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]

Link to SEPIO compliant JSON-LD document

Variant: NM_001306179.2:c.646C>T

CA386964742

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 68b1c9d2-471e-4a56-8c28-b26e39e69c40

HGVS expressions

NM_001306179.2:c.646C>T

NC_000012.12:g.120993639C>T

CM000674.2:g.120993639C>T

NC_000012.11:g.121431442C>T

CM000674.1:g.121431442C>T

NC_000012.10:g.119915825C>T

NG_011731.2:g.19894C>T

ENST00000257555.11:c.646C>T

ENST00000257555.10:c.646C>T

ENST00000400024.6:c.646C>T

ENST00000402929.5:n.781C>T

ENST00000535955.5:n.43-3852C>T

ENST00000538626.2:n.191-3852C>T

ENST00000538646.5:c.527-525C>T

ENST00000540108.1:c.*86C>T

ENST00000541395.5:c.646C>T

ENST00000541924.5:c.646C>T

ENST00000543427.5:c.633+13C>T

ENST00000544413.2:c.646C>T

ENST00000544574.5:c.73-2978C>T

ENST00000560968.5:c.789C>T

ENST00000615446.4:c.-257-2623C>T

ENST00000617366.4:c.586+60C>T

NM_000545.5:c.646C>T

NM_000545.6:c.646C>T

NM_001306179.1:c.646C>T

NM_000545.8:c.646C>T

Pathogenic

PVS1 PP1_Strong PM2_Supporting PP4_Moderate

PS4

Evidence Links 0

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specification: ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HNF1A Version 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.646C>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 216 (p.(Gln216Ter)) 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 in gnomAD v2.1.1 (PM2_Supporting), and 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 (PMID:23348805, internal lab contributors). One of these individuals has a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes, with four informative meioses in two families (PP1_Strong; internal lab contributors). In summary, c.646C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PVS1, PP1_Strong, PP4_Moderate, PM2_Supporting.

PVS1

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).

PP1_Strong

This variant segregated with diabetes, with four informative meioses in two families (PP1_Strong; internal lab contributors).

PM2_Supporting

This variant is absent in gnomAD v2.1.1 (PM2_Supporting).

PP4_Moderate

This variant was identified in an individual with a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; internal lab contributors).

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 (PMID:23348805, internal lab contributors).

Approved on: 2024-01-22

Published on: 2024-01-22

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