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]

Variant: NM_000545.6(HNF1A):c.527-1G>A

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA386963414

449035 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 8e6eb036-78f3-4929-beb7-eb70b67295df

Approved on: 2022-04-10

Published on: 2022-07-12

HGVS expressions

NM_000545.6:c.527-1G>A

NM_000545.6(HNF1A):c.527-1G>A

NC_000012.12:g.120993519G>A

CM000674.2:g.120993519G>A

NC_000012.11:g.121431322G>A

CM000674.1:g.121431322G>A

NC_000012.10:g.119915705G>A

NG_011731.2:g.19774G>A

ENST00000257555.11:c.527-1G>A

ENST00000257555.10:c.527-1G>A

ENST00000400024.6:c.527-1G>A

ENST00000402929.5:n.662-1G>A

ENST00000535955.5:n.43-3972G>A

ENST00000538626.2:n.191-3972G>A

ENST00000538646.5:c.527-645G>A

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

ENST00000541395.5:c.527-1G>A

ENST00000541924.5:c.527-1G>A

ENST00000543427.5:c.527-1G>A

ENST00000544413.2:c.527-1G>A

ENST00000544574.5:c.73-3098G>A

ENST00000560968.5:n.670-1G>A

ENST00000615446.4:c.-257-2743G>A

ENST00000617366.4:c.527-1G>A

NM_000545.5:c.527-1G>A

NM_001306179.1:c.527-1G>A

NM_000545.8:c.527-1G>A

NM_001306179.2:c.527-1G>A

NM_000545.8(HNF1A):c.527-1G>A

Pathogenic

PP1_Strong PVS1 PS4_Moderate PM2_Supporting PP4_Moderate

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 Version 1.1

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.527-1G>A variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice acceptor site in intron 2 of NM_000545.8. This variant is predicted to cause skipping of biologically-relevant exon 3 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). Also, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 5 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 10588527, internal lab contributors). Additionally, this variant was identified in at least 2 individuals with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A), including one considered highly specific based on sulfonylurea-responsiveness (PP4_Moderate; internal lab contributors). This variant segregated with diabetes, with 7 informative meioses in 2 families with MODY (PP1_Strong; PMID: 10588527, internal lab contributors). In summary, c.527-1G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 9/30/2021): PVS1, PM2_Supporting, PS4_Moderate, PP4_Moderate, PP1_Strong.

PP1_Strong

This variant segregated with disease with seven informative meioses in two families with MODY.

PVS1

This variant is predicted to cause loss of function and result in the nonsense mediated decay of a biologically relevant exon.

PS4_Moderate

This variant was identified in five unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 10588527, internal lab contributors).

PM2_Supporting

This variant is absent from gnomAD.

PP4_Moderate

This variant was identified in multiple individuals with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A), including one considered highly specific based on sulfonylurea-responsiveness (internal lab contributors).

Curation History

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