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.1489C>T (p.Gln497Ter)

CA386970379

489311 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: bb4579db-3158-4198-9050-8d3c409e35eb

Approved on: 2021-12-31

Published on: 2022-07-11

HGVS expressions

NM_000545.6:c.1489C>T

NM_000545.6(HNF1A):c.1489C>T (p.Gln497Ter)

NC_000012.12:g.120997653C>T

CM000674.2:g.120997653C>T

NC_000012.11:g.121435456C>T

CM000674.1:g.121435456C>T

NC_000012.10:g.119919839C>T

NG_011731.2:g.23908C>T

ENST00000257555.11:c.1489C>T

ENST00000257555.10:c.1489C>T

ENST00000400024.6:c.1489C>T

ENST00000402929.5:n.2355C>T

ENST00000535955.5:n.205C>T

ENST00000538626.2:n.353C>T

ENST00000538646.5:c.*465C>T

ENST00000540108.1:c.*929C>T

ENST00000541395.5:c.1489C>T

ENST00000541924.5:c.*503C>T

ENST00000543255.1:n.533C>T

ENST00000543427.5:c.952C>T

ENST00000544413.2:c.1489C>T

ENST00000544574.5:c.*252C>T

ENST00000560968.5:n.1306C>T

ENST00000615446.4:c.277C>T

ENST00000617366.4:c.606C>T

NM_000545.5:c.1489C>T

NM_001306179.1:c.1489C>T

NM_000545.8:c.1489C>T

NM_001306179.2:c.1489C>T

NM_000545.8(HNF1A):c.1489C>T (p.Gln497Ter)

Pathogenic

PM2_Supporting PP4 PVS1

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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1489C>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 497 (p.(Gln497Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 7 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 (PM2_Supporting). Lastly, this variant was identified in at least one individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result <50% (45.5%), but negative genetic testing for HNF4A and an extreme response to low dose sulfonylurea) (PP4; internal lab contributors). In summary, c.1489C>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): PVS1, PM2_Supporting, PP4_Supporting.

PM2_Supporting

This variant is absent from gnomAD.

PP4

This variant was identified in one individual with a clinical history suggestive of HNF1A-MODY. While this individual has MODY probability calculator result of only 45.5%, they showed an extreme response to sulfonylurea treatment (internal laboratory contributor).

PVS1

This variant is predicted to cause loss of function by resulting in nonsense mediated decay of a biologically relevant transcript.

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