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_000545.6(HNF1A):c.527-1G>A

CA386963414

449035 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

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

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 PP4_Moderate PS4_Moderate PVS1 PM2_Supporting

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.

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).

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).

PVS1

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

PM2_Supporting

This variant is absent from gnomAD.

Approved on: 2022-04-10

Published on: 2022-07-12

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