Variant: NC_000012.12:g.120978486A>C

CA2286774128

14933 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 78969101-584c-401d-bdec-9e5ea1a2e234

HGVS expressions

NC_000012.12:g.120978486A>C
CM000674.2:g.120978486A>C
NC_000012.11:g.121416289A>C
CM000674.1:g.121416289A>C
NC_000012.10:g.119900672A>C
NG_011731.2:g.4741A>C

Likely Pathogenic

• Met criteria codes: PM2_Supporting PP4_Moderate PM1_Supporting PS3_Supporting PP1_Strong

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.-283A>C in the HNF1 homeobox A gene, HNF1A, is a single nucleotide variant in the promoter of NM_000545.8. This variant is located within the HNF4A binding domain (c.-276 to c.-288) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Functional studies demonstrated the c.-283A>C protein has transactivation below 40% of wildtype, indicating that this variant impacts protein function (PS3_Supporting; PMID:10649494). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), however it was identified in at least one 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). This variant also segregated with diabetes, with 7 informative meioses in two families with MODY (PP1_Strong; PMID:9313764; internal lab contributor). Taken together, this evidence suggests the classification of this variant as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0_: PP1_Strong, PP4_moderate, PM1_Supporting, PM2_Supporting, PS3_Supporting).

Met criteria codes

• PM2_Supporting: This variant is absent in gnomAD v2.1.1 (PM2_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 HNF4A binding domain (c.-276 to c.-288) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).
• PS3_Supporting: Functional studies demonstrated the c.-283A>C protein has transactivation below 40% of wildtype, indicating that this variant impacts protein function (PMID:10649494).
• PP1_Strong: This variant segregated with diabetes, with 7 informative meioses in two families with MODY (PP1_Strong; PMID:9313764; internal lab contributor).

Approved on: 2021-08-18

Published on: 2021-10-29