Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

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

CA386960737

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

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

PM1_Supporting PM2_Supporting PP1_Strong PP3

Evidence Links 0

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

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.

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

PP1_Strong

This variant segregated with diabetes with 10 informative meioses in 1 family (PP1_Strong; internal lab contributors).

PP3

REVEL = 0.84

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