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.694dup (p.Leu232fs)

CA16609272

393456 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 5c6497a2-2278-4b27-9196-b1c924b92b01

HGVS expressions

NM_000545.8:c.694dup

NM_000545.8(HNF1A):c.694dup (p.Leu232fs)

NC_000012.12:g.120993687dup

CM000674.2:g.120993687dup

NC_000012.11:g.121431490dup

CM000674.1:g.121431490dup

NC_000012.10:g.119915873dup

NG_011731.2:g.19942dup

ENST00000257555.11:c.694dup

ENST00000257555.10:c.694dup

ENST00000400024.6:c.694dup

ENST00000402929.5:n.829dup

ENST00000535955.5:n.43-3804dup

ENST00000538626.2:n.191-3804dup

ENST00000538646.5:c.527-477dup

ENST00000540108.1:c.*134dup

ENST00000541395.5:c.694dup

ENST00000541924.5:c.694dup

ENST00000543427.5:c.633+61dup

ENST00000544413.2:c.694dup

ENST00000544574.5:c.73-2930dup

ENST00000560968.5:n.837dup

ENST00000615446.4:c.-257-2575dup

ENST00000617366.4:c.586+108dup

NM_000545.5:c.694dup

NM_000545.6:c.694dup

NM_001306179.1:c.694dup

NM_001306179.2:c.694dup

Pathogenic

PVS1 PP4_Moderate PM2_Supporting

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.694dup variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 232 of NM_000545.8, adding 7 novel amino acids before encountering a stop codon (p.Leu232ProfsTer7). This variant, located in biologically-relevant exon 3 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 also absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; internal lab contributors). In summary, c.694dup 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 9/30/2021): PVS1, PM2_Supporting, PP4_Moderate.

PVS1

A transcript with this variant is predicted to cause loss of function and result in nonsense mediated decay of a biologically relevant exon.

PP4_Moderate

This variant was identified in one individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and antibody-negative).

PM2_Supporting

This variant is absent from gnomAD.

Approved on: 2022-04-12

Published on: 2022-07-12

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