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.582+1G>A

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA409106287

617652 (ClinVar)

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 11353c32-bba9-49ae-940f-86c0cb484fdd

Approved on: 2023-09-15

Published on: 2023-09-15

HGVS expressions

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

NM_175914.5(HNF4A):c.582+1G>A

NC_000020.11:g.44414663G>A

CM000682.2:g.44414663G>A

NC_000020.10:g.43043303G>A

CM000682.1:g.43043303G>A

NC_000020.9:g.42476717G>A

NG_009818.1:g.63863G>A

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

ENST00000619550.5:c.622+1G>A

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Likely Pathogenic

PVS1_Strong PP1 PP4_Moderate 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>A variant in the hepatocyte nuclear factor-4 alpha gene, HNF4A, is predicted to remove a canonical splice donor site in intron 5 of NM_175914.5. This variant is predicted to cause an in-frame deletion of biologically relevant exon 5 of 10, removing more than 10% of the protein (PVS1_Strong). This variant failed QC in gnomAD v2.1.1 , is found in only one individual in BRAVO and absent from the Geisinger and UK Biobanks (PM2_Supporting). This variant was identified in at least 2 individuals with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, history of large for gestational age, and family history of persistent neonatal hypoglycemia) (PP4_Moderate; PMID: 17407387, internal lab contributors). This variant segregated with diabetes, with 3 informative meioses in this family with MODY (PP1; PMID: 17407387). In summary, c.582+1G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.1.0, approved 8/11/2023): PVS1_strong, PM2_supporting, PP4_moderate, PP1.

PVS1_Strong

This variant is predicted to cause an in-frame deletion of biologically relevant exon 5 of 10, removing more than 10% of the protein (PVS1_Strong).

PP1

This variant segregated with diabetes, with 3 informative meioses in this family with MODY (PP1; PMID: 17407387).

PP4_Moderate

This variant was identified in at least 2 individuals with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A, history of large for gestational age, and family history of persistent neonatal hypoglycemia) (PP4_Moderate; PMID: 17407387, internal lab contributors).

PM2_Supporting

This variant failed QC in gnomAD v2.1.1 , is found in only one individual in BRAVO and absent from the Geisinger and UK Biobanks (PM2_Supporting).

Curation History

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