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_000545.8(HNF1A):c.872del (p.Pro291fs)

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA6831848

805637 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: cda51153-0f7d-4a50-9f45-7ed65c1996fa

Approved on: 2021-12-31

Published on: 2022-07-11

HGVS expressions

NM_000545.8:c.872del

NM_000545.8(HNF1A):c.872del (p.Pro291fs)

NC_000012.12:g.120994322del

CM000674.2:g.120994322del

NC_000012.11:g.121432125del

CM000674.1:g.121432125del

NC_000012.10:g.119916508del

NG_011731.2:g.20577del

ENST00000257555.11:c.872del

ENST00000257555.10:c.872del

ENST00000400024.6:c.872del

ENST00000402929.5:n.1007del

ENST00000535955.5:n.43-3169del

ENST00000538626.2:n.191-3169del

ENST00000538646.5:c.685del

ENST00000540108.1:c.*312del

ENST00000541395.5:c.872del

ENST00000541924.5:c.713+616del

ENST00000543427.5:c.633+696del

ENST00000544413.2:c.872del

ENST00000544574.5:c.73-2295del

ENST00000560968.5:n.893+122del

ENST00000615446.4:c.-257-1940del

ENST00000617366.4:c.586+743del

NM_000545.5:c.872del

NM_000545.6:c.872del

NM_001306179.1:c.872del

NM_001306179.2:c.872del

Pathogenic

PP4 PP1_Moderate PVS1

PS4 PM2

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.872del variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 291 (NM_000545.8), adding 51 novel amino acids before encountering a stop codon (p.(Pro291GlnfsTer51). This variant, located in biologically-relevant exon 4 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 segregated with diabetes, with at least 30 informative meioses in multiple families with MODY (PP1_Strong; internal lab contributors). Additionally, 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) (PP4; internal lab contributors). In summary, c.872del 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, PP1_Strong, PP4

PP4

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

PP1_Moderate

This variant segregated with disease with at least 30 informative meioses observed in multiple families with MODY (internal laboratory contributors).

PVS1

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

PS4

PS4 cannot be used if PM2_supporting does not apply.

PM2

Failed gnomAD QC; all carriers have lower than 60 quality.

Curation History

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