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_000545.8(HNF1A):c.557T>C (p.Ile186Thr)

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA160013

134509 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 0f175643-63fc-4154-87fd-815b6a404dff

Approved on: 2025-06-18

Published on: 2025-06-18

HGVS expressions

NM_000545.8:c.557T>C

NM_000545.8(HNF1A):c.557T>C (p.Ile186Thr)

NC_000012.12:g.120993550T>C

CM000674.2:g.120993550T>C

NC_000012.11:g.121431353T>C

CM000674.1:g.121431353T>C

NC_000012.10:g.119915736T>C

NG_011731.2:g.19805T>C

ENST00000560968.6:c.557T>C

ENST00000257555.11:c.557T>C

ENST00000257555.10:c.557T>C

ENST00000400024.6:c.557T>C

ENST00000402929.5:n.692T>C

ENST00000535955.5:n.43-3941T>C

ENST00000538626.2:n.191-3941T>C

ENST00000538646.5:c.527-614T>C

ENST00000540108.1:c.357T>C

ENST00000541395.5:c.557T>C

ENST00000541924.5:c.557T>C

ENST00000543427.5:c.557T>C

ENST00000544413.2:c.557T>C

ENST00000544574.5:c.73-3067T>C

ENST00000560968.5:c.700T>C

ENST00000615446.4:c.-257-2712T>C

ENST00000617366.4:c.557T>C

NM_000545.5:c.557T>C

NM_000545.6:c.557T>C

NM_001306179.1:c.557T>C

NM_001306179.2:c.557T>C

Uncertain Significance

PP4_Moderate

BP4 PP3 PM2 PM1 BS1

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.557T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of isoleucine to threonine at codon 186 (p.(Ile186Thr)) of transcript NM_000545.8. This variant was identified in an individual with a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and antibody negative) (PP4_Moderate; [internal lab contributors]). This variant is located in the HNF1A DNA binding domain, but outside of the region defined as critical for the protein’s function by the ClinGen MDEP (codons 107-174 and 201-280); therefore, PM1_Supporting is not met. The gnomAD PopMax filtering allele frequency of the c.557T<C variant in gnomAD v2.1.1 is 0.00002294, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant has a REVEL score of 0.326, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on HNF1A function. In summary, c.557T>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 VCEP (specification version 2.1.0, approved 8/11/23): PP4_Moderate.

PP4_Moderate

This variant was identified in an individual with a MODY Probability Calculator score of 62.4% with negative genetic testing for HNF4A and negative for diabetes autoantibodies.

BP4

This variant has a REVEL score of 0.326, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on HNF1A function.

PP3

This variant has a REVEL score of 0.326, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on HNF1A function.

PM2

The gnomAD PopMax filtering allele frequency of the c.557T<C variant in gnomAD v2.1.1 is 0.00002294, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied.

PM1

This variant is located the HNF1A DNA binding domain, but outside of the region defined as critical for the protein’s function by the ClinGen MDEP (codons 107-174 and 201-280).

BS1

Curation History

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