NM_000545.8:c.369GCA[4]

36820 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

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

Approved on: 2022-04-10

Published on: 2022-07-12

HGVS expressions

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

Likely Pathogenic

• Met criteria codes: PM2_Supporting PP1_Strong PP4_Moderate PM1_Supporting PM4_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 Version 1.1

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 (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 1.1, approved 9/30/2021): PM4_Supporting, PM1_Supporting, PM2_Supporting, PP4_Moderate, PP1_Strong.

Met criteria codes

• PM2_Supporting: This variant is absent from gnomAD.
• PP1_Strong: This variant segregated with disease with eight informative meioses in two families with MODY
• 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.
• 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 insertion in a non-repeat region.

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).