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.-215A>G

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA2740067583

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 5cac839b-0aa8-4bba-a418-43fd4ef9ded8

Approved on: 2024-03-31

Published on: 2024-03-31

HGVS expressions

NM_001306179.2:c.-215A>G

NC_000012.12:g.120978554A>G

CM000674.2:g.120978554A>G

NC_000012.11:g.121416357A>G

CM000674.1:g.121416357A>G

NC_000012.10:g.119900740A>G

NG_011731.2:g.4809A>G

ENST00000257555.11:c.-215A>G

ENST00000257555.10:c.-215A>G

NM_000545.8:c.-215A>G

Uncertain Significance

PM1_Supporting PM2_Supporting PP4_Moderate

PP1

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.215A>G variant in the HNF1 homeobox A gene, HNF1A, is a single nucleotide variant within the promoter of NM_000545.8. This variant is located within a region of the promoter (–c.-209 to c.-227) of HNF1A which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). 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 SU sensitivity) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes with 2 informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors). In summary, c.-215A>G 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 2.1.0, approved 8/11/2023): PP4_Moderate, PM1_Supporting, PM2_Supporting.

PM1_Supporting

This variant is located within a region of the promoter (–c.-209 to c.-227) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_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 SU sensitivity) (PP4_Moderate; internal lab contributors).

PP1

This variant segregated with diabetes with 2 informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors).

Curation History

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