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_000545.6(HNF1A):c.864del (p.Pro291fs)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA6831842

435424 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: e26e934f-5188-4d08-8f32-c1fb50d132da

Approved on: 2021-12-30

Published on: 2021-12-30

HGVS expressions

NM_000545.6:c.864del

NM_000545.6(HNF1A):c.864del (p.Pro291fs)

NC_000012.12:g.120994314del

CM000674.2:g.120994314del

NC_000012.11:g.121432117del

CM000674.1:g.121432117del

NC_000012.10:g.119916500del

NG_011731.2:g.20569del

ENST00000257555.11:c.864del

ENST00000257555.10:c.864del

ENST00000400024.6:c.864del

ENST00000402929.5:n.999del

ENST00000535955.5:n.43-3177del

ENST00000538626.2:n.191-3177del

ENST00000538646.5:c.677del

ENST00000540108.1:c.*304del

ENST00000541395.5:c.864del

ENST00000541924.5:c.713+608del

ENST00000543427.5:c.633+688del

ENST00000544413.2:c.864del

ENST00000544574.5:c.73-2303del

ENST00000560968.5:n.893+114del

ENST00000615446.4:c.-257-1948del

ENST00000617366.4:c.586+735del

NM_000545.5:c.864del

NM_001306179.1:c.864del

NM_000545.8:c.864del

NM_001306179.2:c.864del

NM_000545.8(HNF1A):c.864del (p.Pro291fs)

Likely Pathogenic

PVS1 PP4_Moderate

PS4 PM2

Evidence Links 0

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.864del 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). This variant was also identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and responded to low dose sulfonylureas) (PP4_Moderate; internal lab contributors). In summary, c.864del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 6/4/2021): PVS1, PP4_Moderate

PVS1

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

PP4_Moderate

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), who was also antibody negative and responded to low dose sulfonylureas (internal laboratory contributor).

PS4

Cannot apply PS4 if PM2_Supporting is not applied.

PM2

The variant failed QC in gnomAD (Most of the carriers have low quality, only 4 carriers quality above 80, 2 above 90

Curation History

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