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.526+4A>G

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA2018007655

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: eb546cb0-67ff-4db5-9f5f-3f8cf8c45ead

Approved on: 2025-02-11

Published on: 2025-02-28

HGVS expressions

NM_001306179.2:c.526+4A>G

NC_000012.12:g.120989036A>G

CM000674.2:g.120989036A>G

NC_000012.11:g.121426839A>G

CM000674.1:g.121426839A>G

NC_000012.10:g.119911222A>G

NG_011731.2:g.15291A>G

ENST00000560968.6:c.526+4A>G

ENST00000257555.11:c.526+4A>G

ENST00000257555.10:c.526+4A>G

ENST00000400024.6:c.526+4A>G

ENST00000402929.5:n.661+4A>G

ENST00000535955.5:n.43-8455A>G

ENST00000538626.2:n.191-8455A>G

ENST00000538646.5:c.526+4A>G

ENST00000540108.1:c.327-4484A>G

ENST00000541395.5:c.526+4A>G

ENST00000541924.5:c.526+4A>G

ENST00000543427.5:c.526+4A>G

ENST00000544413.2:c.526+4A>G

ENST00000544574.5:c.73-7581A>G

ENST00000560968.5:c.669+4A>G

ENST00000615446.4:c.-257-7226A>G

ENST00000617366.4:c.526+4A>G

NM_000545.5:c.526+4A>G

NM_000545.6:c.526+4A>G

NM_001306179.1:c.526+4A>G

NM_000545.8:c.526+4A>G

Uncertain Significance

PM2_Supporting PP3 PP4_Moderate

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.526+4A>G variant in the HNF1 homeobox A gene, HNF1A, is predicted to alter the splice donor site in intron 2 of NM_000545.8. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.48 for donor loss and a score of 0.96 for cryptic donor gain, predicting that the variant disrupts the donor site of intron 2 of HNF1A (PP3). 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 negative GAD and IA2 antibodies) (PP4_Moderate; internal lab contributors). In summary, c.526+4A>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): PM2_Supporting, PP3, PP4_Moderate.

PM2_Supporting

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

PP3

The computational splicing predictor SpliceAI gives a score of 0.48 for donor loss and a score of 0.96 for cryptic donor gain, predicting that the variant disrupts the donor site of intron 2 of HNF1A (PP3).

PP4_Moderate

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 negative GAD and IA2 antibodies) (PP4_Moderate; internal lab contributors).

Curation History

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