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]

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Variant: NM_000545.8(HNF1A):c.539C>T (p.Ala180Val)

CA16609762

402949 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 02bc71c1-509a-4823-9f00-554ac574379b

Approved on: 2024-07-29

Published on: 2024-07-29

HGVS expressions

NM_000545.8:c.539C>T

NM_000545.8(HNF1A):c.539C>T (p.Ala180Val)

NC_000012.12:g.120993532C>T

CM000674.2:g.120993532C>T

NC_000012.11:g.121431335C>T

CM000674.1:g.121431335C>T

NC_000012.10:g.119915718C>T

NG_011731.2:g.19787C>T

ENST00000560968.6:c.539C>T

ENST00000257555.11:c.539C>T

ENST00000257555.10:c.539C>T

ENST00000400024.6:c.539C>T

ENST00000402929.5:n.674C>T

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

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

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

ENST00000540108.1:c.339C>T

ENST00000541395.5:c.539C>T

ENST00000541924.5:c.539C>T

ENST00000543427.5:c.539C>T

ENST00000544413.2:c.539C>T

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

ENST00000560968.5:c.682C>T

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

ENST00000617366.4:c.539C>T

NM_000545.5:c.539C>T

NM_000545.6:c.539C>T

NM_001306179.1:c.539C>T

NM_001306179.2:c.539C>T

Likely Benign

BS2 PM2_Supporting BS3_Supporting

PS4 PP1 PM1

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>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to valine at codon 180 (p.(Ala180Val)) of NM_000545.8. Functional studies demonstrated the p.Ala180Val protein has transactivation above 75% of wildtype, indicating that this variant does not impact protein function (PMID: 28934671) (BS3_Supporting). Additionally, this variant was identified in the homozygous state in a normoglycemic individual (PMID: 28934671) (BS2). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.539C>T meets the criteria to be classified as likely benign for monogenic diabetes, though it likely influences diabetes risk. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): BS3_Supporting, BS2, PM2_Supporting.

BS2

The c.539C>T variant was identified in the homozygous state in a normoglycemic individual.

PM2_Supporting

This variant is absent from gnomAD.

BS3_Supporting

Functional studies demonstrated that cells with this variant displayed transactivation activity 80% of WT, EMSA showed similar DNA binding as WT, and no significant difference in cellular localization compared to WT.

PS4

Only identified in two families.

PP1

Families A & B in PMID: 28934671 displayed a phenotype strongly suggestive of type II diabetes mellitus.

PM1

This variant occurs within a region of the DNA binding domain that shows poor conservation and an increased prevalence of missense variants in gnomAD.

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