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.390G>T

CA386959427

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 44a0d9fb-bff8-48e3-98db-d96bc67d3d92

HGVS expressions

NM_001306179.2:c.390G>T

NC_000012.12:g.120988896G>T

CM000674.2:g.120988896G>T

NC_000012.11:g.121426699G>T

CM000674.1:g.121426699G>T

NC_000012.10:g.119911082G>T

NG_011731.2:g.15151G>T

ENST00000560968.6:c.390G>T

ENST00000257555.11:c.390G>T

ENST00000257555.10:c.390G>T

ENST00000400024.6:c.390G>T

ENST00000402929.5:n.525G>T

ENST00000535955.5:n.43-8595G>T

ENST00000538626.2:n.191-8595G>T

ENST00000538646.5:c.390G>T

ENST00000540108.1:c.327-4624G>T

ENST00000541395.5:c.390G>T

ENST00000541924.5:c.390G>T

ENST00000543427.5:c.390G>T

ENST00000544413.2:c.390G>T

ENST00000544574.5:c.73-7721G>T

ENST00000560968.5:c.533G>T

ENST00000615446.4:c.-257-7366G>T

ENST00000617366.4:c.390G>T

NM_000545.5:c.390G>T

NM_000545.6:c.390G>T

NM_001306179.1:c.390G>T

NM_000545.8:c.390G>T

Likely Pathogenic

PP1 PP3 PM1 PM5_Supporting PM2_Supporting

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.390G>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glutamine to histidine at codon 130 (p.(Gln130His)) of NM_000545.8. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.925, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was segregated with diabetes, with three informative meioses in one family (PP1; PMID: 16834925). Another missense variant, c.388C>G p.Gln130Glu, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.390G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM2_supporting, PM1, PP3, PP1, PM5_Supporting.

PP1

This variant was segregated with diabetes, with three informative meioses in one family (PP1; PMID: 16834925).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.925, which is greater than the MDEP VCEP threshold of 0.70 (PP3).

PM1

This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1).

PM5_Supporting

Another missense variant, c.388C>G p.Gln130Glu, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting).

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_Supporting). gnomAD v4.0.0, absent

Approved on: 2024-06-09

Published on: 2024-06-09

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