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.1137del (p.Val380fs)

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA645372923

435426 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: eb0cda5b-d3a0-4925-84f8-b754b1894602

Approved on: 2021-12-31

Published on: 2022-07-11

HGVS expressions

NM_000545.6:c.1137del

NM_000545.6(HNF1A):c.1137del (p.Val380fs)

NC_000012.12:g.120996570del

CM000674.2:g.120996570del

NC_000012.11:g.121434373del

CM000674.1:g.121434373del

NC_000012.10:g.119918756del

NG_011731.2:g.22825del

ENST00000257555.11:c.1137del

ENST00000257555.10:c.1137del

ENST00000400024.6:c.1137del

ENST00000402929.5:n.1272del

ENST00000535955.5:n.43-921del

ENST00000538626.2:n.191-921del

ENST00000538646.5:c.*113del

ENST00000540108.1:c.*577del

ENST00000541395.5:c.1137del

ENST00000541924.5:c.*151del

ENST00000543255.1:n.181del

ENST00000543427.5:c.634-34del

ENST00000544413.2:c.1137del

ENST00000544574.5:c.73-47del

ENST00000560968.5:n.954del

ENST00000615446.4:c.-76del

ENST00000617366.4:c.587-1064del

NM_000545.5:c.1137del

NM_001306179.1:c.1137del

NM_000545.8:c.1137del

NM_001306179.2:c.1137del

NM_000545.8(HNF1A):c.1137del (p.Val380fs)

Pathogenic

PP1_Strong PVS1 PM2_Supporting PS4

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.1137del variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 380 (NM_000545.8), adding 4 novel amino acids before encountering a stop codon (p.Val380SerfsTer4). This variant, located in biologically-relevant exon 6 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). Also, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in at least 17 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 33538814, internal lab contributors). This variant also segregated with diabetes, with 5 informative meioses in 3 families with MODY (PP1_Strong; internal lab contributors). In summary, c.1137del meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 6/4/2021): PVS1, PM2_Supporting, PS4, PP1_Strong

PP1_Strong

This variant segregated with disease with five informative meioses in three 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.

PM2_Supporting

This variant is absent from gnomAD.

PS4

This variant was identified in at least 17 unrelated individuals non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (internal laboratory contributors).

Curation History

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