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_000545.8(HNF1A):c.485T>C (p.Leu162Pro)

Curation Version - 2.0
Curation History
JSON LD for Version 2.0

CA386960483

447490 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 5f553adc-686d-40f1-99d8-b5dd06f0b5ec

Approved on: 2025-06-27

Published on: 2025-06-27

HGVS expressions

NM_000545.8:c.485T>C

NM_000545.8(HNF1A):c.485T>C (p.Leu162Pro)

NC_000012.12:g.120988991T>C

CM000674.2:g.120988991T>C

NC_000012.11:g.121426794T>C

CM000674.1:g.121426794T>C

NC_000012.10:g.119911177T>C

NG_011731.2:g.15246T>C

ENST00000560968.6:c.485T>C

ENST00000257555.11:c.485T>C

ENST00000257555.10:c.485T>C

ENST00000400024.6:c.485T>C

ENST00000402929.5:n.620T>C

ENST00000535955.5:n.43-8500T>C

ENST00000538626.2:n.191-8500T>C

ENST00000538646.5:c.485T>C

ENST00000540108.1:c.327-4529T>C

ENST00000541395.5:c.485T>C

ENST00000541924.5:c.485T>C

ENST00000543427.5:c.485T>C

ENST00000544413.2:c.485T>C

ENST00000544574.5:c.73-7626T>C

ENST00000560968.5:c.628T>C

ENST00000615446.4:c.-257-7271T>C

ENST00000617366.4:c.485T>C

NM_000545.5:c.485T>C

NM_000545.6:c.485T>C

NM_001306179.1:c.485T>C

NM_001306179.2:c.485T>C

Likely Pathogenic

PP4_Moderate PS4_Moderate PM2_Supporting PP3 PM1_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.485T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to proline at codon 162 (p.(Leu162Pro)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.987, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and persistent C-peptide) (PP4_Moderate; internal lab contributors). This variant was identified in four unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 21224407, 29927023; internal lab contributors). In summary, c.485T>C 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 8/11/23): PP3, PM1_Supporting, PM2_supporting, PP4_Moderate, PS4_Moderate.

PP4_Moderate

This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and persistent C-peptide) (internal lab contributors).

PS4_Moderate

This variant was identified in four unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 21224407, 29927023; internal lab contributors).

PM2_Supporting

This variant is absent from gnomAD v2.1.1 and v4.1.0.

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.987, which is greater than the MDEP threshold of 0.70 (PP3).

PM1_Supporting

This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP.

Curation History

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