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.498C>A (p.Tyr166Ter)

CA386960572

2746579 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 3356147a-60bc-4c49-977a-96c538a4451e

Approved on: 2024-09-19

Published on: 2024-09-19

HGVS expressions

NM_000545.8:c.498C>A

NM_000545.8(HNF1A):c.498C>A (p.Tyr166Ter)

NC_000012.12:g.120989004C>A

CM000674.2:g.120989004C>A

NC_000012.11:g.121426807C>A

CM000674.1:g.121426807C>A

NC_000012.10:g.119911190C>A

NG_011731.2:g.15259C>A

ENST00000560968.6:c.498C>A

ENST00000257555.11:c.498C>A

ENST00000257555.10:c.498C>A

ENST00000400024.6:c.498C>A

ENST00000402929.5:n.633C>A

ENST00000535955.5:n.43-8487C>A

ENST00000538626.2:n.191-8487C>A

ENST00000538646.5:c.498C>A

ENST00000540108.1:c.327-4516C>A

ENST00000541395.5:c.498C>A

ENST00000541924.5:c.498C>A

ENST00000543427.5:c.498C>A

ENST00000544413.2:c.498C>A

ENST00000544574.5:c.73-7613C>A

ENST00000560968.5:c.641C>A

ENST00000615446.4:c.-257-7258C>A

ENST00000617366.4:c.498C>A

NM_000545.5:c.498C>A

NM_000545.6:c.498C>A

NM_001306179.1:c.498C>A

NM_001306179.2:c.498C>A

Likely Pathogenic

PM2_Supporting PVS1

PS4 PP1

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 for HNF1A Version 2.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.498C>A variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 166 (p.(Tyr166Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 2 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). In summary, c.498C>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023: PVS1, PM2_Supporting.

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

PVS1

This variant, located in biologically-relevant exon 2 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805).

PS4

This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors).

PP1

This variant segregated with diabetes with 1 informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors).

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