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]

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Variant: NM_000545.8(HNF1A):c.686G>A (p.Arg229Gln)

CA16606085

379904 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: e739ac30-b1d8-481c-9382-de08bbb585f6

HGVS expressions

NM_000545.8:c.686G>A

NM_000545.8(HNF1A):c.686G>A (p.Arg229Gln)

NC_000012.12:g.120993679G>A

CM000674.2:g.120993679G>A

NC_000012.11:g.121431482G>A

CM000674.1:g.121431482G>A

NC_000012.10:g.119915865G>A

NG_011731.2:g.19934G>A

ENST00000257555.11:c.686G>A

ENST00000257555.10:c.686G>A

ENST00000400024.6:c.686G>A

ENST00000402929.5:n.821G>A

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

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

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

ENST00000540108.1:c.*126G>A

ENST00000541395.5:c.686G>A

ENST00000541924.5:c.686G>A

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

ENST00000544413.2:c.686G>A

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

ENST00000560968.5:n.829G>A

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

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

NM_000545.5:c.686G>A

NM_000545.6:c.686G>A

NM_001306179.1:c.686G>A

NM_001306179.2:c.686G>A

Pathogenic

PS4 PM1_Supporting PP1_Strong PP4_Moderate PP3 PS3_Supporting PM2_Supporting

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>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to glutamine at codon 229 (p.(Arg229Gln)) 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) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.953, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in at two individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies in both and positive C-peptide in one) (PP4_Moderate; PMID: 27913849). The c.686G>A variant was identified in 27 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 29927023, 28395978, 27913849, 9032114, 18513305, internal lab contributors). Functional studies demonstrated the p.Arg229Gln protein has transactivation below 40% of wildtype, indicating that this variant impacts protein function (PS3_Supporting; PMIDs: 12530534, 12574234). Lastly, this variant segregated with diabetes, with at least 17 informative meioses in at more than three families with MODY (PP1_Strong; PMID: 18513305; internal lab contributors). In summary, c.686G>A 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 9/30/21): PS3_Supporting, PP1_strong, PS4, PM1_Supporting, PM2_Supporting, PP4_Moderate, PP3.

PS4

This variant was identified in 27 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes.

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.

PP1_Strong

This variant segregated with diabetes, with 17 informative meioses in more than three families with MODY (PMID: 18513305, internal lab contributors).

PP4_Moderate

This variant was identified in two individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and antibody negative both and positive C-peptide in one).

PP3

REVEL 0.953+ FATHMM, LRT, MetaLR, MetaSVM, MutationTaster, PROVEAN and SIFT all predict deleterious; MutationAssessor said Medium, GERP score 4.45.

PS3_Supporting

Functional in vitro studies demonstrated that HeLa cells with this variant showed reduced DNA binding affinity and reduced transactivation activity (PMID: 12530534). Furthermore, Bjorkhaug et al. (2003) demonstrated that cells with R229Q HNF1A variant retained only 11% of DNA binding compared to the WT, and the luciferase assay showed about 25% transactivation activity compared to WT (PMID: 12574234).

PM2_Supporting

This variant is absent from gnomAD.

Approved on: 2022-04-12

Published on: 2022-07-12

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