Variant: NM_001306179.2:c.196dup

CA2573051037

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 5cca4c3e-5d03-4a5e-82be-70f44731486c

Approved on: 2022-04-03

Published on: 2022-07-12

HGVS expressions

NM_001306179.2:c.196dup
NC_000012.12:g.120978964dup
CM000674.2:g.120978964dup
NC_000012.11:g.121416767dup
CM000674.1:g.121416767dup
NC_000012.10:g.119901150dup
NG_011731.2:g.5219dup
ENST00000257555.11:c.196dup
ENST00000257555.10:c.196dup
ENST00000400024.6:c.196dup
ENST00000402929.5:n.331dup
ENST00000535955.5:n.42+272dup
ENST00000538626.2:n.190+124dup
ENST00000538646.5:c.196dup
ENST00000540108.1:c.196dup
ENST00000541395.5:c.196dup
ENST00000541924.5:c.196dup
ENST00000543427.5:c.196dup
ENST00000544413.2:c.196dup
ENST00000544574.5:c.72+124dup
ENST00000560968.5:n.339dup
ENST00000615446.4:c.-258+253dup
ENST00000617366.4:c.196dup
NM_000545.5:c.196dup
NM_000545.6:c.196dup
NM_001306179.1:c.196dup
NM_000545.8:c.196dup

Pathogenic

• Met criteria codes: PS4_Moderate PM2_Supporting PP4_Moderate PVS1 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.196dupG variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 66 (NM_000545.8), adding 30 novel amino acids before encountering a stop codon (p.(Glu66GlyfsTer30)). 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) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant segregated with diabetes, with four informative meioses in two families with MODY (PP1_Strong; internal lab contributors). This variant was identified in four unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). Lastly, this variant was identified in at least two individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative autoantibodies) (PP4_Moderate; internal lab contributors). In summary, c.196dupG 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, PM2_Supporting, PP1_Strong, PP4_Moderate, PS4_Moderate.

Met criteria codes

• PS4_Moderate: This variant was identified in four unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (internal lab contributors).
• PM2_Supporting: Absent from gnomAD.
• PP4_Moderate: Identified in at least two individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative autoantibodies) (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).
• PP1_Strong: Segregated with diabetes, with four informative meioses in two families with MODY (internal lab contributors).