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_000545.8(HNF1A):c.872C>A (p.Pro291Gln)

CA6831858

835515 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: fbde9f74-a46c-4dae-a145-de54c3d9c665

HGVS expressions

NM_000545.8:c.872C>A

NM_000545.8(HNF1A):c.872C>A (p.Pro291Gln)

NC_000012.12:g.120994322C>A

CM000674.2:g.120994322C>A

NC_000012.11:g.121432125C>A

CM000674.1:g.121432125C>A

NC_000012.10:g.119916508C>A

NG_011731.2:g.20577C>A

ENST00000257555.11:c.872C>A

ENST00000257555.10:c.872C>A

ENST00000400024.6:c.872C>A

ENST00000402929.5:n.1007C>A

ENST00000535955.5:n.43-3169C>A

ENST00000538626.2:n.191-3169C>A

ENST00000538646.5:c.685C>A

ENST00000540108.1:c.*312C>A

ENST00000541395.5:c.872C>A

ENST00000541924.5:c.713+616C>A

ENST00000543427.5:c.633+696C>A

ENST00000544413.2:c.872C>A

ENST00000544574.5:c.73-2295C>A

ENST00000560968.5:n.893+122C>A

ENST00000615446.4:c.-257-1940C>A

ENST00000617366.4:c.586+743C>A

NM_000545.5:c.872C>A

NM_000545.6:c.872C>A

NM_001306179.1:c.872C>A

NM_001306179.2:c.872C>A

Likely Benign

BS2 BS3_Supporting

PS4 PP3 PM2

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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.872C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to glutamine at codon 291 (p.(Pro291Gln)) of NM_000545.8. Functional studies demonstrated the p.Pro291Gln protein has expression and DNA binding 1.5 times that of wild type and nuclear localization 60% of wild type, indicating that this variant does not impact protein function (PMID: 32910913) (BS3_Supporting). This variant was identified in a normoglycemic individual >70 years old, and the expected penetrance for HNF1A-MODY is 95% by age 70 (BS2; internal lab contributors). In summary, c.872C>A meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): BS3_Supporting, BS2

BS2

Individual in large US biobank diagnosed with diabetes at age 79

BS3_Supporting

Althari et al. 2020 (PMID: 32910913): Luciferase activity >100% of WT (Oxford group). ~1.5 fold change in expression by Oxford group. Nuclear localization ~60% WT by Bergen and Oxford groups. DNA binding ~1.5 of WT (Oxford group).

PS4

5 cases: 4 individuals in large US biobank, one individual in PMID: 23771925. Does not meet PM2 so cannot use PS4.

PP3

REVEL = 0.4469

PM2

PM2_Supporting: gnomAD ENF MAF 0.000009264 (1 allele) + 4 AA alleles

Approved on: 2022-02-21

Published on: 2022-07-11

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