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:c.278G>C

CA409104280

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 0941223d-5840-418a-9380-0202df7633ef

HGVS expressions

NM_175914.5:c.278G>C

NC_000020.11:g.44407434G>C

CM000682.2:g.44407434G>C

NC_000020.10:g.43036074G>C

CM000682.1:g.43036074G>C

NC_000020.9:g.42469488G>C

NG_009818.1:g.56634G>C

ENST00000316673.9:c.278G>C

ENST00000316099.10:c.344G>C

ENST00000619550.5:c.318G>C

ENST00000681977.1:c.320G>C

ENST00000682169.1:c.297G>C

ENST00000683148.1:n.320G>C

ENST00000683657.1:n.1468G>C

ENST00000684046.1:c.320G>C

ENST00000684136.1:c.330G>C

ENST00000684476.1:c.301G>C

ENST00000316099.9:c.344G>C

ENST00000316099.8:c.344G>C

ENST00000316673.8:c.278G>C

ENST00000372920.1:c.*111G>C

ENST00000415691.2:c.344G>C

ENST00000443598.6:c.344G>C

ENST00000457232.5:c.278G>C

ENST00000609262.5:c.269G>C

ENST00000609795.5:c.278G>C

ENST00000619550.4:c.269G>C

NM_000457.4:c.344G>C

NM_001030003.2:c.278G>C

NM_001030004.2:c.278G>C

NM_001258355.1:c.323G>C

NM_001287182.1:c.269G>C

NM_001287183.1:c.269G>C

NM_001287184.1:c.269G>C

NM_175914.4:c.278G>C

NM_178849.2:c.344G>C

NM_178850.2:c.344G>C

NM_001030003.3:c.278G>C

NM_001030004.3:c.278G>C

NM_001258355.2:c.323G>C

NM_001287182.2:c.269G>C

NM_001287184.2:c.269G>C

NM_178849.3:c.344G>C

NM_178850.3:c.344G>C

NM_000457.5:c.344G>C

NM_000457.6:c.344G>C

NM_001287183.2:c.269G>C

Pathogenic

PS2 PM2_Supporting PP4_Moderate PP3 PM1

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.278G>C variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of cysteine to serine at codon 93 (p.(Cys93Ser)) of NM_175914.5. This variant is absent in gnomAD v2.1.1 (PM2_Supporting). It was identified in an individual with a clinical history highly specific for HNF4A-MODY neonatal hypoglycemia that is responsive to diazoxide, negative genetic testing for ABCC8 and KCNJ11, and history of macrosomia in the absence of sufficient maternal hyperglycemia)(PP4_Moderate; PMID: 20164212). This variant was identified as a de novo occurrence with confirmed parental relationships in this individual (PS2; PMID: 20164212). This variant resides in an amino acid within the HNF4A DNA binding domain that directly binds DNA and is necessary for zinc finger formation 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 0.986, which is greater than the MDEP VCEP threshold of 0.70 (PP3). In summary, c.278G>C 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 10/11/23): PS2, PP4_Moderate, PM1, PP3, PM2_Supporting.

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 (neonatal hypoglycemia that is responsive to diazoxide, hyperinsulinemic hypoglycemia, and negative genetic testing for ABCC8 and KCNJ11)(PS2; PMID: 20164212).

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-MODY neonatal hypoglycemia that is responsive to diazoxide, negative genetic testing for ABCC8 and KCNJ11, and history of macrosomia in the absence of sufficient maternal hyperglycemia)(PP4_Moderate; internal lab contributor).

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).

PM1

This variant resides in an amino acid within the HNF4A DNA binding domain that directly binds DNA and is necessary for zinc finger formation which is defined as critical for the protein’s function by the ClinGen MDEP (PM1).

Approved on: 2024-04-06

Published on: 2024-04-06

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