Variant: NM_000545.8(HNF1A):c.663GAA[1] (p.Lys222del)

CA214314

36825 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: a55731b7-7bf1-4f46-99d8-166ab65545f4

Approved on: 2025-07-24

Published on: 2025-07-24

HGVS expressions

NM_000545.8:c.663GAA[1]
NM_000545.8(HNF1A):c.663GAA[1] (p.Lys222del)
NC_000012.12:g.120993659_120993661del
CM000674.2:g.120993659_120993661del
NC_000012.11:g.121431462_121431464del
CM000674.1:g.121431462_121431464del
NC_000012.10:g.119915845_119915847del
NG_011731.2:g.19914_19916del
ENST00000560968.6:c.666_668del
ENST00000257555.11:c.666_668del
ENST00000257555.10:c.666_668del
ENST00000400024.6:c.666_668del
ENST00000402929.5:n.801_803del
ENST00000535955.5:n.43-3832_43-3830del
ENST00000538626.2:n.191-3832_191-3830del
ENST00000538646.5:c.527-505_527-503del
ENST00000540108.1:c.*106_*108del
ENST00000541395.5:c.666_668del
ENST00000541924.5:c.666_668del
ENST00000543427.5:c.633+33_633+35del
ENST00000544413.2:c.666_668del
ENST00000544574.5:c.73-2958_73-2956del
ENST00000560968.5:c.809_811del
ENST00000615446.4:c.-257-2603_-257-2601del
ENST00000617366.4:c.586+80_586+82del
NM_000545.5:c.666_668del
NM_000545.6:c.666_668del
NM_001306179.1:c.666_668del
NM_000545.8:c.666_668del
NM_001306179.2:c.666_668del

Likely Pathogenic

• Met criteria codes: PM2_Supporting PM1_Supporting PM4_Supporting PP4_Moderate PP1 PS3_Supporting

• Not Met criteria codes: PS4

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specification: ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HNF1A Version 3.0.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.666_668del variant in the HNF1 homeoboxA gene, HNF1A, results in the inframe deletion of a single lysine at codon 222 of NM_000545.6 (PM4_Supporting). Functional in vitro studies demonstrated that cells with this variant showed severely impaired transactivation activity and DNA binding (significantly below 40%). Furthermore, cells with this variant showed low protein expression levels and impaired nuclear targeting with elevated immunofluorescence signal in the cytoplasm compared to WT HNF1A (PS3_Supporting; Janne Molnes, personal communication). This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP. (PM1_Supporting). This variant was identified in two individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea-responsiveness in both and negative antibodies in one) (PP4_Moderate; PMID: 27913849, internal lab contributor). This variant segregated with disease with three informative meioses in a single family with MODY (PP1; internal lab contributor). Additionally, this variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 27913849, ClinVar: SCV000053177.2, internal lab contributors). In summary, c.666_668del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.0.0, approved 6/30/2025): PS3_Supporting, PM1_Supporting, PP4_Moderate, PM2_Supporting, PM4_Supporting, PP1.

Met criteria codes

• PM2_Supporting: This variant is absent from gnomAD v2.1.1 and v4.1.0.
• PM1_Supporting: This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP.
• PM4_Supporting: The total protein length changes as a result of this single amino acid deletion in a non-repeat region.
• PP4_Moderate: This variant was identified in at least 2 individuals with a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and and sulfonylurea-responsiveness in both and negative antibodies in one) (PP4_Moderate; internal lab contributors).
• PP1: This variant segregated with diabetes, with 3 informative meioses in 1 family (PP1, internal lab contributors).
• PS3_Supporting: Functional in vitro studies demonstrated that cells with this variant showed severely impaired transactivation activity and DNA binding (significantly below 40%). Furthermore, cells with this variant showed low protein expression levels and impaired nuclear targeting with elevated immunofluorescence signal in the cytoplasm compared to WT HNF1A (PS3_Supporting; internal lab contributors).

Not Met criteria codes

• PS4: This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 27913849, ClinVar: SCV000053177.2, internal lab contributors).