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

CA6831842

435424 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

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

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

PM2 PS4

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).

PM2

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

PS4

Cannot apply PS4 if PM2_Supporting is not applied.

Approved on: 2021-12-30

Published on: 2021-12-30

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