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_001306179.2:c.339G>A

CA386958847

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 312b8987-2733-435e-93e2-d94e62005cb3

Approved on: 2024-09-10

Published on: 2024-09-10

HGVS expressions

NM_001306179.2:c.339G>A

NC_000012.12:g.120988845G>A

CM000674.2:g.120988845G>A

NC_000012.11:g.121426648G>A

CM000674.1:g.121426648G>A

NC_000012.10:g.119911031G>A

NG_011731.2:g.15100G>A

ENST00000560968.6:c.339G>A

ENST00000257555.11:c.339G>A

ENST00000257555.10:c.339G>A

ENST00000400024.6:c.339G>A

ENST00000402929.5:n.474G>A

ENST00000535955.5:n.43-8646G>A

ENST00000538626.2:n.191-8646G>A

ENST00000538646.5:c.339G>A

ENST00000540108.1:c.327-4675G>A

ENST00000541395.5:c.339G>A

ENST00000541924.5:c.339G>A

ENST00000543427.5:c.339G>A

ENST00000544413.2:c.339G>A

ENST00000544574.5:c.73-7772G>A

ENST00000560968.5:c.482G>A

ENST00000615446.4:c.-257-7417G>A

ENST00000617366.4:c.339G>A

NM_000545.5:c.339G>A

NM_000545.6:c.339G>A

NM_001306179.1:c.339G>A

NM_000545.8:c.339G>A

Pathogenic

PP1_Strong PP4_Moderate PM2_Supporting PVS1

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 2.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.339G>A variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 113 (p.(Trp113Ter)) 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 was identified in 3 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 (PMIDs: 21437455, 11692182, 29439679). One of these individuals had a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, negative antibodies) (PP4_Moderate; PMID: 29439679). This variant segregated with diabetes with five informative meioses in two families (PP1_Strong, PMIDs: 27236918, 21437455; internal lab contributor). In summary, c.339G>A 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.

PP1_Strong

This variant segregated with diabetes with five informative meioses in two families (PMIDs: 27236918, 21437455; internal lab contributor).

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, negative antibodies, and a three generation family history of diabetes) (PP4_Moderate; PMID: 29439679).

PM2_Supporting

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

PVS1

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).

PS4

This variant was identified in 3 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 (PMIDs: 21437455, 11692182, 29439679).

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