Variant: NM_001306179.2:c.517G>A

CA386960737

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: ab38715f-437b-43fc-9576-98294188b41e

Approved on: 2024-01-22

Published on: 2024-01-22

HGVS expressions

NM_001306179.2:c.517G>A
NC_000012.12:g.120989023G>A
CM000674.2:g.120989023G>A
NC_000012.11:g.121426826G>A
CM000674.1:g.121426826G>A
NC_000012.10:g.119911209G>A
NG_011731.2:g.15278G>A
ENST00000257555.11:c.517G>A
ENST00000257555.10:c.517G>A
ENST00000400024.6:c.517G>A
ENST00000402929.5:n.652G>A
ENST00000535955.5:n.43-8468G>A
ENST00000538626.2:n.191-8468G>A
ENST00000538646.5:c.517G>A
ENST00000540108.1:c.327-4497G>A
ENST00000541395.5:c.517G>A
ENST00000541924.5:c.517G>A
ENST00000543427.5:c.517G>A
ENST00000544413.2:c.517G>A
ENST00000544574.5:c.73-7594G>A
ENST00000560968.5:c.660G>A
ENST00000615446.4:c.-257-7239G>A
ENST00000617366.4:c.517G>A
NM_000545.5:c.517G>A
NM_000545.6:c.517G>A
NM_001306179.1:c.517G>A
NM_000545.8:c.517G>A

Likely Pathogenic

• Met criteria codes: PP3 PP1_Strong PM1_Supporting PM2_Supporting

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.517G>A variant in the e.g. HNF1 homeobox A gene, HNF1A, causes an amino acid change of valine to methionine at codon 173 (p.(Val173Met)) of NM_000545.8. This variant is located within the DNA binding domains (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.84, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Lastly, this variant segregated with diabetes, with at least ten informative meioses in one family (PP1_Strong; internal lab contributors). In summary, c.517G>A 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 8/11/2023): PM1_Supporting, PM2_Supporting, PP3, PP1_Strong.

Met criteria codes

• PP3: REVEL = 0.84
• PP1_Strong: This variant segregated with diabetes with 10 informative meioses in 1 family (PP1_Strong; internal lab contributors).
• 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).
• PM2_Supporting: Absent in gnomAD 2.1.1