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]

Variant: NM_000545.6(HNF1A):c.608G>A (p.Arg203His)

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA153100

129235 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 72ad3997-eb69-48ef-8b9c-c9fb9facd124

Approved on: 2022-04-11

Published on: 2022-07-12

HGVS expressions

NM_000545.6:c.608G>A

NM_000545.6(HNF1A):c.608G>A (p.Arg203His)

NC_000012.12:g.120993601G>A

CM000674.2:g.120993601G>A

NC_000012.11:g.121431404G>A

CM000674.1:g.121431404G>A

NC_000012.10:g.119915787G>A

NG_011731.2:g.19856G>A

ENST00000257555.11:c.608G>A

ENST00000257555.10:c.608G>A

ENST00000400024.6:c.608G>A

ENST00000402929.5:n.743G>A

ENST00000535955.5:n.43-3890G>A

ENST00000538626.2:n.191-3890G>A

ENST00000538646.5:c.527-563G>A

ENST00000540108.1:c.*48G>A

ENST00000541395.5:c.608G>A

ENST00000541924.5:c.608G>A

ENST00000543427.5:c.608G>A

ENST00000544413.2:c.608G>A

ENST00000544574.5:c.73-3016G>A

ENST00000560968.5:n.751G>A

ENST00000615446.4:c.-257-2661G>A

ENST00000617366.4:c.586+22G>A

NM_000545.5:c.608G>A

NM_001306179.1:c.608G>A

NM_000545.8:c.608G>A

NM_001306179.2:c.608G>A

NM_000545.8(HNF1A):c.608G>A (p.Arg203His)

Pathogenic

PS4 PP3 PP4_Moderate PM1 PS3_Supporting PP1_Strong PM2_Supporting

BS3

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.608G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to histidine at codon 203 (p.(Arg203His)) of NM_000545.8. This variant segregated with diabetes, in more than 10 families with MODY (PP1_Strong; internal lab contributors). Additionally, this variant was identified in at least 15 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 23348805, 27913849, internal lab contributors). This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1) and is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.958, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Functional studies demonstrated the p.Arg203His protein has abnormal nuclear localization below 40% of wildtype, indicating that this variant impacts protein function (PMID: 32910913) (PS3_Supporting). Lastly, 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 antibody negative) (PP4_Moderate; PMID:27913849). In summary, c.608G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 9/30/21): PS4, PP1_Strong, PM1, PM2_Supporting, PP4_Moderate,PP3, PS3_Supporting.

PS4

This variant was identified in at least 19 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PMIDs: 23348805, 27913849, internal lab contributors).

PP3

REVEL 0.958 + DANN, GERP, FATHMM, LRT, MutationAssessor, MutationTaster, PROVEAN and SIFT all predict deleterious

PP4_Moderate

This variant was identified in three individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and, in one case, negative antibodies) (PMID: 27913849, internal lab contributors).

PM1

This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP.

PS3_Supporting

DNA binding <40% of WT by both Bergen and Oxford groups in Althari et al. 2020 (PMID: 32910913). Luciferase only <40% in HeLa cell assay from Bergen, protein expression and nuclear localization only decreased in Bergen assays.

PP1_Strong

The R203H variant segregated with disease in over 10 families with MODY.

PM2_Supporting

This variant has a minor allele frequency in gnomAD of less than 0.00002 in the European non-Finnish population (actual value = 0.000008797) + 1 copy present in the African population.

BS3

In Bjørkhaug et al. (2005) functional in vitro studies demonstrated “more normal” localization with R203H variant, but this was still significantly different than WT.

Curation History

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