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.866C>G (p.Pro289Arg)

CA244533104

972753 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 69d2896b-6579-44d0-828d-d88c18193b64

HGVS expressions

NM_000545.8:c.866C>G

NM_000545.8(HNF1A):c.866C>G (p.Pro289Arg)

NC_000012.12:g.120994316C>G

CM000674.2:g.120994316C>G

NC_000012.11:g.121432119C>G

CM000674.1:g.121432119C>G

NC_000012.10:g.119916502C>G

NG_011731.2:g.20571C>G

ENST00000257555.11:c.866C>G

ENST00000257555.10:c.866C>G

ENST00000400024.6:c.866C>G

ENST00000402929.5:n.1001C>G

ENST00000535955.5:n.43-3175C>G

ENST00000538626.2:n.191-3175C>G

ENST00000538646.5:c.679C>G

ENST00000540108.1:c.*306C>G

ENST00000541395.5:c.866C>G

ENST00000541924.5:c.713+610C>G

ENST00000543427.5:c.633+690C>G

ENST00000544413.2:c.866C>G

ENST00000544574.5:c.73-2301C>G

ENST00000560968.5:n.893+116C>G

ENST00000615446.4:c.-257-1946C>G

ENST00000617366.4:c.586+737C>G

NM_000545.5:c.866C>G

NM_000545.6:c.866C>G

NM_001306179.1:c.866C>G

NM_001306179.2:c.866C>G

Uncertain Significance

PP4_Moderate PM2_Supporting

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.866C>G variant in the e.g. HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to arginine at codon 289 (p.(Pro289Arg)) of NM_000545.8. This variant is absent from the gnomAD v2.1.1 European non-Finnish population and is found in one individual in another subpopulation, which is less than the ClinGen MDEP threshold for PM2_Supporting (≤0.00002 and ≤1 copy in any other subpopulation) (PM2_Supporting). 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 sulfonylurea-sensitive) (PP4_Moderate; internal lab contributors). Two other missense variants, c.866C>A (p.Pro289His) and c.865C>T (p.Pro289Ser), have been classified as VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.866C>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): PM2_Supporting, PP4_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 sulfonylurea-sensitive) (PP4_Moderate; internal lab contributors).

PM2_Supporting

Absent in gnomAD v2.1.1 ENF and one allele in Latino subpopulation.

PM5

Two other missense variants, c.866C>A (p.Pro289His) and c.865C>T (p.Pro289Ser), have been classified as VUS by the ClinGen MDEP; therefore, PM5 will not be applied.

Approved on: 2022-04-15

Published on: 2022-07-12

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