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.4delG (p.Val2Phefs)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA658658175

447493 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 398ecaa8-8d9a-41cc-9853-8f67eef44c26

Approved on: 2022-02-22

Published on: 2022-02-22

HGVS expressions

NM_000545.6(HNF1A):c.4delG (p.Val2Phefs)

NC_000012.12:g.120978772del

CM000674.2:g.120978772del

NC_000012.11:g.121416575del

CM000674.1:g.121416575del

NC_000012.10:g.119900958del

NG_011731.2:g.5027del

ENST00000257555.11:c.4del

ENST00000257555.10:c.4del

ENST00000400024.6:c.4del

ENST00000402929.5:n.139del

ENST00000535955.5:n.42+80del

ENST00000538626.2:n.122del

ENST00000538646.5:c.4del

ENST00000540108.1:c.4del

ENST00000541395.5:c.4del

ENST00000541924.5:c.4del

ENST00000543427.5:c.4del

ENST00000544413.2:c.4del

ENST00000544574.5:c.4del

ENST00000560968.5:n.147del

ENST00000615446.4:c.-258+61del

ENST00000617366.4:c.4del

NM_000545.5:c.4del

NM_000545.6:c.4del

NM_001306179.1:c.4del

NM_000545.8:c.4del

NM_001306179.2:c.4del

NM_000545.8(HNF1A):c.4del (p.Val2fs)

Pathogenic

PP4 PVS1 PM2_Supporting

BA1 BS1

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. 4delG variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 2 (NM_000545.6), adding 4 novel amino acids before encountering a stop codon (p.(Val2PhefsTer4)). This variant, located in biologically-relevant exon 1 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, the variant is absent from gnomAD v2.1.1 (PM2_Supporting). Lastly, 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, this variant 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.

PP4

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).

PVS1

This variant, located in biologically-relevant exon 1 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).

PM2_Supporting

This variant is absent in gnomAD v2.1.1 (PM2_Supporting).

BA1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Curation History

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