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.613A>C

CA386964305

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 23999536-3c9f-4a51-8823-2b9119dfc7e3

HGVS expressions

NM_001306179.2:c.613A>C

NC_000012.12:g.120993606A>C

CM000674.2:g.120993606A>C

NC_000012.11:g.121431409A>C

CM000674.1:g.121431409A>C

NC_000012.10:g.119915792A>C

NG_011731.2:g.19861A>C

ENST00000257555.11:c.613A>C

ENST00000257555.10:c.613A>C

ENST00000400024.6:c.613A>C

ENST00000402929.5:n.748A>C

ENST00000535955.5:n.43-3885A>C

ENST00000538626.2:n.191-3885A>C

ENST00000538646.5:c.527-558A>C

ENST00000540108.1:c.*53A>C

ENST00000541395.5:c.613A>C

ENST00000541924.5:c.613A>C

ENST00000543427.5:c.613A>C

ENST00000544413.2:c.613A>C

ENST00000544574.5:c.73-3011A>C

ENST00000560968.5:n.756A>C

ENST00000615446.4:c.-257-2656A>C

ENST00000617366.4:c.586+27A>C

NM_000545.5:c.613A>C

NM_000545.6:c.613A>C

NM_001306179.1:c.613A>C

NM_000545.8:c.613A>C

Uncertain Significance

PS3_Supporting PP3 PM2_Supporting PM1

PS4 PP1 PP4

Evidence Links 3

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.613A>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of lysine to glutamine at codon 205 (p.(Lys205Gln)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.867, which is greater than the MDEP threshold of 0.70 (PP3). Additionally, this variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Functional studies demonstrated the p.Lys205Gln protein has nuclear transactivation below 40% of wildtype, indicating that this variant impacts protein function (PS3_Supporting, PMID: 10585442). In summary, c.613A>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PP3, PM1, PM2_Supporting, PS3_Supporting.

PS3_Supporting

Functional studies demonstrated the p.Lys205Gln protein has reduced transactivation in comparison to wildtype (PMID: 10585442)

To assess the trans-activation potential of the HNF1a p.Lys205Gln mutant compared with that of the native protein, increasing amounts of the HNF1a expression vector were transfected together with a CAT reporter gene under the control of the chimeric b28 promoter containing three HNF1a binding sites upstream of the rat b-fibrinogen TATA box sequence. Transfections were performed in the human epithelial C33 cells, which lack any endogeneous HNF1 expression. PubMed:10585442

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.867.

PM2_Supporting

This variant is absent from gnomAD (PM2_Supporting).

PM1

This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1).

Lys205 is an amino acid that directly binds DNA. PubMed:28410371

Lys205 is an amino acid that directly binds DNA. PubMed:12453420

PS4

Two independent cases (PMID: 9287053 and Exeter Genomics Laboratory, UK).

PP1

This variant segregated with disease with 2 informative meioses in 1 family with MODY (PMID: 9287053).

PP4

Two cases (PMID: 9287053 and Exeter Genomics Laboratory, UK), however none met both: MODY probability calculator result >50% and had HNF4A tested.

Approved on: 2022-08-04

Published on: 2022-08-04

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