Variant: NM_000545.8(HNF1A):c.494G>A (p.Trp165Ter)

CA386960529

447491 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 0cb0439e-cbf8-4132-9320-0f0e33231278

HGVS expressions

NM_000545.8:c.494G>A
NM_000545.8(HNF1A):c.494G>A (p.Trp165Ter)
NC_000012.12:g.120989000G>A
CM000674.2:g.120989000G>A
NC_000012.11:g.121426803G>A
CM000674.1:g.121426803G>A
NC_000012.10:g.119911186G>A
NG_011731.2:g.15255G>A
ENST00000257555.11:c.494G>A
ENST00000257555.10:c.494G>A
ENST00000400024.6:c.494G>A
ENST00000402929.5:n.629G>A
ENST00000535955.5:n.43-8491G>A
ENST00000538626.2:n.191-8491G>A
ENST00000538646.5:c.494G>A
ENST00000540108.1:c.327-4520G>A
ENST00000541395.5:c.494G>A
ENST00000541924.5:c.494G>A
ENST00000543427.5:c.494G>A
ENST00000544413.2:c.494G>A
ENST00000544574.5:c.73-7617G>A
ENST00000560968.5:n.637G>A
ENST00000615446.4:c.-257-7262G>A
ENST00000617366.4:c.494G>A
NM_000545.5:c.494G>A
NM_000545.6:c.494G>A
NM_001306179.1:c.494G>A
NM_001306179.2:c.494G>A

Pathogenic

• Met criteria codes: PM2_Supporting PVS1 PP1_Moderate PP4

• Not Met criteria codes: PS4

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.494G>A variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 165 (p.(Trp165Ter)) of NM_000545.8. 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 is absent from gnomAD v2.1.1 (PM2_Supporting). Furthermore, this variant segregated with diabetes, with three informative meioses, in one family with MODY (PP1_Moderate; internal lab contributors). This variant was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability estimated between 39-59% based on available clinical information, sulfonylurea-sensitive, and negative genetic testing for HNF4A) (PP4; internal lab contributors). In summary, c.494G>A 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 9/30/21): PVS1, PM2_Supporting, PP1_Moderate, PP4.

Met criteria codes

• PM2_Supporting: This variant is absent from gnomAD.
• PVS1: A transcript with this variant is predicted to undergo nonsense mediated decay and this exon is present in a biologically relevant transcript.
• PP1_Moderate: This variant segregated with disease in four informative meioses in one family with MODY (internal lab contributors).
• PP4: This variant was identified in one individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result at least 38.5%, negative genetic testing for HNF4A, and sulfonylurea-sensitive),

Not Met criteria codes

• PS4: This variant was identified in two unrelated individuals 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 (internal lab contributors).

Approved on: 2022-06-10

Published on: 2022-06-10