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.871C>A (p.Pro291Thr)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA6831857

972814 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 08babbaa-0ebb-4af0-b035-ef9aa7c9f4ca

Approved on: 2021-12-30

Published on: 2021-12-30

HGVS expressions

NM_000545.8:c.871C>A

NM_000545.8(HNF1A):c.871C>A (p.Pro291Thr)

NC_000012.12:g.120994321C>A

CM000674.2:g.120994321C>A

NC_000012.11:g.121432124C>A

CM000674.1:g.121432124C>A

NC_000012.10:g.119916507C>A

NG_011731.2:g.20576C>A

ENST00000257555.11:c.871C>A

ENST00000257555.10:c.871C>A

ENST00000400024.6:c.871C>A

ENST00000402929.5:n.1006C>A

ENST00000535955.5:n.43-3170C>A

ENST00000538626.2:n.191-3170C>A

ENST00000538646.5:c.684C>A

ENST00000540108.1:c.*311C>A

ENST00000541395.5:c.871C>A

ENST00000541924.5:c.713+615C>A

ENST00000543427.5:c.633+695C>A

ENST00000544413.2:c.871C>A

ENST00000544574.5:c.73-2296C>A

ENST00000560968.5:n.893+121C>A

ENST00000615446.4:c.-257-1941C>A

ENST00000617366.4:c.586+742C>A

NM_000545.5:c.871C>A

NM_000545.6:c.871C>A

NM_001306179.1:c.871C>A

NM_001306179.2:c.871C>A

Uncertain Significance

PP4 PP1 BS2

PP3 PM2 PM5 PM1 PS4 PS3

Evidence Links 0

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.871C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to threonine at codon 291 (p.(Pro291Thr)) of NM_000545.8. This variant segregated with diabetes, with three informative meioses in one families with MODY (PP1; PMID: 22432108). Additionally, 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 contributor). Lastly, the c.871C>A 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) (PP4; PMID: 18003757. In summary, c.871C>A 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 6/4/2021): BS2, PP4, PP1

PP4

MPC 45.5% but negative antibodies, low hsCRP, and dominant family history so using at supporting level of evidence

PP1

Three informative meioses in PMID: 22432108

BS2

Individual diagnosed with diabetes at age 80 and had documented non-diabetic glucoses in her 70s

PP3

REVEL = 0.587

PM2

gnomAD ENF MAF 0.000009234 but 2 LatinX alleles

PM5

No other variants at Pro291 are curated as pathogenic or likely pathogenic

PM1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PS4

2 cases

PS3

Transactivation activity 59.2% of WT, DNA binding and protein expression normal in Juszczak et al. 2019 (PMID: 18003757, Gloyn group)

Curation History

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