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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000545.8(HNF1A):c.1781G>T (p.Ser594Ile)

CA386940977

1315998 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: e4592074-d88e-48ee-8e72-bc40c284f533

Approved on: 2022-07-01

Published on: 2022-07-01

HGVS expressions

NM_000545.8:c.1781G>T

NM_000545.8(HNF1A):c.1781G>T (p.Ser594Ile)

NC_000012.12:g.121001077G>T

CM000674.2:g.121001077G>T

NC_000012.11:g.121438880G>T

CM000674.1:g.121438880G>T

NC_000012.10:g.119923263G>T

NG_011731.2:g.27332G>T

ENST00000257555.11:c.1781G>T

ENST00000257555.10:c.1781G>T

ENST00000288757.7:c.*3076C>A

ENST00000540108.1:c.*1221G>T

ENST00000541395.5:c.1874G>T

ENST00000543427.5:c.1244G>T

ENST00000544413.2:c.1802G>T

ENST00000560968.5:n.1598G>T

ENST00000615446.4:c.569G>T

ENST00000617366.4:c.*190G>T

NM_000545.5:c.1781G>T

NM_000545.6:c.1781G>T

NM_001306179.1:c.1802G>T

NM_001286191.2:c.*3076C>A

NM_001286196.2:c.*3076C>A

NM_001306179.2:c.1802G>T

NM_022895.3:c.*3076C>A

Pathogenic

PM2_Supporting PP1_Strong PS4 PP4 PP3

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.1781G>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to isoleucine at codon 594 (p.(Ser594Ile)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.73, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant was identified in at least 8 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 9392505, internal lab contributors). This variant segregated with diabetes, with at least 5 informative meioses in four families with MODY (PP1_Strong; internal lab contributors). Lastly, this variant was identified in at least one individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result <50% but antibody-negative and sulfonylurea-sensitive, negative genetic testing for HNF4A) (PP4; PMID: internal lab contributors). In summary, c.1781G>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): PP3, PM2_Supporting, PS4, PP1_Strong, PP4.

PM2_Supporting

Absent in gnomAD

PP1_Strong

5 meioses in 4 families

PS4

This variant was identified in at least 8 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (internal lab contributors).

PP4

1 case with MPC < 50% but SU sensitive and antibody negative, HNF4A tested

PP3

REVEL = 0.73

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