Variant: NM_000545.8(HNF1A):c.369GCA[4] (p.Gln125dup)

CA214301

36820 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 3844f61d-bca2-405e-bb0d-6edb82218d6a

Approved on: 2025-06-09

Published on: 2025-06-09

HGVS expressions

NM_000545.8:c.375_377dup
NM_000545.8(HNF1A):c.369GCA[4] (p.Gln125dup)
NC_000012.12:g.120988881_120988883dup
CM000674.2:g.120988881_120988883dup
NC_000012.11:g.121426684_121426686dup
CM000674.1:g.121426684_121426686dup
NC_000012.10:g.119911067_119911069dup
NG_011731.2:g.15136_15138dup
ENST00000560968.6:c.375_377dup
ENST00000257555.11:c.375_377dup
ENST00000257555.10:c.375_377dup
ENST00000400024.6:c.375_377dup
ENST00000402929.5:n.510_512dup
ENST00000535955.5:n.43-8610_43-8608dup
ENST00000538626.2:n.191-8610_191-8608dup
ENST00000538646.5:c.375_377dup
ENST00000540108.1:c.327-4639_327-4637dup
ENST00000541395.5:c.375_377dup
ENST00000541924.5:c.375_377dup
ENST00000543427.5:c.375_377dup
ENST00000544413.2:c.375_377dup
ENST00000544574.5:c.73-7736_73-7734dup
ENST00000560968.5:c.518_520dup
ENST00000615446.4:c.-257-7381_-257-7379dup
ENST00000617366.4:c.375_377dup
NM_000545.5:c.375_377dup
NM_000545.6:c.375_377dup
NM_001306179.1:c.375_377dup
NM_001306179.2:c.375_377dup

Likely Pathogenic

• Met criteria codes: PM4_Supporting PP1_Strong PM2_Supporting PM1_Supporting PP4_Moderate

• 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 2.1.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.375_377dup variant in the HNF1 homeobox A gene, HNF1A, is a 3 base pair insertion resulting in the in-frame addition of 1 amino acid at codon 125 (p.Gln125dup) within exon 2 of NM_000545.8. The c.375_377dup variant is predicted to change the length of the protein due to an in-frame insertion of a single amino acid in a nonrepeat region (PM4_Supporting). This variant is also 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 is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). Additionally, 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 response to low dose sulfonylureas) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes, with 8 informative meioses in 2 families with MODY (PP1_Strong; internal lab contributors). In summary, c.375_377dup meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/23): PM4_Supporting, PM1_Supporting, PM2_Supporting, PP4_Moderate, PP1_Strong.

Met criteria codes

• PM4_Supporting: The total protein length changes as a result of this single amino acid insertion in a non-repeat region.
• PP1_Strong: This variant segregated with disease with eight informative meioses in two families with MODY
• PM2_Supporting: This variant is absent from gnomAD v2 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.
• PP4_Moderate: This variant was identified in one individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A), who also responded to low dose sulfonylureas.

Not Met criteria codes

• PS4: This variant was identified in two 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 (internal lab contributors).