Variant: NM_001306179.2:c.186del

CA2573051036

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: cd54b981-0f08-49d3-bb4b-5a12825f9850

Approved on: 2022-04-03

Published on: 2022-07-12

HGVS expressions

NM_001306179.2:c.186del
NC_000012.12:g.120978954del
CM000674.2:g.120978954del
NC_000012.11:g.121416757del
CM000674.1:g.121416757del
NC_000012.10:g.119901140del
NG_011731.2:g.5209del
ENST00000257555.11:c.186del
ENST00000257555.10:c.186del
ENST00000400024.6:c.186del
ENST00000402929.5:n.321del
ENST00000535955.5:n.42+262del
ENST00000538626.2:n.190+114del
ENST00000538646.5:c.186del
ENST00000540108.1:c.186del
ENST00000541395.5:c.186del
ENST00000541924.5:c.186del
ENST00000543427.5:c.186del
ENST00000544413.2:c.186del
ENST00000544574.5:c.72+114del
ENST00000560968.5:n.329del
ENST00000615446.4:c.-258+243del
ENST00000617366.4:c.186del
NM_000545.5:c.186del
NM_000545.6:c.186del
NM_001306179.1:c.186del
NM_000545.8:c.186del

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: PP1 PS1

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.2186delT 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.(Asn62LysfsTer93)). 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). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMIDs: 26431509, 27236918). The nucleotide change c.185delA, which causes the same frameshift, has been classified as pathogenic by the ClinGen MDEP; however, PS1 is not applied to frameshift variants by the ClinGen MDEP. In summary, c.186delT 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 2.1.1.

Not Met criteria codes

• PP1: This variant segregated with diabetes with one informative meiosis in a single family (PMID: 26431509).
• PS1: The nucleotide change c.185delA, which causes the same frameshift, has been classified as pathogenic by the ClinGen MDEP; however, PS1 is not applied to frameshift variants by the ClinGen MDEP.