Variant: NM_000545.8(HNF1A):c.24_35dup (p.Gln9_Leu12dup)

CA2573051030

1338407 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 3567b156-65f2-47d9-ae7e-f8202f54eccc

HGVS expressions

NM_000545.8:c.24_35dup
NM_000545.8(HNF1A):c.24_35dup (p.Gln9_Leu12dup)
NC_000012.12:g.120978792_120978803dup
CM000674.2:g.120978792_120978803dup
NC_000012.11:g.121416595_121416606dup
CM000674.1:g.121416595_121416606dup
NC_000012.10:g.119900978_119900989dup
NG_011731.2:g.5047_5058dup
ENST00000257555.11:c.24_35dup
ENST00000257555.10:c.24_35dup
ENST00000400024.6:c.24_35dup
ENST00000402929.5:n.159_170dup
ENST00000535955.5:n.42+100_42+111dup
ENST00000538626.2:n.142_153dup
ENST00000538646.5:c.24_35dup
ENST00000540108.1:c.24_35dup
ENST00000541395.5:c.24_35dup
ENST00000541924.5:c.24_35dup
ENST00000543427.5:c.24_35dup
ENST00000544413.2:c.24_35dup
ENST00000544574.5:c.24_35dup
ENST00000560968.5:n.167_178dup
ENST00000615446.4:c.-258+81_-258+92dup
ENST00000617366.4:c.24_35dup
NM_000545.5:c.24_35dup
NM_000545.6:c.24_35dup
NM_001306179.1:c.24_35dup
NM_001306179.2:c.24_35dup

Likely Pathogenic

• Met criteria codes: PM2_Supporting PP4_Moderate PM1_Supporting PM4

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.24_35dup variant in the HNF1 homeobox A gene, HNF1A, is a 12 base pair insertion resulting in the in-frame addition of 3 amino acid(s) at codon 9 (p.(Gln9_Leu12dup)) within exon 1 of NM_000545.8. This variant is located within the DNA dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is also absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, the c.24_35dup variant is predicted to change the length of the protein due an in-frame insertion of three amino acids in a non-repeat region (PM4). 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 negative antibodies) (PP4_Moderate; PMID: 25174781). In summary, c.24_35dup 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 9/30/21): PM1_Supporting, PM2_Supporting, PM4, PP4_Moderate.

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 negative antibodies) (PP4_Moderate; PMID: 25174781).
• PM1_Supporting: This variant is located within the DNA dimerization domain (codons 1-32) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).
• PM4: The c.24_35dup variant is predicted to change the length of the protein due an in-frame insertion of three amino acids in a non-repeat region (PM4)

Approved on: 2022-03-25

Published on: 2022-07-12