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:c.582+1G>C

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA409106289

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: c5ced43c-2303-4d61-9951-12704ad58db7

Approved on: 2023-03-26

Published on: 2023-03-26

HGVS expressions

NM_175914.5:c.582+1G>C

NC_000020.11:g.44414663G>C

CM000682.2:g.44414663G>C

NC_000020.10:g.43043303G>C

CM000682.1:g.43043303G>C

NC_000020.9:g.42476717G>C

NG_009818.1:g.63863G>C

ENST00000316099.10:c.648+1G>C

ENST00000619550.5:n.622+1G>C

ENST00000683148.1:n.624+1G>C

ENST00000683657.1:n.1772+1G>C

ENST00000316099.9:c.648+1G>C

ENST00000316099.8:c.648+1G>C

ENST00000316673.8:c.582+1G>C

ENST00000372920.1:c.*415+1G>C

ENST00000415691.2:c.648+1G>C

ENST00000443598.6:c.648+1G>C

ENST00000457232.5:c.582+1G>C

ENST00000609795.5:c.582+1G>C

ENST00000619550.4:c.573+1G>C

NM_000457.4:c.648+1G>C

NM_001030003.2:c.582+1G>C

NM_001030004.2:c.582+1G>C

NM_001258355.1:c.627+1G>C

NM_001287182.1:c.573+1G>C

NM_001287183.1:c.573+1G>C

NM_001287184.1:c.573+1G>C

NM_175914.4:c.582+1G>C

NM_178849.2:c.648+1G>C

NM_178850.2:c.648+1G>C

NM_001030003.3:c.582+1G>C

NM_001030004.3:c.582+1G>C

NM_001258355.2:c.627+1G>C

NM_001287182.2:c.573+1G>C

NM_001287184.2:c.573+1G>C

NM_178849.3:c.648+1G>C

NM_178850.3:c.648+1G>C

NM_000457.5:c.648+1G>C

NM_000457.6:c.648+1G>C

NM_001287183.2:c.573+1G>C

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

PVS1_Strong PP4 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 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.582+1G>C variant in the hepatocyte nuclear factor-4 alpha gene, HNF4A, is predicted to remove a canonical splice donor site in intron 5 of transcript NM_175914.5. This variant is predicted to cause an in-frame deletion of the biologically-relevant exon 5 of 10, removing more than 10% of the protein (PVS1_Strong; PMID: 23348805). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was also identified in an individual with a clinical history suggestive of HNF4A-MODY (neonatal hypoglycemia that is responsive to diazoxide with negative genetic testing for ABCC8 and KCNJ11)(PP4; internal lab contributors). In summary, c.582+1G>C, meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0.0, approved 11/16/2022): PVS1_Strong, PM2_Supporting, PP4.

PVS1_Strong

This variant is predicted to cause an in-frame deletion of the biologically-relevant exon 5 of 10, removing more than 10% of an important region of the protein (PMID 23348805).

PP4

Identified in an individual with a clinical history suggestive of HNF4A-MODY (neonatal hypoglycemia that is responsive to diazoxide with negative genetic testing for ABCC8 and KCNJ11; internal lab contributors).

PM2_Supporting

Absent from gnomAD 2.1.1

Curation History

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