

This variant was identified in 10 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:12413008, PMID:12627330, internal lab contributors).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.896, which is greater than the MDEP VCEP threshold of 0.70 (PP3).

Curation History

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