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.956-2A>G

CA386967815

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: c0d87338-e61d-456e-a0bf-9d7ef3430c5b

Approved on: 2022-08-05

Published on: 2022-08-05

HGVS expressions

NM_001306179.2:c.956-2A>G

NC_000012.12:g.120996260A>G

CM000674.2:g.120996260A>G

NC_000012.11:g.121434063A>G

CM000674.1:g.121434063A>G

NC_000012.10:g.119918446A>G

NG_011731.2:g.22515A>G

ENST00000257555.11:c.956-2A>G

ENST00000257555.10:c.956-2A>G

ENST00000400024.6:c.956-2A>G

ENST00000402929.5:n.1091-2A>G

ENST00000535955.5:n.43-1231A>G

ENST00000538626.2:n.191-1231A>G

ENST00000538646.5:c.769-2A>G

ENST00000540108.1:c.*396-2A>G

ENST00000541395.5:c.956-2A>G

ENST00000541924.5:c.714-2A>G

ENST00000543427.5:c.634-344A>G

ENST00000544413.2:c.956-2A>G

ENST00000544574.5:c.73-357A>G

ENST00000560968.5:n.894-123A>G

ENST00000615446.4:c.-257-2A>G

ENST00000617366.4:c.587-1374A>G

NM_000545.5:c.956-2A>G

NM_000545.6:c.956-2A>G

NM_001306179.1:c.956-2A>G

NM_000545.8:c.956-2A>G

Pathogenic

PVS1 PP1_Strong PM2_Supporting

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 Version 1.1

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.956-2A>G variant in the HNF1 homeobox A gene, HNF1A, is predicted to remove a canonical splice donor site in intron 4 of NM_000545.8. This variant is predicted to cause skipping of biologically-relevant exon 5 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). 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 8945470, internal lab contributor). This variant segregated with diabetes, with 9 informative meioses in two families with MODY (PP1_Strong; PMID 8945470, internal lab contributor). In summary, c.956-2A>G 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 9/30/2021): PVS1, PP1_Strong, PM2_Supporting.

PVS1

This variant is predicted to cause skipping of biologically-relevant exon 5 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).

PP1_Strong

This variant segregated with diabetes, with 9 informative meioses in two families with MODY (PP1_Strong; PMID 8945470, internal lab contributor).

PM2_Supporting

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

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 8945470, internal lab contributor).

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