Variant: NM_000545.8(HNF1A):c.526C>T (p.Gln176Ter)

CA6831769

372380 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 5d825561-7155-4df0-9661-ceff7d791b78

HGVS expressions

NM_000545.8:c.526C>T
NM_000545.8(HNF1A):c.526C>T (p.Gln176Ter)
NC_000012.12:g.120989032C>T
CM000674.2:g.120989032C>T
NC_000012.11:g.121426835C>T
CM000674.1:g.121426835C>T
NC_000012.10:g.119911218C>T
NG_011731.2:g.15287C>T
ENST00000257555.11:c.526C>T
ENST00000257555.10:c.526C>T
ENST00000400024.6:c.526C>T
ENST00000402929.5:n.661C>T
ENST00000535955.5:n.43-8459C>T
ENST00000538626.2:n.191-8459C>T
ENST00000538646.5:c.526C>T
ENST00000540108.1:c.327-4488C>T
ENST00000541395.5:c.526C>T
ENST00000541924.5:c.526C>T
ENST00000543427.5:c.526C>T
ENST00000544413.2:c.526C>T
ENST00000544574.5:c.73-7585C>T
ENST00000560968.5:n.669C>T
ENST00000615446.4:c.-257-7230C>T
ENST00000617366.4:c.526C>T
NM_000545.5:c.526C>T
NM_000545.6:c.526C>T
NM_001306179.1:c.526C>T
NM_001306179.2:c.526C>T

Pathogenic

• Met criteria codes: PS4 PP1_Strong PP4_Moderate PVS1 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 1.1

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.526C>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 176 (p.(Gln176Ter)) 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 also was identified in 15 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 18003757, internal lab contributors). This variant has a minor allele frequency of 0.000008856 in the gnomAD v2.1.1 European non-Finnish population and zero copies in other subpopulations, which is less than the ClinGen MDEP threshold for PM2_Supporting (≤0.00002 and ≤1 copy in any other subpopulation) (PM2_Supporting). Additionally, this variant segregated with diabetes, with 5 informative meioses in 4 families with MODY (PP1_Strong; internal lab contributors). 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, and negative antibodies) (PP4_Moderate; internal lab contributors). In summary, c.526C>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, PS4, PM2_Supporting, PP1_Strong, PP4_Moderate.

Met criteria codes

• PS4: This variant was identified in 15 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PMID: 18003757, internal lab contributors).
• PP1_Strong: This variant segregated with disease with five informative meioses in four families with MODY (internal lab contributors).
• PP4_Moderate: This variant was identified in two individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (internal lab contributors).
• PVS1: A transcript with this variant is predicted to undergo nonsense mediated decay and this exon is present in a biologically relevant transcript.
• PM2_Supporting: This variant has a minor allele frequency in gnomAD of less than 0.00002 in the European non-Finnish population (actual value = 0.000008856) and zero copies in any other sub-population.

Approved on: 2022-04-10

Published on: 2022-07-12