Variant: NM_000545.8(HNF1A):c.1772_1773del (p.Ser591fs)

CA2573051041

1687070 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 51d6369d-1647-40f9-a793-63a732d42966

Approved on: 2025-10-03

Published on: 2025-10-03

HGVS expressions

NM_000545.8:c.1772_1773del
NM_000545.8(HNF1A):c.1772_1773del (p.Ser591fs)
NC_000012.12:g.121001068_121001069del
CM000674.2:g.121001068_121001069del
NC_000012.11:g.121438871_121438872del
CM000674.1:g.121438871_121438872del
NC_000012.10:g.119923254_119923255del
NG_011731.2:g.27323_27324del
ENST00000560968.6:c.*519_*520del
ENST00000257555.11:c.1772_1773del
ENST00000257555.10:c.1772_1773del
ENST00000288757.7:c.*3084_*3085del
ENST00000540108.1:c.*1212_*1213del
ENST00000541395.5:c.1865_1866del
ENST00000543427.5:c.1235_1236del
ENST00000544413.2:c.1793_1794del
ENST00000560968.5:c.1589_1590del
ENST00000615446.4:c.560_561del
ENST00000617366.4:c.*181_*182del
NM_000545.5:c.1772_1773del
NM_000545.6:c.1772_1773del
NM_001306179.1:c.1793_1794del
NM_001286191.2:c.*3084_*3085del
NM_001286196.2:c.*3084_*3085del
NM_001306179.2:c.1793_1794del
NM_022895.3:c.*3084_*3085del

Likely Pathogenic

• Met criteria codes: PM2_Supporting PP4 PVS1_Strong

• Not Met criteria codes: PP1

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.1772_1773del variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 591 NM_000545.8, adding 57 novel amino acids before encountering a stop codon (p.(Ser591PhefsTer57)). While this variant, located in exon 10 of 10, is not predicted to result in nonsense-mediated decay of the transcript, it will significantly disrupt the transactivation domain of the protein (PVS1_Strong; PMID: 23348805). Additionally, this variant was identified in at least one individual with a clinical history specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributors). This variant is absent from gnomAD v4.1 (PM2_Supporting). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918; [internal lab contributors]). In summary, c.1772_1733del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/25): PVS1_Strong, PP4, PM2_Supporting.

Met criteria codes

• PM2_Supporting: This variant is absent from gnomAD v4.1.0 (PM2_Supporting)
• PP4: This variant was identified in an individual with a clinical history specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4_Moderate; internal lab contributors).
• PVS1_Strong: While this variant, located in exon 10 of 10, is not predicted to result in nonsense-mediated decay of the transcript, it will significantly disrupt the transactivation domain of the protein.(PVS1_Strong)

Not Met criteria codes

• PP1: This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, [internal lab contributors]).