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.686G>C

CA386965177

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 6946ce49-473e-4ab8-9a7e-16cf0e1351e5

HGVS expressions

NM_001306179.1:c.686G>C

NC_000012.12:g.120993679G>C

CM000674.2:g.120993679G>C

NC_000012.11:g.121431482G>C

CM000674.1:g.121431482G>C

NC_000012.10:g.119915865G>C

NG_011731.2:g.19934G>C

ENST00000257555.11:c.686G>C

ENST00000257555.10:c.686G>C

ENST00000400024.6:c.686G>C

ENST00000402929.5:n.821G>C

ENST00000535955.5:n.43-3812G>C

ENST00000538626.2:n.191-3812G>C

ENST00000538646.5:c.527-485G>C

ENST00000540108.1:c.*126G>C

ENST00000541395.5:c.686G>C

ENST00000541924.5:c.686G>C

ENST00000543427.5:c.633+53G>C

ENST00000544413.2:c.686G>C

ENST00000544574.5:c.73-2938G>C

ENST00000560968.5:n.829G>C

ENST00000615446.4:c.-257-2583G>C

ENST00000617366.4:c.586+100G>C

NM_000545.5:c.686G>C

NM_000545.6:c.686G>C

NM_000545.8:c.686G>C

NM_001306179.2:c.686G>C

Pathogenic

PS4 PP3 PM5 PM1 PP4_Moderate PM2_Supporting PP1_Moderate

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.686G>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to proline at codon 229 (p.Arg229Pro) of NM_000545.8. This variant segregated with diabetes, with 14 informative meioses in 2 families with MODY (PP1_Strong; internal lab contributors). Also, 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 was also identified in 6 individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, positive C-peptide, and 2 were antibody negative) (PP4_Moderate; internal lab contributors). Another missense variant, c.686G>A p.Arg229Gln has been interpreted as pathogenic by the ClinGen MDEP and p.Arg229Pro has an equal or greater Grantham distance (PM5). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.973, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in at least 4 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 15928245, internal lab contributors). In summary, c.686G>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PP1_Strong, PM1_Supporting, PM2_Supporting, PP4_Moderate, PM5, PP3, PS4_Moderate.

PS4

This variant was identified in four unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PMID: 15928245, internal lab contributors).

PP3

REVEL 0.973 + FATHMM, LRT, MetaLR, MetaSVM, MutationTaster, PROVEAN and SIFT all predict deleterious; MutationAssessor said Medium, GERP score 4.45

PM5

The p.Arg229Gln variant has been interpreted as pathogenic by the MDEP and has a lower Grantham distance than p.Arg229Pro.

PM1

This variant affects the DNA binding domain of HNF1A, which is critical for the protein’s function.

PP4_Moderate

This variant was identified in six individuals in one family with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50% and normal C-peptide). Two of the individuals were also antibody negative.

PM2_Supporting

This variant is absent from population databases (gnomAD).

PP1_Moderate

This variant segregated with disease with 14 informative meioses in two families with MODY.

Approved on: 2022-04-12

Published on: 2022-07-12

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