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.788G>A (p.Arg263His)

CA16606475

379138 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: e613a19a-b574-44b5-9300-22020e589dd7

HGVS expressions

NM_000545.8:c.788G>A

NM_000545.8(HNF1A):c.788G>A (p.Arg263His)

NC_000012.12:g.120994238G>A

CM000674.2:g.120994238G>A

NC_000012.11:g.121432041G>A

CM000674.1:g.121432041G>A

NC_000012.10:g.119916424G>A

NG_011731.2:g.20493G>A

ENST00000257555.11:c.788G>A

ENST00000257555.10:c.788G>A

ENST00000400024.6:c.788G>A

ENST00000402929.5:n.923G>A

ENST00000535955.5:n.43-3253G>A

ENST00000538626.2:n.191-3253G>A

ENST00000538646.5:c.601G>A

ENST00000540108.1:c.*228G>A

ENST00000541395.5:c.788G>A

ENST00000541924.5:c.713+532G>A

ENST00000543427.5:c.633+612G>A

ENST00000544413.2:c.788G>A

ENST00000544574.5:c.73-2379G>A

ENST00000560968.5:n.893+38G>A

ENST00000615446.4:c.-257-2024G>A

ENST00000617366.4:c.586+659G>A

NM_000545.5:c.788G>A

NM_000545.6:c.788G>A

NM_001306179.1:c.788G>A

NM_001306179.2:c.788G>A

Pathogenic

PS3_Supporting PP1_Strong PM2_Supporting PS4 PP3 PM1 PP4_Moderate

PM5

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.788G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to histidine at codon 263 (p.Arg263His) of NM_000545.8. 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). This variant 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 0.957, which is greater thanthe MDEP VCEP threshold of 0.70 (PP3). This variant was identified in at least 16 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 19336507, 26853433, 28012402, 29927023, 31166087, internal lab contributors). Additionally, functional studies demonstrated the p.Arg263His protein has DNA binding and nuclear localization below 40% of wild type, indicating that this variant impacts protein function (PS3_Supporting; PMID: 26853433). 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). Finally, this variant segregated with diabetes, with 9 informative meioses in multiple families with MODY (PP1_Strong; 19336507, internal lab contributors). While two additional missense variants, c.787C>T (p.Arg263His) and c.788G>T (p.Arg263Leu) have been classified as pathogenic by the ClinGen MDEP, p.Arg263His has the lowest Grantham distance and was used as the base variant to apply PM5 to Arg263Cys and PM5_Strong to Arg263Leu and thus PM5 is not applied to p.Arg263His. In summary, c.788G>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 9/30/2021): PM1, PM2_Supporting, PP3, PS4, PS3_Supporting, PP4_Moderate, PP1_Strong.

PS3_Supporting

Functional in vitro studies demonstrated that cells with this variant have no binding activity, only 28% of WT nuclear translocation, and 50% of WT transactivation activity.

PP1_Strong

This variant segregated with disease with nine informative meioses in multiple families with MODY.

PM2_Supporting

This variant is absent from gnomAD.

PS4

This variant was identified in at least 16 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes.

PP3

REVEL 0.957 + FATHMM, LRT, MetaLR, MetaSVM, MutationTaster, PROVEAN and SIFT all predict deleterious; MutationAssessor said Medium, GERP score 4.84

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.

PP4_Moderate

This variant was identified in one individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A, response to low dose sulfonylureas).

PM5

While two additional missense variants, c.787C>T (p.Arg263His) and c.788G>T (p.Arg263Leu) have been classified as pathogenic by the ClinGen MDEP, p.Arg263His has the lowest Grantham distance and was used as the base variant to apply PM5 to Arg263His and PM5_Strong to Arg263Leu.

Approved on: 2022-04-14

Published on: 2022-07-12

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