Variant: NM_000545.6(HNF1A):c.1A>T (p.Met1Leu)

CA386951973

502525 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 9119b620-1951-443c-96fd-5a29455f8200

HGVS expressions

NM_000545.6:c.1A>T
NM_000545.6(HNF1A):c.1A>T (p.Met1Leu)
NC_000012.12:g.120978769A>T
CM000674.2:g.120978769A>T
NC_000012.11:g.121416572A>T
CM000674.1:g.121416572A>T
NC_000012.10:g.119900955A>T
NG_011731.2:g.5024A>T
ENST00000257555.11:c.1A>T
ENST00000257555.10:c.1A>T
ENST00000400024.6:c.1A>T
ENST00000402929.5:n.136A>T
ENST00000535955.5:n.42+77A>T
ENST00000538626.2:n.119A>T
ENST00000538646.5:c.1A>T
ENST00000540108.1:c.1A>T
ENST00000541395.5:c.1A>T
ENST00000541924.5:c.1A>T
ENST00000543427.5:c.1A>T
ENST00000544413.2:c.1A>T
ENST00000544574.5:c.1A>T
ENST00000560968.5:n.144A>T
ENST00000615446.4:c.-258+58A>T
ENST00000617366.4:c.1A>T
NM_000545.5:c.1A>T
NM_001306179.1:c.1A>T
NM_000545.8:c.1A>T
NM_001306179.2:c.1A>T
NM_000545.8(HNF1A):c.1A>T (p.Met1Leu)

Pathogenic

• Met criteria codes: PVS1 PP4_Moderate PM2_Supporting

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

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1A>T variant in the HNF1 homeobox A gene, HNF1A, results in the loss of the initiation codon (p.Met1Leu) of transcript NM_000545.8. By altering the start codon of the coding sequence, this variant is predicted to cause a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). 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 calculator result >50%, negative genetic testing for HNF4A, sulfonylurea-responsive, and antibody negative) (PP4_Moderate; internal lab contributor). In summary, c.1A>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PVS1, PM2_Supporting and PP4_Moderate.

Met criteria codes

• PVS1: A transcript with this variant is predicted to cause loss of function and result in nonsense mediated decay of a biologically relevant exon.
• PP4_Moderate: This variant was identified in one individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A), who was also antibody negative.
• PM2_Supporting: This variant is absent from gnomAD.

Approved on: 2022-03-04

Published on: 2022-07-11