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_001306179.2:c.539C>G

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA386963548

2574164 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: db410e53-6cc4-45a1-a207-69c8992c93b5

Approved on: 2024-07-29

Published on: 2024-07-29

HGVS expressions

NM_001306179.2:c.539C>G

NC_000012.12:g.120993532C>G

CM000674.2:g.120993532C>G

NC_000012.11:g.121431335C>G

CM000674.1:g.121431335C>G

NC_000012.10:g.119915718C>G

NG_011731.2:g.19787C>G

ENST00000560968.6:c.539C>G

ENST00000257555.11:c.539C>G

ENST00000257555.10:c.539C>G

ENST00000400024.6:c.539C>G

ENST00000402929.5:n.674C>G

ENST00000535955.5:n.43-3959C>G

ENST00000538626.2:n.191-3959C>G

ENST00000538646.5:c.527-632C>G

ENST00000540108.1:c.339C>G

ENST00000541395.5:c.539C>G

ENST00000541924.5:c.539C>G

ENST00000543427.5:c.539C>G

ENST00000544413.2:c.539C>G

ENST00000544574.5:c.73-3085C>G

ENST00000560968.5:c.682C>G

ENST00000615446.4:c.-257-2730C>G

ENST00000617366.4:c.539C>G

NM_000545.5:c.539C>G

NM_000545.6:c.539C>G

NM_001306179.1:c.539C>G

NM_000545.8:c.539C>G

Uncertain Significance

PM2_Supporting PP4_Moderate

PM5 BP4 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 HNF1A Version 2.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.539C>G variant in the HNF1 homeobox A gene, HNF1A causes an amino acid change of alanine to glycine at codon 180 (p.(Ala180Gly)) of NM_000545.8. This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sensitive to sulfonylurea treatment) (PP4_Moderate; internal lab contributor). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.539C>T (p.Ala180Val) has been classified as a likely benign by the ClinGen MDEP; therefore, PM5 will not be applied. This variant has a REVEL score of 0.492, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on HNF1A function. In summary, c.539C>G meets the criteria to be classified as a VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/111/2023): PP4_Moderate, PM2_Supporting.

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

PP4_Moderate

This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sensitive to sulfonylurea treatment) (PP4_Moderate; internal lab contributor).

PM5

Another missense variant, c.539C>G (p.Ala180Val) has been classified as a likely benign by the ClinGen MDEP; therefore, PM5 will not be applied.

BP4

This variant has a REVEL score of 0.492, 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 0.492, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on HNF1A function.

Curation History

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