Variant: NM_001306179.2:c.399_405del

CA2573051300

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 61f5fc7a-01ce-44ed-8ad7-caf876ff602c

HGVS expressions

NM_001306179.2:c.399_405del
NC_000012.12:g.120988905_120988911del
CM000674.2:g.120988905_120988911del
NC_000012.11:g.121426708_121426714del
CM000674.1:g.121426708_121426714del
NC_000012.10:g.119911091_119911097del
NG_011731.2:g.15160_15166del
ENST00000257555.11:c.399_405del
ENST00000257555.10:c.399_405del
ENST00000400024.6:c.399_405del
ENST00000402929.5:n.534_540del
ENST00000535955.5:n.43-8586_43-8580del
ENST00000538626.2:n.191-8586_191-8580del
ENST00000538646.5:c.399_405del
ENST00000540108.1:c.327-4615_327-4609del
ENST00000541395.5:c.399_405del
ENST00000541924.5:c.399_405del
ENST00000543427.5:c.399_405del
ENST00000544413.2:c.399_405del
ENST00000544574.5:c.73-7712_73-7706del
ENST00000560968.5:n.542_548del
ENST00000615446.4:c.-257-7357_-257-7351del
ENST00000617366.4:c.399_405del
NM_000545.5:c.399_405del
NM_000545.6:c.399_405del
NM_001306179.1:c.399_405del
NM_000545.8:c.399_405del

Likely Pathogenic

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

• Met criteria codes: PM2_Supporting PVS1

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.399_405del variant in the HNF1 Homeobox A gene, HNF1A, causes a frameshift in the protein at codon 134 of NM_000545.8, adding 19 novel amino acids before encountering a stop codon (p.(Val134ProfsTer19)). This variant, located in biologically-relevant exon 2 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 in absent in gnomAD v2.1.1 (PM2_Supporting). In summary, the c.399_405del variant 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

• PM2_Supporting: This variant in absent in gnomAD v2.1.1 (PM2_Supporting).
• PVS1: This variant, located in biologically-relevant exon 2 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).

Approved on: 2022-06-24

Published on: 2022-06-24