Variant: NM_001306179.2:c.427del

CA2023554331

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 70cd5b7b-7049-4fa0-a7f3-87f7ea86a6de

HGVS expressions

NM_001306179.2:c.427del
NC_000012.12:g.120988933del
CM000674.2:g.120988933del
NC_000012.11:g.121426736del
CM000674.1:g.121426736del
NC_000012.10:g.119911119del
NG_011731.2:g.15188del
ENST00000257555.11:c.427del
ENST00000257555.10:c.427del
ENST00000400024.6:c.427del
ENST00000402929.5:n.562del
ENST00000535955.5:n.43-8558del
ENST00000538626.2:n.191-8558del
ENST00000538646.5:c.427del
ENST00000540108.1:c.327-4587del
ENST00000541395.5:c.427del
ENST00000541924.5:c.427del
ENST00000543427.5:c.427del
ENST00000544413.2:c.427del
ENST00000544574.5:c.73-7684del
ENST00000560968.5:n.570del
ENST00000615446.4:c.-257-7329del
ENST00000617366.4:c.427del
NM_000545.5:c.427del
NM_000545.6:c.427del
NM_001306179.1:c.427del
NM_000545.8:c.427del

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: PS4 PP1 PP4

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.427del variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 143 (NM_000545.8), adding 12 novel amino acids before encountering a stop codon (p.(His143ThrfsTer12)). 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). Additionally, this variant is absent in 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 (PMID 18003757, internal lab contributor). Additionally, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID 18003757). This variant segregated with diabetes with two informative meioses in this individual's family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributor). In summary, this evidence supports the classification of this variant as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0, approved 8/24/21): PVS1, PM2_Supporting.

Met criteria codes

• PM2_Supporting: This variant is 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)

Not Met criteria codes

• PS4: This variant was identified in one individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID 18003757).
• PP1: This variant segregated with diabetes with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (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, internal lab contributor).

Approved on: 2021-10-29

Published on: 2021-11-19