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_000545.6(HNF1A):c.476G>A (p.Arg159Gln)

CA386960413

586792 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: ed6e9cb1-5384-4744-a9d9-e7febc7b5765

Approved on: 2021-12-30

Published on: 2021-12-30

HGVS expressions

NM_000545.6:c.476G>A

NM_000545.6(HNF1A):c.476G>A (p.Arg159Gln)

NC_000012.12:g.120988982G>A

CM000674.2:g.120988982G>A

NC_000012.11:g.121426785G>A

CM000674.1:g.121426785G>A

NC_000012.10:g.119911168G>A

NG_011731.2:g.15237G>A

ENST00000257555.11:c.476G>A

ENST00000257555.10:c.476G>A

ENST00000400024.6:c.476G>A

ENST00000402929.5:n.611G>A

ENST00000535955.5:n.43-8509G>A

ENST00000538626.2:n.191-8509G>A

ENST00000538646.5:c.476G>A

ENST00000540108.1:c.327-4538G>A

ENST00000541395.5:c.476G>A

ENST00000541924.5:c.476G>A

ENST00000543427.5:c.476G>A

ENST00000544413.2:c.476G>A

ENST00000544574.5:c.73-7635G>A

ENST00000560968.5:n.619G>A

ENST00000615446.4:c.-257-7280G>A

ENST00000617366.4:c.476G>A

NM_000545.5:c.476G>A

NM_001306179.1:c.476G>A

NM_000545.8:c.476G>A

NM_001306179.2:c.476G>A

NM_000545.8(HNF1A):c.476G>A (p.Arg159Gln)

Pathogenic

PP4_Moderate PM1 PS4 PP1 PP3 PM2_Supporting

Evidence Links 0

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.476G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to glutamine at codon 159 (p.Arg159Gln) of NM_000545.8. This variant was identified in more than 10 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDS: 10078571, 12488961, 15928245, 20132997, 9097962, 10754480, internal lab contributors). Also, this variant segregated with diabetes, with at least 11 informative meioses in 17 families with MODY (PP1_Strong; PMIDs: 9097962, 10754480, internal lab contributors). 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 also absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and response to low-dose sulfonylureas) (PP4_Moderate; internal lab contributors). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.976, which is greater than or equal to the MDEP VCEP threshold of 0.70 (PP3). Lastly, functional studies demonstrated the p.Arg159Gln protein has DNA binding below 40% of wild type, indicating that this variant impacts protein function (PS3_Supporting; PMID: 10585442). In summary, c.476G>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 6/4/2021): PS4, PP1_Strong, PM1_Supporting, PM2_Supporting, PP4_Moderate, PP3, PS3_Supporting

PP4_Moderate

This variant was identified in multiple individuals with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A), one of whom was also antibody negative.

PM1

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

PS4

This variant was identified in unrelated individuals from 24 families with a clinical picture consistent with monogenic diabetes.

PP1

This variant segregated with disease with more than four informative meioses observed in multiple families with MODY.

PP3

REVEL score of 0.976

PM2_Supporting

This variant is absent from gnomAD.

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