Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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Variant: NM_000545.6(HNF1A):c.685C>T (p.Arg229Ter)

CA6831796

420064 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: ef883e91-9835-45c6-8c64-acb061f549b0

HGVS expressions

NM_000545.6:c.685C>T

NM_000545.6(HNF1A):c.685C>T (p.Arg229Ter)

NC_000012.12:g.120993678C>T

CM000674.2:g.120993678C>T

NC_000012.11:g.121431481C>T

CM000674.1:g.121431481C>T

NC_000012.10:g.119915864C>T

NG_011731.2:g.19933C>T

ENST00000257555.11:c.685C>T

ENST00000257555.10:c.685C>T

ENST00000400024.6:c.685C>T

ENST00000402929.5:n.820C>T

ENST00000535955.5:n.43-3813C>T

ENST00000538626.2:n.191-3813C>T

ENST00000538646.5:c.527-486C>T

ENST00000540108.1:c.*125C>T

ENST00000541395.5:c.685C>T

ENST00000541924.5:c.685C>T

ENST00000543427.5:c.633+52C>T

ENST00000544413.2:c.685C>T

ENST00000544574.5:c.73-2939C>T

ENST00000560968.5:n.828C>T

ENST00000615446.4:c.-257-2584C>T

ENST00000617366.4:c.586+99C>T

NM_000545.5:c.685C>T

NM_001306179.1:c.685C>T

NM_000545.8:c.685C>T

NM_001306179.2:c.685C>T

NM_000545.8(HNF1A):c.685C>T (p.Arg229Ter)

Pathogenic

PS4 PVS1 PP1_Strong PM2_Supporting

PP4

Evidence Links 0

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.685C>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 229 (p.(Arg229Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 3 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). Additionally, this variant was identified in at least 34 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 29666556, 23517481, 25411618, internal lab contributors). This variant segregated with diabetes, with at least 13 informative meioses in multiple families with MODY (PP1_Strong; internal lab contributors). In summary, c.685C>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 6/4/2021): PVS1, PM2_Supporting, PS4, PP1_Strong

PS4

This variant was identified in at least 14 unrelated individuals with a clinical picture consistent with monogenic diabetes.

PVS1

A transcript with this variant is predicted to cause loss of function by resulting in nonsense mediated decay of a biologically relevant exon.

PP1_Strong

This variant segregated with disease with 10 informative meioses in four families with MODY.

PM2_Supporting

This variant has a minor allele frequency in gnomAD of less than 0.00002 in the European non-Finnish population (actual value = 0.000008802 + 1 copy in Latino population).

PP4

This variant was identified in one individual (PMID: 25411618) with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%), but there was no negative HNF4A testing.

Approved on: 2021-12-30

Published on: 2021-12-30

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