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.1321A>G (p.Ile441Val)

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA213913

36345 (ClinVar)

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: a2587a88-8193-4949-94fa-a8203f614da4

Approved on: 2023-05-27

Published on: 2023-05-27

HGVS expressions

NM_175914.5:c.1321A>G

NM_175914.5(HNF4A):c.1321A>G (p.Ile441Val)

NC_000020.11:g.44429627A>G

CM000682.2:g.44429627A>G

NC_000020.10:g.43058267A>G

CM000682.1:g.43058267A>G

NC_000020.9:g.42491681A>G

NG_009818.1:g.78827A>G

ENST00000316099.10:c.1387A>G

ENST00000316099.9:c.1387A>G

ENST00000316099.8:c.1387A>G

ENST00000316673.8:c.1321A>G

ENST00000372920.1:c.*1154A>G

ENST00000415691.2:c.1357A>G

ENST00000457232.5:c.1291A>G

ENST00000619550.4:c.1312A>G

NM_000457.4:c.1387A>G

NM_001030003.2:c.1291A>G

NM_001258355.1:c.1366A>G

NM_001287182.1:c.1282A>G

NM_001287183.1:c.1312A>G

NM_175914.4:c.1321A>G

NM_178849.2:c.1357A>G

NM_001030003.3:c.1291A>G

NM_001258355.2:c.1366A>G

NM_001287182.2:c.1282A>G

NM_178849.3:c.1357A>G

NM_000457.5:c.1387A>G

NM_000457.6:c.1387A>G

NM_001287183.2:c.1312A>G

Benign

PP4_Moderate BA1 BS3_Supporting BS4 BP5

PS4 PM1 PP3 BP4

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.1321A>G p.(Ile441Val) variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0005025, which is greater than the MDEP threshold for BA1 (BA1). 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 GAD negative) (PP4_Moderate, internal contributors). There is evidence in vitro that this variant has identical transactivation activity to wildtype, indicating that this variant does not impact protein function (BS3_Supporting, PMID: 30191603). This variant does not segregate with diabetes in three families (BS4; internal lab contributors, PMIDs: 25905084, 10227563, 33324081). This variant was identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributors). In summary, c.1321A>G p.(Ile441Val) meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0.0, approved 11/16/2022): BA1, PP4_Moderate, BS3_Supporting, BS4, BP5.

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 GAD negative) (PP4_Moderate, internal contributors).

BA1

Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0005025, which is greater than the MDEP threshold for BA1 (BA1).

BS3_Supporting

There is evidence in vitro that this variant has identical transactivation activity to wildtype, indicating that this variant does not impact protein function (BS3_Supporting, PMID: 30191603).

BS4

This variant does not segregate with diabetes in three families (BS4; internal lab contributors, PMIDs: 25905084, 10227563, 33324081).

BP5

This variant was identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributors).

PS4

Cannot be applied because PM2_Supporting is not met.

PM1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP3

REVEL = 0.354

BP4

REVEL = 0.354

Curation History

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