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.224+2T>C

CA16607985

393110 (ClinVar)

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: cdcd3d44-96f0-470b-92a2-72bbab6c3dcb

HGVS expressions

NM_175914.5:c.224+2T>C

NM_175914.5(HNF4A):c.224+2T>C

NC_000020.11:g.44406234T>C

CM000682.2:g.44406234T>C

NC_000020.10:g.43034874T>C

CM000682.1:g.43034874T>C

NC_000020.9:g.42468288T>C

NG_009818.1:g.55434T>C

ENST00000316099.10:c.290+2T>C

ENST00000619550.5:n.264+2T>C

ENST00000681977.1:n.266+2T>C

ENST00000682169.1:n.243+2T>C

ENST00000683148.1:n.266+2T>C

ENST00000683657.1:n.268T>C

ENST00000684046.1:n.266+2T>C

ENST00000684136.1:n.266+2T>C

ENST00000684476.1:n.247+2T>C

ENST00000316099.9:c.290+2T>C

ENST00000316099.8:c.290+2T>C

ENST00000316673.8:c.224+2T>C

ENST00000372920.1:c.*57+2T>C

ENST00000415691.2:c.290+2T>C

ENST00000443598.6:c.290+2T>C

ENST00000457232.5:c.224+2T>C

ENST00000609262.5:c.215+2T>C

ENST00000609795.5:c.224+2T>C

ENST00000619550.4:c.215+2T>C

NM_000457.4:c.290+2T>C

NM_001030003.2:c.224+2T>C

NM_001030004.2:c.224+2T>C

NM_001258355.1:c.269+2T>C

NM_001287182.1:c.215+2T>C

NM_001287183.1:c.215+2T>C

NM_001287184.1:c.215+2T>C

NM_175914.4:c.224+2T>C

NM_178849.2:c.290+2T>C

NM_178850.2:c.290+2T>C

NM_001030003.3:c.224+2T>C

NM_001030004.3:c.224+2T>C

NM_001258355.2:c.269+2T>C

NM_001287182.2:c.215+2T>C

NM_001287184.2:c.215+2T>C

NM_178849.3:c.290+2T>C

NM_178850.3:c.290+2T>C

NM_000457.5:c.290+2T>C

NM_000457.6:c.290+2T>C

NM_001287183.2:c.215+2T>C

Pathogenic

PM2_Supporting PP4_Moderate PVS1

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.224+2T>C variant in the Hepatocyte Nuclear Factor 4 Alpha gene, HNF4A, is predicted to remove a canonical splice donor site in intron 2 of NM_175914.5. This variant is predicted to cause skipping of biologically-relevant exon 3 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). 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 treated with low-dose sulfonylurea) (PP4; Internal lab contributors). In summary, c.224+2T>C meets the criteria to be classified as Pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0.0, approved 11/16/2022): PVS1, PM2_Supporting, PP4_Moderate.

PM2_Supporting

This variant is absent from gnomAD v2.1.1

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 an individual treated with low-dose sulfonylurea) (PP4; Internal lab contributors).

PVS1

This variant is predicted to cause skipping of biologically-relevant exon 3 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805).

Approved on: 2023-05-27

Published on: 2023-05-27

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