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_001306179.1:c.475C>G

CA386960405

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: af17ef65-f2c4-4f2b-bcda-7f56fd1510d7

HGVS expressions

NM_001306179.1:c.475C>G

NC_000012.12:g.120988981C>G

CM000674.2:g.120988981C>G

NC_000012.11:g.121426784C>G

CM000674.1:g.121426784C>G

NC_000012.10:g.119911167C>G

NG_011731.2:g.15236C>G

ENST00000257555.11:c.475C>G

ENST00000257555.10:c.475C>G

ENST00000400024.6:c.475C>G

ENST00000402929.5:n.610C>G

ENST00000535955.5:n.43-8510C>G

ENST00000538626.2:n.191-8510C>G

ENST00000538646.5:c.475C>G

ENST00000540108.1:c.327-4539C>G

ENST00000541395.5:c.475C>G

ENST00000541924.5:c.475C>G

ENST00000543427.5:c.475C>G

ENST00000544413.2:c.475C>G

ENST00000544574.5:c.73-7636C>G

ENST00000560968.5:n.618C>G

ENST00000615446.4:c.-257-7281C>G

ENST00000617366.4:c.475C>G

NM_000545.5:c.475C>G

NM_000545.6:c.475C>G

NM_000545.8:c.475C>G

NM_001306179.2:c.475C>G

Likely Pathogenic

PM5_Strong PP3 PM2_Supporting PM1

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 Version 1.1

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.475C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to glycine at codon 159 (p.(Arg159Gly)) of NM_000545.8. 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). 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 0.905, which is greater than the MDEP threshold of 0.70 (PP3). Two other missense variants, c.476G>A (p.Arg159Gln) and c.475C>T (p.Arg159Trp), have been interpreted as pathogenic by the ClinGen MDEP, and p.(Arg.159Gly) has a greater Grantham distance than both (PM5_Strong). In summary, c.475C>G 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 September 30, 2021): PM1_Supporting, PM2_Supporting, PM5_Strong, PP3.

PM5_Strong

Two other missense variants, c.476G>A (p.Arg159Gln) and c.475C>T (p.Arg159Trp), have been interpreted as pathogenic by the ClinGen MDEP, and p.(Arg.159Gly) has a greater Grantham distance than both.

PP3

REVEL = 0.905

PM2_Supporting

This variant is absent from gnomAD.

PM1

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.

Approved on: 2022-04-09

Published on: 2022-07-12

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