Variant: NM_022895.3:c.*3072del

CA2573051042

Gene: C12orf43

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

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

• Met criteria codes: PP4 PVS1_Strong PM2_Supporting

• Not Met criteria codes: PP1

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

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.

Met criteria codes

• 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).
• 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).
• PM2_Supporting: Absent from gnomAD.

Not Met criteria codes

• 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).