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]

Link to SEPIO compliant JSON-LD document

Variant: NM_175914.5(HNF4A):c.590T>C (p.Leu197Pro)

CA409106752

447518 (ClinVar)

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 0ef8dd5f-ce70-41a5-a054-2171695b8bb7

Approved on: 2023-12-25

Published on: 2023-12-25

HGVS expressions

NM_175914.5:c.590T>C

NM_175914.5(HNF4A):c.590T>C (p.Leu197Pro)

NC_000020.11:g.44418432T>C

CM000682.2:g.44418432T>C

NC_000020.10:g.43047072T>C

CM000682.1:g.43047072T>C

NC_000020.9:g.42480486T>C

NG_009818.1:g.67632T>C

ENST00000316099.10:c.656T>C

ENST00000619550.5:c.630T>C

ENST00000683148.1:n.632T>C

ENST00000683657.1:n.1780T>C

ENST00000316099.9:c.656T>C

ENST00000316099.8:c.656T>C

ENST00000316673.8:c.590T>C

ENST00000372920.1:c.*423T>C

ENST00000415691.2:c.656T>C

ENST00000443598.6:c.656T>C

ENST00000457232.5:c.590T>C

ENST00000609795.5:c.590T>C

ENST00000619550.4:c.581T>C

NM_000457.4:c.656T>C

NM_001030003.2:c.590T>C

NM_001030004.2:c.590T>C

NM_001258355.1:c.635T>C

NM_001287182.1:c.581T>C

NM_001287183.1:c.581T>C

NM_001287184.1:c.581T>C

NM_175914.4:c.590T>C

NM_178849.2:c.656T>C

NM_178850.2:c.656T>C

NM_001030003.3:c.590T>C

NM_001030004.3:c.590T>C

NM_001258355.2:c.635T>C

NM_001287182.2:c.581T>C

NM_001287184.2:c.581T>C

NM_178849.3:c.656T>C

NM_178850.3:c.656T>C

NM_000457.5:c.656T>C

NM_000457.6:c.656T>C

NM_001287183.2:c.581T>C

Uncertain Significance

PM1_Supporting PP3 PM2_Supporting

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.590T>C variant in the hepatic nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of leucine to proline at codon 197 (p.(Leu197Pro)) of NM_175914.5. This variant is located within the ligand-binding domain (codons 180-220 and 300-350) of HNF4A, 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 0.986, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.590T>C 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 2.0.0, approved 10/11/2023): PP3, PM1_Supporting, PM2_Supporting.

PM1_Supporting

This variant is located within the ligand-binding domain (codons 180-220 and 300-350) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.986, 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).

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.