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.787C>T (p.Arg263Cys)

CA6831834

562367 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: dfa508d2-1967-4ee6-b589-b0d5dce61488

HGVS expressions

NM_000545.6:c.787C>T

NM_000545.6(HNF1A):c.787C>T (p.Arg263Cys)

NC_000012.12:g.120994237C>T

CM000674.2:g.120994237C>T

NC_000012.11:g.121432040C>T

CM000674.1:g.121432040C>T

NC_000012.10:g.119916423C>T

NG_011731.2:g.20492C>T

ENST00000257555.11:c.787C>T

ENST00000257555.10:c.787C>T

ENST00000400024.6:c.787C>T

ENST00000402929.5:n.922C>T

ENST00000535955.5:n.43-3254C>T

ENST00000538626.2:n.191-3254C>T

ENST00000538646.5:c.600C>T

ENST00000540108.1:c.*227C>T

ENST00000541395.5:c.787C>T

ENST00000541924.5:c.713+531C>T

ENST00000543427.5:c.633+611C>T

ENST00000544413.2:c.787C>T

ENST00000544574.5:c.73-2380C>T

ENST00000560968.5:n.893+37C>T

ENST00000615446.4:c.-257-2025C>T

ENST00000617366.4:c.586+658C>T

NM_000545.5:c.787C>T

NM_001306179.1:c.787C>T

NM_000545.8:c.787C>T

NM_001306179.2:c.787C>T

NM_000545.8(HNF1A):c.787C>T (p.Arg263Cys)

Pathogenic

PM2_Supporting PS3_Supporting PS4 PP3 PP1_Strong PM5 PM1 PP4_Moderate

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.787C>T variant in the HNF1 homeobox A] gene, HNF1A, causes an amino acid change of arginine to cysteine at codon 263 (p.Arg263Cys) 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 in the gnomAD v2.1.1 European non-Finnish population, and there is one copy in another subpopulation, which is less than the ClinGen MDEP threshold for PM2_Supporting (≤0.00002 and ≤1 copy in any other subpopulation) (PM2_Supporting). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.948, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in at least 21 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 30155490, 12574234, 25414397, 9287053; internal lab contributors). Additionally, another missense variant, c.788G>A (p.Arg263His), has been interpreted as pathogenic by the ClinGen MDEP and p.Arg263Cys has a greater Grantham distance (PM5). Functional studies demonstrated the p.Arg263Cys protein has DNA binding and transactivation activity below 40% of wild type, indicating that this variant impacts protein function (PS3_Supporting; PMID: 12574234). Also, 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). Lastly, this variant segregated with diabetes, with 7 informative meioses in 2 families with MODY (PP1_Strong; PMID: 12574234, internal lab contributors). In summary, c.787C>T 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, PM5, PS3_Supporting, PP4_Moderate, PP1_Strong.

PM2_Supporting

This variant is absent from the gnomAD European non-Finnish population, and only one copy is present in the Ashkenazi Jewish population.

PS3_Supporting

Functional in vitro studies demonstrated that cells with this variant retained 78% of WT nuclear localization, but showed no binding activity and only 25% of WT transactivation activity (PMID: 12574234).

PS4

This variant was identified in at least 21 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes.

PP3

REVEL 0.948 + FATHMM, LRT, MetaLR, MetaSVM, MutationTaster, PROVEAN and SIFT all predict deleterious; MutationAssessor said Medium, GERP score 4.84

PP1_Strong

This variant segregated with diabetes with seven informative meioses in two families with MODY.

PM5

Another missense variant, c.788G>A (p.Arg263His), has been interpreted as pathogenic by the ClinGen MDEP, and p.Arg263Cys has a greater Grantham distance.

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 one 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) (internal lab contributor).

Approved on: 2022-04-14

Published on: 2022-07-12

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