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]

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Variant: NM_022895.3:c.*3072del

CA2573051042

Gene: C12orf43

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: a620f883-8ce6-41fb-9cd3-e02de3f542df

Approved on: 2022-07-01

Published on: 2022-07-01

HGVS expressions

NM_022895.3:c.*3072del

NC_000012.12:g.121001082del

CM000674.2:g.121001082del

NC_000012.11:g.121438885del

CM000674.1:g.121438885del

NC_000012.10:g.119923268del

NG_011731.2:g.27337del

ENST00000257555.11:c.1786del

ENST00000257555.10:c.1786del

ENST00000288757.7:c.*3072del

ENST00000540108.1:c.*1226del

ENST00000541395.5:c.1879del

ENST00000543427.5:c.1249del

ENST00000544413.2:c.1807del

ENST00000560968.5:n.1603del

ENST00000615446.4:c.574del

ENST00000617366.4:c.*195del

NM_000545.5:c.1786del

NM_000545.6:c.1786del

NM_001306179.1:c.1807del

NM_000545.8:c.1786del

NM_001286191.2:c.*3072del

NM_001286196.2:c.*3072del

NM_001306179.2:c.1807del

Likely Pathogenic

PVS1_Strong PP4 PM2_Supporting

PP1

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 1.1

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1786delG variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 596 (NM_000545.8), adding 64 novel amino acids before encountering a stop codon (p.(Val596CysfsTer64)). While this variant, located in exon 10 of 10, is not predicted to result in nonsense mediated decay of the transcript, it will significantly disrupt the transactivation domain of the protein (PVS1_Strong). 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) and is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). In summary, c.1786delG 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 9/30/21): PVS1_Strong, PP4, PM2_Supporting.

PVS1_Strong

While this variant, located 5' of c.1854 in exon 10 of 10, is not predicted to result in nonsense mediated decay of the transcript, it will significantly disrupt the transactivation domain of the protein (PVS1_Strong).

PP4

This variant was identified in an individual with a clinical history specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (internal lab contributors).

PM2_Supporting

Absent from gnomAD.

PP1

This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors).

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