Variant: NM_000545.8(HNF1A):c.511C>T (p.Arg171Ter)

CA16606083

377965 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: b56e5c2d-f615-46c2-9373-143f326142cb

HGVS expressions

NM_000545.8:c.511C>T
NM_000545.8(HNF1A):c.511C>T (p.Arg171Ter)
NC_000012.12:g.120989017C>T
CM000674.2:g.120989017C>T
NC_000012.11:g.121426820C>T
CM000674.1:g.121426820C>T
NC_000012.10:g.119911203C>T
NG_011731.2:g.15272C>T
ENST00000257555.11:c.511C>T
ENST00000257555.10:c.511C>T
ENST00000400024.6:c.511C>T
ENST00000402929.5:n.646C>T
ENST00000535955.5:n.43-8474C>T
ENST00000538626.2:n.191-8474C>T
ENST00000538646.5:c.511C>T
ENST00000540108.1:c.327-4503C>T
ENST00000541395.5:c.511C>T
ENST00000541924.5:c.511C>T
ENST00000543427.5:c.511C>T
ENST00000544413.2:c.511C>T
ENST00000544574.5:c.73-7600C>T
ENST00000560968.5:n.654C>T
ENST00000615446.4:c.-257-7245C>T
ENST00000617366.4:c.511C>T
NM_000545.5:c.511C>T
NM_000545.6:c.511C>T
NM_001306179.1:c.511C>T
NM_001306179.2:c.511C>T

Pathogenic

• Met criteria codes: PP1_Strong PVS1 PP4_Moderate PS4 PM2_Supporting PM1

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.511C>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 171 (p.(Arg171Ter)) 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). This variant segregated with diabetes, with 13 informative meioses in 5 families with MODY (PP1_Strong; internal lab contributors). This variant was identified in 14 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 9097962, 10102714, 12530534, 12574234, 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.511C>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 September 30, 2021): PVS1, PS4, PP1_Strong, PM2_Supporting, PP4_Moderate.

Met criteria codes

• PP1_Strong: This variant segregated with disease with 13 informative meioses in five families with MODY.
• PVS1: A transcript with this variant is predicted to undergo nonsense mediated decay and this exon is present in a biologically relevant transcript.
• PP4_Moderate: 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).
• PS4: This variant was identified in 14 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PMIDs: 9097962, 10102714, 12530534, 12574234, internal lab contributors).
• PM2_Supporting: This variant is absent from gnomAD.
• PM1: This variant is located within the dimerization domain of HNF1A.

Approved on: 2022-04-10

Published on: 2022-07-12