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 BS4 BP5 BS3_Supporting

PM1 BP4 PS4 PP3

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).

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).

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).

PM1

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

BP4

REVEL = 0.354

PS4

Cannot be applied because PM2_Supporting is not met.

PP3

REVEL = 0.354

Curation History

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