Variant: NM_000545.8(HNF1A):c.169del (p.Leu57fs)

CA214284

36809 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 4d480331-52c6-40f2-a1f5-354aa23b9c8c

HGVS expressions

NM_000545.8:c.169del
NM_000545.8(HNF1A):c.169del (p.Leu57fs)
NC_000012.12:g.120978937del
CM000674.2:g.120978937del
NC_000012.11:g.121416740del
CM000674.1:g.121416740del
NC_000012.10:g.119901123del
NG_011731.2:g.5192del
ENST00000257555.11:c.169del
ENST00000257555.10:c.169del
ENST00000400024.6:c.169del
ENST00000402929.5:n.304del
ENST00000535955.5:n.42+245del
ENST00000538626.2:n.190+97del
ENST00000538646.5:c.169del
ENST00000540108.1:c.169del
ENST00000541395.5:c.169del
ENST00000541924.5:c.169del
ENST00000543427.5:c.169del
ENST00000544413.2:c.169del
ENST00000544574.5:c.72+97del
ENST00000560968.5:n.312del
ENST00000615446.4:c.-258+226del
ENST00000617366.4:c.169del
NM_000545.5:c.169del
NM_000545.6:c.169del
NM_001306179.1:c.169del
NM_001306179.2:c.169del

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

• Met criteria codes: PVS1 PM2_Supporting

• Not Met criteria codes: PP4

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.169delC variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 57 (NM_000545.8), adding 98 novel amino acids before encountering a stop codon (p.(Leu57TrpfsTer98)). 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). This variant was previously reported in ClinVar, but no clinical information was provided, so PP4 could not be applied. In summary, c.142delG meets the criteria to be classified as likely 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.

Met criteria codes

• PVS1: Predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID: 23348805).
• PM2_Supporting: Absent from gnomAD.

Not Met criteria codes

• PP4: One case reported in ClinVar but no clinical information provided.

Approved on: 2022-04-03

Published on: 2022-07-12