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]

Variant: NM_001306179.2:c.282dup

CA2573051039

1676696 (ClinVar)

Gene: HNF1A (HGNC:6927)

Condition: monogenic diabetes (MONDO:0015967)

Inheritance Mode: Autosomal dominant inheritance

UUID: fca6ab0d-ccd3-41ae-b000-163d2c424bdd

Approved on: 2025-06-09

Published on: 2025-06-09

HGVS expressions

NM_001306179.2:c.282dup

NC_000012.12:g.120979050dup

CM000674.2:g.120979050dup

NC_000012.11:g.121416853dup

CM000674.1:g.121416853dup

NC_000012.10:g.119901236dup

NG_011731.2:g.5305dup

ENST00000560968.6:c.282dup

ENST00000257555.11:c.282dup

ENST00000257555.10:c.282dup

ENST00000400024.6:c.282dup

ENST00000402929.5:n.417dup

ENST00000535955.5:n.42+358dup

ENST00000538626.2:n.190+210dup

ENST00000538646.5:c.282dup

ENST00000540108.1:c.282dup

ENST00000541395.5:c.282dup

ENST00000541924.5:c.282dup

ENST00000543427.5:c.282dup

ENST00000544413.2:c.282dup

ENST00000544574.5:c.72+210dup

ENST00000560968.5:c.425dup

ENST00000615446.4:c.-258+339dup

ENST00000617366.4:c.282dup

NM_000545.5:c.282dup

NM_000545.6:c.282dup

NM_001306179.1:c.282dup

NM_000545.8:c.282dup

Likely Pathogenic

PVS1 PM2_Supporting

PS4 PP4

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.282dup variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 95 (p.(Glu95Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 1 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). Additionally, this variant is absent from gnomAD v2.1.1 and v4.1.0 (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 was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (internal lab contributors); therefore, PP4 cannot be applied. In summary, c.282dup 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 8/11/23): PVS1, PM2_Supporting.

PVS1

Predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805).

PM2_Supporting

Absent from gnomAD v2.1.1; absent from gnomAD v4.1.0.

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).

PP4

This variant was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (internal lab contributors).

Curation History

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