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.7A>C (p.Ser3Arg)

Curation Version - 1.0
Curation History
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CA9870022

1761584 (ClinVar)

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 85a934a7-92e0-4a4e-a130-11fd757256d7

Approved on: 2025-01-03

Published on: 2025-01-03

HGVS expressions

NM_175914.5:c.7A>C

NM_175914.5(HNF4A):c.7A>C (p.Ser3Arg)

NC_000020.11:g.44355811A>C

CM000682.2:g.44355811A>C

NC_000020.10:g.42984451A>C

CM000682.1:g.42984451A>C

NC_000020.9:g.42417865A>C

NG_009818.1:g.5011A>C

ENST00000316673.9:c.7A>C

ENST00000316673.8:c.7A>C

ENST00000457232.5:c.7A>C

ENST00000609262.5:c.-225A>C

ENST00000609795.5:c.7A>C

ENST00000619550.4:c.-225A>C

NM_001030003.2:c.7A>C

NM_001030004.2:c.7A>C

NM_001287182.1:c.-225A>C

NM_001287183.1:c.-225A>C

NM_001287184.1:c.-225A>C

NM_175914.4:c.7A>C

NM_001030003.3:c.7A>C

NM_001030004.3:c.7A>C

NM_001287182.2:c.-225A>C

NM_001287184.2:c.-225A>C

NM_001287183.2:c.-225A>C

Uncertain Significance

BP5

PS4 PP3 PM2 BA1 BS1 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 HNF1A Version 2.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.7A>C variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of serine to arginine at codon 3 (p.(Ser3Arg)) of NM_175914.5. This variant has a REVEL score of 0.256, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function. While c.7A>C has a GrpMax filtering allele frequency of less than 0.000003 in the European non-Finnish population in gnomAD v2.1.1, but it has 11 copies in the Ashkenazi Jewish subpopulation; therefore, this variant does not meet the ClinGen MDEP-established cutoff for PM2_Supporting. This variant was identified in 3 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). One of these individuals had an alternate molecular basis for disease (BP5; internal lab contributors). In summary, c.7A>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): BP5.

BP5

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

PS4

This variant was identified in 3 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors).

PP3

This variant has a REVEL score of 0.256, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function.

PM2

While c.7A>C has a GrpMax filtering allele frequency of < 0.000003 the European non-Finnish population in gnomAD v2.1.1, it has 11 copies in the Ashkenazi Jewish subpopulation; therefore, this variant does not meet the ClinGen MDEP-established cutoff for PM2_Supporting.

BA1

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

BS1

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

BP4

This variant has a REVEL score of 0.256, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on HNF4A function.

Curation History

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