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.1138G>A (p.Val380Ile)

Curation Version - 1.0
Curation History
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CA120217

9213 (ClinVar)

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 61553ca5-c6ef-4c35-a09d-d289ce55f55b

Approved on: 2024-12-20

Published on: 2024-12-20

HGVS expressions

NM_175914.5:c.1138G>A

NM_175914.5(HNF4A):c.1138G>A (p.Val380Ile)

NC_000020.11:g.44428409G>A

CM000682.2:g.44428409G>A

NC_000020.10:g.43057049G>A

CM000682.1:g.43057049G>A

NC_000020.9:g.42490463G>A

NG_009818.1:g.77609G>A

ENST00000316673.9:c.1138G>A

ENST00000316099.10:c.1204G>A

ENST00000316099.9:c.1204G>A

ENST00000316099.8:c.1204G>A

ENST00000316673.8:c.1138G>A

ENST00000372920.1:c.*971G>A

ENST00000415691.2:c.1204G>A

ENST00000457232.5:c.1138G>A

ENST00000619550.4:c.1129G>A

NM_000457.4:c.1204G>A

NM_001030003.2:c.1138G>A

NM_001258355.1:c.1183G>A

NM_001287182.1:c.1129G>A

NM_001287183.1:c.1129G>A

NM_175914.4:c.1138G>A

NM_178849.2:c.1204G>A

NM_001030003.3:c.1138G>A

NM_001258355.2:c.1183G>A

NM_001287182.2:c.1129G>A

NM_178849.3:c.1204G>A

NM_000457.5:c.1204G>A

NM_000457.6:c.1204G>A

NM_001287183.2:c.1129G>A

Uncertain Significance

PM2_Supporting PS4_Moderate PP4 BS3_Supporting

BP4 PP1 PP3 PM5

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 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1138G>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of valine to isoleucine at codon 380 (p.(Val380Ile)) of NM_175914.5. This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to 2 copies in the European non-Finnish subpopulation and 0 copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF GrpmaxPopmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in 4 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 9449683, 23227446, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50% and, negative genetic testing for HNF1A) (PP4; internal lab contributors). This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, 9449683). This variant has a REVEL score of 0.344, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. Functional studies demonstrated the p.Val380Ile protein has abnormal nuclear localization/transactivation above 75% of wildtype, indicating that this variant does not impact protein function (PMID: 30191603) (BS3_Supporting). Another missense variant, [1139T>G p.(Val380Gly)] has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.1138G>A meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PS4_moderate, PP4, PM2_supporting, BS3_supporting.

PM2_Supporting

This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to 2 copies in the European non-Finnish subpopulation and 0 copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF GrpmaxPopmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). gnomAD v2.1.0: ENF GrpmaxPopmax FAF = 0.000001940

PS4_Moderate

This variant was identified in 4 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 9449683, 23227446, internal lab contributors).

PP4

This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50% and, negative genetic testing for HNF1A) (PP4; internal lab contributors).

BS3_Supporting

Functional studies demonstrated the p.Val380Ile protein has abnormal nuclear localization/transactivation above 75% of wildtype, indicating that this variant does not impact protein function (PMID: 30191603) (BS3_Supporting)

BP4

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

PP1

This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, 9449683).

PP3

This variant has a REVEL score of 0.344, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function

PM5

Another missense variant, [1139T>G p.(Val380Gly)] has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied.

Curation History

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