Variant: NM_001306179.2:c.185del

CA2573051035

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 5a98b6ce-ec4a-4069-a155-32df213fc50b

HGVS expressions

NM_001306179.2:c.185del
NC_000012.12:g.120978953del
CM000674.2:g.120978953del
NC_000012.11:g.121416756del
CM000674.1:g.121416756del
NC_000012.10:g.119901139del
NG_011731.2:g.5208del
ENST00000257555.11:c.185del
ENST00000257555.10:c.185del
ENST00000400024.6:c.185del
ENST00000402929.5:n.320del
ENST00000535955.5:n.42+261del
ENST00000538626.2:n.190+113del
ENST00000538646.5:c.185del
ENST00000540108.1:c.185del
ENST00000541395.5:c.185del
ENST00000541924.5:c.185del
ENST00000543427.5:c.185del
ENST00000544413.2:c.185del
ENST00000544574.5:c.72+113del
ENST00000560968.5:n.328del
ENST00000615446.4:c.-258+242del
ENST00000617366.4:c.185del
NM_000545.5:c.185del
NM_000545.6:c.185del
NM_001306179.1:c.185del
NM_000545.8:c.185del

Pathogenic

• Met criteria codes: PP1_Strong PVS1 PP4_Moderate PM2_Supporting

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.185delA variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 62 (NM_000545.8), adding 93 novel amino acids before encountering a stop codon (p.(Asn62MetfsTer93)). 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). This variant segregated with diabetes, with 8 informative meioses in one family with MODY (PP1_Strong; internal lab contributors). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). 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, response to low dose sulfonylurea, and low renal threshold) (PP4_Moderate; PMID: 28701371, internal lab contributors). In summary, c.185delA 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 9/30/21): PVS1, PM2_Supporting, PP1_Strong, PP4_Moderate

Met criteria codes

• PP1_Strong: Segregated with diabetes, with 8 informative meioses in one family with MODY (internal lab contributors).
• PVS1: Predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID: 23348805).
• PP4_Moderate: Identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and response to low dose sulfonylurea, and low renal threshold) (PMID: 28701371, internal lab contributors).
• PM2_Supporting: Absent from gnomAD.

Approved on: 2022-04-03

Published on: 2022-04-03