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_001306179.2:c.607C>T

CA386964246

1338381 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 0854bd4e-545d-4e20-a7b8-8792b87172b2

HGVS expressions

NM_001306179.2:c.607C>T

NC_000012.12:g.120993600C>T

CM000674.2:g.120993600C>T

NC_000012.11:g.121431403C>T

CM000674.1:g.121431403C>T

NC_000012.10:g.119915786C>T

NG_011731.2:g.19855C>T

ENST00000257555.11:c.607C>T

ENST00000257555.10:c.607C>T

ENST00000400024.6:c.607C>T

ENST00000402929.5:n.742C>T

ENST00000535955.5:n.43-3891C>T

ENST00000538626.2:n.191-3891C>T

ENST00000538646.5:c.527-564C>T

ENST00000540108.1:c.*47C>T

ENST00000541395.5:c.607C>T

ENST00000541924.5:c.607C>T

ENST00000543427.5:c.607C>T

ENST00000544413.2:c.607C>T

ENST00000544574.5:c.73-3017C>T

ENST00000560968.5:n.750C>T

ENST00000615446.4:c.-257-2662C>T

ENST00000617366.4:c.586+21C>T

NM_000545.5:c.607C>T

NM_000545.6:c.607C>T

NM_001306179.1:c.607C>T

NM_000545.8:c.607C>T

NM_000545.8(HNF1A):c.607C>T (p.Arg203Cys)

Pathogenic

PS4 PS2 PP1_Strong PP4_Moderate PP3 PM5 PM1 PM2_Supporting

PS3

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.607C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to cysteine at codon 203 (p.(Arg203Cys)) of NM_000545.8. This variant was identified as a de novo occurrence with confirmed parental relationships in an individual with a clinical picture highly consistent with HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea-responsive) (internal lab contributors). (PS2; internal lab contributors). Additionally, this variant was identified in eight unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs:15928245, 10078571, 18811724,20393147,23517481, internal lab contributors). The c.607C>T 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 was identified in at least two individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea sensitive or antibody negative (PP4_Moderate; internal lab contributors). Another missense variant, c.608G>A (p.Arg203His) has been interpreted as pathogenic by the ClinGen MDEP, and p. Arg203Cys has a greater Grantham distance (PM5). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.91, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Lastly, this variant segregated with diabetes, with at least five informative meioses in three families with MODY (PP1_Strong; PMID:18811724; internal lab contributors). Functional studies demonstrated the p.Arg203Cys protein has transactivation 53% of wildtype; however, this is between the ClinGen MDEP cutoffs for PS3_Supporting and BS3_Supporting (PMID: 15522234). In summary, c.607C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 9/30/21): PS2, PS4, PM1, PM2_Supporting, PP4_Moderate, PM5, PP3, PP1_Strong.

PS4

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

PS2

This variant was identified as a de novo occurrence with confirmed parental relationships in an individual with a clinical picture highly consistent with HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea-responsive) (internal lab contributors).

PP1_Strong

This variant segregated with disease with five informative meioses in three families with MODY (PMID: 18811724, internal lab contributors).

PP4_Moderate

This variant was identified in one individual with a clinical picture consistent with HNF1A-MODY (MODY probability calculator result >50% an negative genetic testing for HNF4A), who also responded to low dose sulfonylurea treatment.

PP3

REVEL 0.91 + DANN, GERP, FATHMM, LRT, MutationAssessor, MutationTaster, PROVEAN and SIFT all predict deleterious

PM5

The c.608G>A p.Arg603His variant has been interpreted to be pathogenic by the MDEP.

PM1

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

PM2_Supporting

This variant is absent from the gnomAD v.2.1.1 European non-Finnish population and only one copy is present in the East Asian population.

PS3

Functional studies demonstrated the p.Arg203Cys protein has transactivation 53% of wildtype; however, this is between the ClinGen MDEP cutoffs for PS3_Supporting and BS3_Supporting (PMID: 15522234).

Approved on: 2022-04-11

Published on: 2022-07-12

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