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.188G>A (p.Arg63Gln)

CA16043128

372382 (ClinVar)

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: b3f02629-63c0-4004-ae89-406467301f00

HGVS expressions

NM_175914.5:c.188G>A

NM_175914.5(HNF4A):c.188G>A (p.Arg63Gln)

NC_000020.11:g.44406196G>A

CM000682.2:g.44406196G>A

NC_000020.10:g.43034836G>A

CM000682.1:g.43034836G>A

NC_000020.9:g.42468250G>A

NG_009818.1:g.55396G>A

ENST00000316673.9:c.188G>A

ENST00000316099.10:c.254G>A

ENST00000619550.5:c.228G>A

ENST00000681977.1:c.230G>A

ENST00000682169.1:c.207G>A

ENST00000683148.1:n.230G>A

ENST00000683657.1:n.230G>A

ENST00000684046.1:c.230G>A

ENST00000684136.1:c.230G>A

ENST00000684476.1:c.211G>A

ENST00000316099.9:c.254G>A

ENST00000316099.8:c.254G>A

ENST00000316673.8:c.188G>A

ENST00000372920.1:c.*21G>A

ENST00000415691.2:c.254G>A

ENST00000443598.6:c.254G>A

ENST00000457232.5:c.188G>A

ENST00000609262.5:c.179G>A

ENST00000609795.5:c.188G>A

ENST00000619550.4:c.179G>A

NM_000457.4:c.254G>A

NM_001030003.2:c.188G>A

NM_001030004.2:c.188G>A

NM_001258355.1:c.233G>A

NM_001287182.1:c.179G>A

NM_001287183.1:c.179G>A

NM_001287184.1:c.179G>A

NM_175914.4:c.188G>A

NM_178849.2:c.254G>A

NM_178850.2:c.254G>A

NM_001030003.3:c.188G>A

NM_001030004.3:c.188G>A

NM_001258355.2:c.233G>A

NM_001287182.2:c.179G>A

NM_001287184.2:c.179G>A

NM_178849.3:c.254G>A

NM_178850.3:c.254G>A

NM_000457.5:c.254G>A

NM_000457.6:c.254G>A

NM_001287183.2:c.179G>A

Pathogenic

PP1 PP3 PP4_Moderate PM1 PM2_Supporting PS4_Moderate PS2

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.188G>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to glutamine at codon 63 (p.(Arg63Gln)) of NM_175914.5. This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in at least 6 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). One of these individuals has a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and sulfonylurea sensitive) (PP4_Moderate; internal lab contributor). This variant segregated with diabetes, with two informative meioses in two families with MODY (PP1; internal lab contributors). It was also identified as a de novo occurrence with confirmed parental relationships in an individual with a clinical picture consistent with HNF4A-MODY (persistent neonatal hypoglycemia and negative testing for ABCC8 and KCNJ11) (PS2; internal lab contributor). Additionally, this variant resides in an amino acid within the HNF4α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). It is also predicted to be deleterious by computational evidence, with a REVEL score of 0.921, which is greater than the MDEP VCEP threshold of 0.70 (PP3). In summary, c.188G>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): PS2, PP4_Moderate, PM1, PS4_Moderate, PP1, PP3, PM2_Supporting.

PP1

This variant segregated with diabetes, with two informative meioses in two families with MODY (PP1; internal lab contributors).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.921, which is greater than the MDEP VCEP threshold of 0.70 (PP3).

PP4_Moderate

This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, and sulfonylurea sensitive) (PP4_Moderate; internal lab contributor).

PM1

This variant resides in an amino acid within the HNF4α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1).

PM2_Supporting

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

PS4_Moderate

This variant was identified in at least 6 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors).

PS2

This variant was identified as a de novo occurrence with confirmed parental relationships in an individual with a clinical picture consistent with HNF4A-MODY (persistent neonatal hypoglycemia and negative testing for ABCC8 and KCNJ11) (PS2; internal lab contributor).

Approved on: 2024-04-06

Published on: 2024-04-06

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.