Variant: NM_001306179.2:c.404del

CA2497030023

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 16475fd8-01fc-44a7-bd03-f07814f30c39

HGVS expressions

NM_001306179.2:c.404del
NC_000012.12:g.120988910del
CM000674.2:g.120988910del
NC_000012.11:g.121426713del
CM000674.1:g.121426713del
NC_000012.10:g.119911096del
NG_011731.2:g.15165del
ENST00000257555.11:c.404del
ENST00000257555.10:c.404del
ENST00000400024.6:c.404del
ENST00000402929.5:n.539del
ENST00000535955.5:n.43-8581del
ENST00000538626.2:n.191-8581del
ENST00000538646.5:c.404del
ENST00000540108.1:c.327-4610del
ENST00000541395.5:c.404del
ENST00000541924.5:c.404del
ENST00000543427.5:c.404del
ENST00000544413.2:c.404del
ENST00000544574.5:c.73-7707del
ENST00000560968.5:n.547del
ENST00000615446.4:c.-257-7352del
ENST00000617366.4:c.404del
NM_000545.5:c.404del
NM_000545.6:c.404del
NM_001306179.1:c.404del
NM_000545.8:c.404del

Pathogenic

• Met criteria codes: PM2_Supporting PVS1 PS4 PP4_Moderate PP1_Strong

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.404del variant in the HNF1 Homeobox A gene, HMF1A, causes a frameshift in the protein at codon 135 (NM_000545.8), adding 20 novel amino acids before encountering a stop codon (p.(Asp135ValfsTer20)). This variant, located in biologically-relevant exon 2 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 is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in 9 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID 30269055, internal lab contributors). At least one of these individuals has a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sensitive to sulfonylureas) (PP4_Moderate; PMID 30269055, internal lab contributor). This variant also segregated with diabetes, with at least 11 informative meioses in six families with MODY (PP1_Strong; internal lab contributor). In summary, the c.404del 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 9/30/21): PVS1, PP1_Strong, PS4, PP4_Moderate, PM2_Supporting.

Met criteria codes

• PM2_Supporting: This variant is absent in gnomAD v2.1.1 (PM2_Supporting).
• PVS1: This variant, located in biologically-relevant exon 2 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).
• PS4: This variant was identified in 9 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID 30269055, internal lab contributors).
• PP4_Moderate: This variant was identified in at least one individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sensitive to sulfonylureas) (PP4_Moderate; PMID 30269055, internal lab contributor).
• PP1_Strong: This variant segregated with diabetes, with at least 11 informative meioses in six families with MODY (PP1_Strong; internal lab contributor).

Approved on: 2022-07-01

Published on: 2022-07-01