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.670C>T (p.Pro224Ser)

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA214317

36826 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: e586f251-a3d4-479a-8235-73e932704a5b

Approved on: 2025-11-26

Published on: 2025-11-26

HGVS expressions

NM_000545.8:c.670C>T

NM_000545.8(HNF1A):c.670C>T (p.Pro224Ser)

NC_000012.12:g.120993663C>T

CM000674.2:g.120993663C>T

NC_000012.11:g.121431466C>T

CM000674.1:g.121431466C>T

NC_000012.10:g.119915849C>T

NG_011731.2:g.19918C>T

ENST00000560968.6:c.670C>T

ENST00000257555.11:c.670C>T

ENST00000257555.10:c.670C>T

ENST00000400024.6:c.670C>T

ENST00000402929.5:n.805C>T

ENST00000535955.5:n.43-3828C>T

ENST00000538626.2:n.191-3828C>T

ENST00000538646.5:c.527-501C>T

ENST00000540108.1:c.*110C>T

ENST00000541395.5:c.670C>T

ENST00000541924.5:c.670C>T

ENST00000543427.5:c.633+37C>T

ENST00000544413.2:c.670C>T

ENST00000544574.5:c.73-2954C>T

ENST00000560968.5:c.813C>T

ENST00000615446.4:c.-257-2599C>T

ENST00000617366.4:c.586+84C>T

NM_000545.5:c.670C>T

NM_000545.6:c.670C>T

NM_001306179.1:c.670C>T

NM_001306179.2:c.670C>T

Likely Pathogenic

PP3 PM2_Supporting PP1_Strong PM1_Supporting PP4_Moderate

PS4

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 3.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.670C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to serine at codon 224 (p.(Pro224Ser)) 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) 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 0.944, which is greater than the MDEP VCEP threshold of 0.70 (PP3). The c.670C>T variant was identified in an individual with a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and responsive to low-dose sulfonylureas) (PP4_Moderate; internal lab contributor). This variant segregated with diabetes, with four informative meioses in three families with MODY (PP1_Strong; PMID:15031772, internal lab contributors). In summary, c.670C>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 3.1.0, approved 10/10/2025): PP1_Strong, PM1_Supporting, PM2_Supporting, PP3, PP4_Moderate.

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.944, which is greater than the MDEP VCEP threshold of 0.70 (PP3).

PM2_Supporting

This variant is absent from gnomAD v4.1.0 (PM2_Supporting).

PP1_Strong

This variant segregated with diabetes, with four informative meioses in three families with MODY (PP1_Strong; PMID:15031772, internal lab contributors).

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 (PM1_Supporting).

PP4_Moderate

This variant was identified in an individual with a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and responsive to low-dose sulfonylureas) (PP4_Moderate; internal lab contributor).

PS4

This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 15031772, internal lab contributors).

Curation History

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