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

CA386960413

586792 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: ed6e9cb1-5384-4744-a9d9-e7febc7b5765

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

• Met criteria codes: PS4 PP1 PP3 PM1 PP4_Moderate PM2_Supporting

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

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

Met criteria codes

• 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
• PM1: This variant is located within the DNA binding domain of HNF1A, which is critical for the protein’s function.
• 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.
• PM2_Supporting: This variant is absent from gnomAD.

Approved on: 2021-12-30

Published on: 2021-12-30