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

CA244520175

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 82e625a0-c863-467a-ad31-ad8c97e19617

Approved on: 2021-08-18

Published on: 2021-10-29

HGVS expressions

NM_001306179.2:c.-187C>T

NC_000012.12:g.120978582C>T

CM000674.2:g.120978582C>T

NC_000012.11:g.121416385C>T

CM000674.1:g.121416385C>T

NC_000012.10:g.119900768C>T

NG_011731.2:g.4837C>T

ENST00000257555.11:c.-187C>T

ENST00000257555.10:c.-187C>T

ENST00000400024.6:c.-187C>T

NM_000545.6:c.-187C>T

NM_001306179.1:c.-187C>T

NM_000545.8:c.-187C>T

Uncertain Significance

PP4_Moderate PM1_Supporting

PS4 PM2

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.-187C>T variant in the HNF1 homeobox A gene, HNF1A, is a single nucleotide variant within the promoter of NM_000545.8. This variant is located within the API binding site (c.-187 to c.-195) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). While c.-187C>T is absent in the European non-Finnish population in gnomAD v2.1.1, it has 2 copies in the African subpopulation; therefore, this variant does not meet the ClinGen MDEP-established cutoff for PM2_Supporting. This variant was identified in 4 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because the variant does not meet the PM2_Supporting cutoff (internal lab contributors). One of these individuals has 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 contributor). Taken together, this criteria supports the classification of c.-187C>T as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0, approved): PP4_moderate, PM1_Supporting.

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 contributor).

PM1_Supporting

This variant is located within the API binding site (c.-187 to c.-195) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).

PS4

This variant was identified in 4 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because the variant does not meet the PM2_Supporting cutoff (internal lab contributors).

PM2

While c.-187C>T is absent in the European non-Finnish population in gnomAD v2.1.1, it has 2 copies in the African subpopulation; therefore, this variant does not meet the ClinGen MDEP-established cutoff for PM2_Supporting.

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