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.80T>C

Curation Version - 1.4
Curation History
JSON LD for Version 1.4

CA386952722

1676692 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 5314a2ef-194f-41ac-b98b-ac9623f93d9f

Approved on: 2025-07-24

Published on: 2025-07-24

HGVS expressions

NM_001306179.2:c.80T>C

NC_000012.12:g.120978848T>C

CM000674.2:g.120978848T>C

NC_000012.11:g.121416651T>C

CM000674.1:g.121416651T>C

NC_000012.10:g.119901034T>C

NG_011731.2:g.5103T>C

ENST00000560968.6:c.80T>C

ENST00000257555.11:c.80T>C

ENST00000257555.10:c.80T>C

ENST00000400024.6:c.80T>C

ENST00000402929.5:n.215T>C

ENST00000535955.5:n.42+156T>C

ENST00000538626.2:n.190+8T>C

ENST00000538646.5:c.80T>C

ENST00000540108.1:c.80T>C

ENST00000541395.5:c.80T>C

ENST00000541924.5:c.80T>C

ENST00000543427.5:c.80T>C

ENST00000544413.2:c.80T>C

ENST00000544574.5:c.72+8T>C

ENST00000560968.5:c.223T>C

ENST00000615446.4:c.-258+137T>C

ENST00000617366.4:c.80T>C

NM_000545.5:c.80T>C

NM_000545.6:c.80T>C

NM_001306179.1:c.80T>C

NM_000545.8:c.80T>C

Uncertain Significance

PM2_Supporting PM1_Supporting PP3

PM5 PS4 PP4

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 3.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.80T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of isoleucine to threonine at codon 27 (p.(Ile27Thr)) of NM_000545.8. This variant is located within the DNA dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting) and is absent from gnomAD v4.1.0 (PM2_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.844, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested and therefore PP4 could not be applied (PMID: 18003757). Another missense variant, c.80T>G (p.Ile27Ser), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 could not be applied. In summary, c.80T>C 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 3.0.0, approved 6/30/2025): PM1_Supporting, PM2_Supporting, PP3.

PM2_Supporting

Absent from gnomAD

PM1_Supporting

In the dimerization domain

PP3

REVEL = 0.844

PM5

Another missense variant, c.80T>G (p.Ile27Ser), has been classified as a VUS by the ClinGen MDEP.

PS4

One individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PMID: 18003757)

PP4

This variant was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (PMID: 18003757).

Curation History

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