Variant: NM_001306179.2:c.327-1G>A

CA386958691

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 02b4827f-16fc-4d88-8766-4abce391251a

HGVS expressions

NM_001306179.2:c.327-1G>A
NC_000012.12:g.120988832G>A
CM000674.2:g.120988832G>A
NC_000012.11:g.121426635G>A
CM000674.1:g.121426635G>A
NC_000012.10:g.119911018G>A
NG_011731.2:g.15087G>A
ENST00000257555.11:c.327-1G>A
ENST00000257555.10:c.327-1G>A
ENST00000400024.6:c.327-1G>A
ENST00000402929.5:n.462-1G>A
ENST00000535955.5:n.43-8659G>A
ENST00000538626.2:n.191-8659G>A
ENST00000538646.5:c.327-1G>A
ENST00000540108.1:c.327-4688G>A
ENST00000541395.5:c.327-1G>A
ENST00000541924.5:c.327-1G>A
ENST00000543427.5:c.327-1G>A
ENST00000544413.2:c.327-1G>A
ENST00000544574.5:c.73-7785G>A
ENST00000560968.5:n.470-1G>A
ENST00000615446.4:c.-257-7430G>A
ENST00000617366.4:c.327-1G>A
NM_000545.5:c.327-1G>A
NM_000545.6:c.327-1G>A
NM_001306179.1:c.327-1G>A
NM_000545.8:c.327-1G>A

Pathogenic

• Met criteria codes: PM2_Supporting PP4 PVS1

• Not Met criteria codes: PS1 PS4

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.327-1G>A variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice acceptor site in intron 2 of NM_000545.8. This variant is predicted to cause skipping of biologically-relevant exon 2/10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2.1.1. (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability <50%, but clinical judgment applied given that the individual was diagnosed before age 30 with a non-obese BMI, negative genetic testing for HNF4A, sulfonylurea-responsive, and antibody negative) (PP4). The nucleotide change c.327-1G>T has been reported in a patient with MODY; however, the c.327-1G>T variant has not met the criteria to be classified as pathogenic provided by the ClinGen MDEP without the supporting evidence from this variant, and PS1 cannot be applied. Taken together, this evidence supports the classification of this variant as pathogenic for HNF1A-MODY by the ClinGen MDEP. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.1, approved 9/30/2021): PVS1, PM2_Supporting, PP4.

Met criteria codes

• PM2_Supporting: This variant is absent from gnomAD v2.1.1.
• PP4: This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability <50%, but clinical judgment applied given that the individual was diagnosed before age 30 with non-obese BMI, negative genetic testing for HNF4A, sulfonylurea-responsive, and antibody negative) (PP4).
• PVS1: This variant is predicted to cause skipping of biologically-relevant exon 2/10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).

Not Met criteria codes

• PS1: The nucleotide change c.327-1G>T has been reported in a patient with MODY; however, the c.327-1G>T variant has not met the criteria to be classified as pathogenic provided by the ClinGen MDEP without the supporting evidence from this variant.
• PS4: This variant was identified in one individual with a diabetes; however this number does not meet the MDEP cutoff for PS4_Moderate (internal lab contributor)

Approved on: 2022-08-05

Published on: 2022-08-05