Variant: NM_001306179.2:c.380_382del

CA2573130154

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: f42f3bb8-88fd-4ede-a8cb-df4138f51773

HGVS expressions

NM_001306179.2:c.380_382del
NC_000012.12:g.120988886_120988888del
CM000674.2:g.120988886_120988888del
NC_000012.11:g.121426689_121426691del
CM000674.1:g.121426689_121426691del
NC_000012.10:g.119911072_119911074del
NG_011731.2:g.15141_15143del
ENST00000257555.11:c.380_382del
ENST00000257555.10:c.380_382del
ENST00000400024.6:c.380_382del
ENST00000402929.5:n.515_517del
ENST00000535955.5:n.43-8605_43-8603del
ENST00000538626.2:n.191-8605_191-8603del
ENST00000538646.5:c.380_382del
ENST00000540108.1:c.327-4634_327-4632del
ENST00000541395.5:c.380_382del
ENST00000541924.5:c.380_382del
ENST00000543427.5:c.380_382del
ENST00000544413.2:c.380_382del
ENST00000544574.5:c.73-7731_73-7729del
ENST00000560968.5:n.523_525del
ENST00000615446.4:c.-257-7376_-257-7374del
ENST00000617366.4:c.380_382del
NM_000545.5:c.380_382del
NM_000545.6:c.380_382del
NM_001306179.1:c.380_382del
NM_000545.8:c.380_382del

Likely Pathogenic

• Met criteria codes: PM2_Supporting PM1_Supporting PP4_Moderate PS3_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.380_382del variant in the HNF1 homeobox A gene, HNF1A, is a three base pair deletion resulting in the in-frame deletion of one amino acid at codon 127 (p.(Asn127del)) within exon two of NM_000545.8. The c.380_382del variant is predicted to change the length of the protein due to an in-frame deletion of a single amino acid in a nonrepeat region (PM4_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 (PM1_Supporting). Functional studies have also demonstrated the p.Asn127del protein has transactivation below 40% of wildtype, indicating that this variant impacts protein function (PMID: 12530534). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and 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 antibody negative) (PP4_Moderate; internal lab contributor). In summary, c.380_382del 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): PP4_Moderate, PM1_Supporting, PM2_Supporting, PM4_Supporting, PS3_Supporting.

Met criteria codes

• PM2_Supporting: This variant is absent in gnomAD v2.1.1 (PM2_Supporting).
• 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 (PM1_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 antibody negative) (PP4_Moderate; internal lab contributor).
• PS3_Supporting: Functional studies demonstrated the p.Asn127del protein has transactivation below 40% of wildtype], indicating that this variant impacts protein function (PMID: 12530534).
• PM4_Supporting: The c.380_382del variant is predicted to change the length of the protein due to an in-frame deletion of a single amino acid in a nonrepeat region (PM4_Supporting).

Not Met criteria codes

• PS4: 2 cases (internal lab contributors).

Approved on: 2022-06-15

Published on: 2022-06-15