Variant: NM_000545.6(HNF1A):c.1129del (p.Leu377fs)

CA214257

36796 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: dee335c5-889c-471f-bd08-e9e81e19c16d

Approved on: 2021-12-31

Published on: 2022-07-11

HGVS expressions

NM_000545.6:c.1129del
NM_000545.6(HNF1A):c.1129del (p.Leu377fs)
NC_000012.12:g.120996562del
CM000674.2:g.120996562del
NC_000012.11:g.121434365del
CM000674.1:g.121434365del
NC_000012.10:g.119918748del
NG_011731.2:g.22817del
ENST00000257555.11:c.1129del
ENST00000257555.10:c.1129del
ENST00000400024.6:c.1129del
ENST00000402929.5:n.1264del
ENST00000535955.5:n.43-929del
ENST00000538626.2:n.191-929del
ENST00000538646.5:c.*105del
ENST00000540108.1:c.*569del
ENST00000541395.5:c.1129del
ENST00000541924.5:c.*143del
ENST00000543255.1:n.173del
ENST00000543427.5:c.634-42del
ENST00000544413.2:c.1129del
ENST00000544574.5:c.73-55del
ENST00000560968.5:n.946del
ENST00000615446.4:c.-84del
ENST00000617366.4:c.587-1072del
NM_000545.5:c.1129del
NM_001306179.1:c.1129del
NM_000545.8:c.1129del
NM_001306179.2:c.1129del
NM_000545.8(HNF1A):c.1129del (p.Leu377fs)

Pathogenic

• Met criteria codes: PP4 PVS1 PM2_Supporting

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

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1129delC variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 377 (NM_000545.8), adding 7 novel amino acids before encountering a stop codon (p.(Leu377SerfsTer7)). This variant, located in biologically-relevant exon 6 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 from gnomAD v2.1.1 (PM2_Supporting). Also, 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). In summary, c.1129delC meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.1, approved 6/4/2021): PVS1, PP4, PM2_Supporting

Met criteria codes

• PP4: This variant was identified in one individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A).
• PVS1: This variant is predicted to cause loss of function by resulting in nonsense mediated decay of a biologically relevant transcript.
• PM2_Supporting: This variant is absent from gnomAD.