Variant: NM_001306179.2:c.164_168del

CA2573051034

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 75db9296-74f4-4510-96bf-aa29cbeb6819

HGVS expressions

NM_001306179.2:c.164_168del
NC_000012.12:g.120978932_120978936del
CM000674.2:g.120978932_120978936del
NC_000012.11:g.121416735_121416739del
CM000674.1:g.121416735_121416739del
NC_000012.10:g.119901118_119901122del
NG_011731.2:g.5187_5191del
ENST00000257555.11:c.164_168del
ENST00000257555.10:c.164_168del
ENST00000400024.6:c.164_168del
ENST00000402929.5:n.299_303del
ENST00000535955.5:n.42+240_42+244del
ENST00000538626.2:n.190+92_190+96del
ENST00000538646.5:c.164_168del
ENST00000540108.1:c.164_168del
ENST00000541395.5:c.164_168del
ENST00000541924.5:c.164_168del
ENST00000543427.5:c.164_168del
ENST00000544413.2:c.164_168del
ENST00000544574.5:c.72+92_72+96del
ENST00000560968.5:n.307_311del
ENST00000615446.4:c.-258+221_-258+225del
ENST00000617366.4:c.164_168del
NM_000545.5:c.164_168del
NM_000545.6:c.164_168del
NM_001306179.1:c.164_168del
NM_000545.8:c.164_168del

Pathogenic

• Met criteria codes: PP1_Strong PP4 PVS1 PM2_Supporting

• Not Met criteria codes: PS4

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.164_168del variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 55 (NM_000545.8), adding 3 novel amino acids before encountering a stop codon (p.(Gly55AlafsTer3)). 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; 23348805) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant segregated with diabetes, with 12 informative meioses in two families with MODY (PP1_Strong; PMID: 14598263, internal lab contributor). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, HNF4A not tested but hepatic adenomatosis present) (PP4; internal lab contributor). This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 14598263, internal lab contributor). In summary, c.164_169del 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.

Met criteria codes

• PP1_Strong: Segregated with diabetes in at least 12 meisoses in 2 families (PMID: 14598263, internal lab contributor).
• PP4: Identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, not tested for HNF4A but had hepatic adenomatosis) (PP4; internal lab contributor).
• PVS1: Predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism.
• PM2_Supporting: Absent from gnomAD.

Not Met criteria codes

• PS4: Identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes.

Approved on: 2022-04-03

Published on: 2022-07-12