Variant: NM_001306179.2:c.206del

CA2573051038

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: aaa34b82-9101-4a0f-9abc-92a0ba3a12be

HGVS expressions

NM_001306179.2:c.206del
NC_000012.12:g.120978974del
CM000674.2:g.120978974del
NC_000012.11:g.121416777del
CM000674.1:g.121416777del
NC_000012.10:g.119901160del
NG_011731.2:g.5229del
ENST00000257555.11:c.206del
ENST00000257555.10:c.206del
ENST00000400024.6:c.206del
ENST00000402929.5:n.341del
ENST00000535955.5:n.42+282del
ENST00000538626.2:n.190+134del
ENST00000538646.5:c.206del
ENST00000540108.1:c.206del
ENST00000541395.5:c.206del
ENST00000541924.5:c.206del
ENST00000543427.5:c.206del
ENST00000544413.2:c.206del
ENST00000544574.5:c.72+134del
ENST00000560968.5:n.349del
ENST00000615446.4:c.-258+263del
ENST00000617366.4:c.206del
NM_000545.5:c.206del
NM_000545.6:c.206del
NM_001306179.1:c.206del
NM_000545.8:c.206del

Likely Pathogenic

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

• Met criteria codes: PM2_Supporting PVS1

• Not Met criteria codes: PP1 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.206delG variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 69 (NM_000545.8), adding 86 novel amino acids before encountering a stop codon (p.(Gly69AlafsTer86)). 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 was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested, and PP4 could not be applied (PMID: 18003757, internal lab contributor). 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 (PMID: 27236918, internal lab contributor). In summary, c.209delG meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 9/30/21): PVS1, PM2_Supporting.

Met criteria codes

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

Not Met criteria codes

• PP1: Segregated with diabetes with one informative meiosis in a single family (PMID: 27236918, internal lab contributor).
• PP4: This variant was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (PMID: 18003757).

Approved on: 2022-04-04

Published on: 2022-07-12