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.80T>G

CA386952724

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 7d3e7bd5-6186-4a1d-8b07-a25a04a707ce

Approved on: 2022-04-02

Published on: 2022-07-12

HGVS expressions

NM_001306179.2:c.80T>G

NC_000012.12:g.120978848T>G

CM000674.2:g.120978848T>G

NC_000012.11:g.121416651T>G

CM000674.1:g.121416651T>G

NC_000012.10:g.119901034T>G

NG_011731.2:g.5103T>G

ENST00000257555.11:c.80T>G

ENST00000257555.10:c.80T>G

ENST00000400024.6:c.80T>G

ENST00000402929.5:n.215T>G

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

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

ENST00000538646.5:c.80T>G

ENST00000540108.1:c.80T>G

ENST00000541395.5:c.80T>G

ENST00000541924.5:c.80T>G

ENST00000543427.5:c.80T>G

ENST00000544413.2:c.80T>G

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

ENST00000560968.5:n.223T>G

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

ENST00000617366.4:c.80T>G

NM_000545.5:c.80T>G

NM_000545.6:c.80T>G

NM_001306179.1:c.80T>G

NM_000545.8:c.80T>G

Uncertain Significance

PP3 PM1_Supporting PM2_Supporting

PP4 PM5

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 Version 1.1

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.80T>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of isoleucine to serine at codon 27 (p.Leu16Pro) 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 v2.1.1 (PM2_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.861, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50% and PP4 could not be applied (PMID 18003757). Another missense variant, c.80T>C (p.Ile27Thr), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.80T>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 1.1, approved 9/30/21): PM1_Supporting, PM2_Supporting, PP3.

PP3

REVEL = 0.861

PM1_Supporting

In the dimerization domain.

PM2_Supporting

Absent from gnomAD.

PP4

This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50% (PMID 18003757).

PM5

Another missense variant, c.80T>C (p.Ile27Thr), has been classified as a VUS by the ClinGen MDEP.

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