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.1340C>T (p.Pro447Leu)

CA124454

14928 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: c0326a24-f74a-4d2d-8623-525b5be1ae24

HGVS expressions

NM_000545.6:c.1340C>T

NM_000545.6(HNF1A):c.1340C>T (p.Pro447Leu)

NC_000012.12:g.120997504C>T

CM000674.2:g.120997504C>T

NC_000012.11:g.121435307C>T

CM000674.1:g.121435307C>T

NC_000012.10:g.119919690C>T

NG_011731.2:g.23759C>T

ENST00000257555.11:c.1340C>T

ENST00000257555.10:c.1340C>T

ENST00000400024.6:c.1340C>T

ENST00000402929.5:n.2206C>T

ENST00000535955.5:n.56C>T

ENST00000538626.2:n.204C>T

ENST00000538646.5:c.*316C>T

ENST00000540108.1:c.*780C>T

ENST00000541395.5:c.1340C>T

ENST00000541924.5:c.*354C>T

ENST00000543255.1:n.384C>T

ENST00000543427.5:c.803C>T

ENST00000544413.2:c.1340C>T

ENST00000544574.5:c.*103C>T

ENST00000560968.5:n.1157C>T

ENST00000615446.4:c.128C>T

ENST00000617366.4:c.587-130C>T

NM_000545.5:c.1340C>T

NM_001306179.1:c.1340C>T

NM_000545.8:c.1340C>T

NM_001306179.2:c.1340C>T

NM_000545.8(HNF1A):c.1340C>T (p.Pro447Leu)

Pathogenic

PS4 PS2_Supporting PP1_Strong PP3 PP4 PS3_Moderate PM2_Supporting

Evidence Links 3

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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1340C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to leucine at codon 447 (p.(Pro447Leu)) of NM_000545.8. This variant was identified as a de novo occurrence with unconfirmed parental relationships in an individual with diabetes, but whose clinical picture is not highly specific for HNF1A-MODY ([MODY probability calculator result <50%/HNF4A not tested) (PS2_Supporting; internal lab contributors). A luciferase assay meeting the ClinGen MDEP quality control specifications demonstrated that the p.Pro447Leu protein has transactivation activity below 40% of wildtype, indicating that this variant impacts protein function (PS3_Moderate, PMIDs: 27899486, 12530534, 10585442, 32910913, 32910913). This variant was identified in 11 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; internal lab contributors) and is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with diabetes, with at least 15 informative meioses in families with MODY (PP1_Strong; internal lab contributors), and is predicted to be deleterious by computational evidence, with a REVEL score of 0.957, which is greater than or equal to the MDEP VCEP threshold of 0.70 (PP3). Lastly, 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) (PP4; internal lab contributors). In summary, c.1340C>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 6/4/2021): PS4, PP1_Strong, PP3, PP4, PS2_Supporting, PM2_Supporting, PS3_Moderate.

PS4

This variant was identified in 15 unrelated individuals with a clinical picture consistent with monogenic diabetes (internal laboratory contributors).

PS2_Supporting

This variant was also presumed de novo in an individual with a clinical picture consistent with HNF1A-MODY, but not highly specific to this form of monogenic diabetes.

PP1_Strong

This variant segregated with disease with 15 informative meioses observed in multiple families with MODY (internal laboratory contributors).

PP3

This variant is predicted to be deleterious by multiple lines of computational evidence with a REVEL score of 0.957.

PP4

This variant was identified in two individuals with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A).

PS3_Moderate

Functional in vitro studies demonstrated that cells with this variant retained 20% of WT transcriptional activity, <10%-50% of WT transactivation activity, and low DNA binding

Reports that the variant retained less than 10% of transactivation activity and low DNA binding (no exact percentages reported) PubMed:10585442

Reported that the variant retained about 50% of WT transactivation activity PubMed:12530534

Reported that the variant retained 20% of WT transcriptional activity PubMed:27899486

PM2_Supporting

This variant is absent from gnomAD.

Approved on: 2021-12-31

Published on: 2022-07-11

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