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]

Link to SEPIO compliant JSON-LD document

Variant: NM_001306179.2:c.539C>G

CA386963548

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

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

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

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:n.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

PP3 PM5 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 Version 1.2

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>G (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 2.0.0, approved 1//11/2023): 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).

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.

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.

Approved on: 2023-07-30

Published on: 2023-07-30

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.