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.745T>C

CA386965901

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 29080ea6-8328-4407-b6f6-59950e3aec2f

HGVS expressions

NM_001306179.2:c.745T>C

NC_000012.12:g.120994195T>C

CM000674.2:g.120994195T>C

NC_000012.11:g.121431998T>C

CM000674.1:g.121431998T>C

NC_000012.10:g.119916381T>C

NG_011731.2:g.20450T>C

ENST00000257555.11:c.745T>C

ENST00000257555.10:c.745T>C

ENST00000400024.6:c.745T>C

ENST00000402929.5:n.880T>C

ENST00000535955.5:n.43-3296T>C

ENST00000538626.2:n.191-3296T>C

ENST00000538646.5:c.558T>C

ENST00000540108.1:c.*185T>C

ENST00000541395.5:c.745T>C

ENST00000541924.5:c.713+489T>C

ENST00000543427.5:c.633+569T>C

ENST00000544413.2:c.745T>C

ENST00000544574.5:c.73-2422T>C

ENST00000560968.5:n.888T>C

ENST00000615446.4:c.-257-2067T>C

ENST00000617366.4:c.586+616T>C

NM_000545.5:c.745T>C

NM_000545.6:c.745T>C

NM_001306179.1:c.745T>C

NM_000545.8:c.745T>C

Uncertain Significance

PP4 PP3 PM2_Supporting PM1_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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.745T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of serine to proline at codon 249 (p.(Ser249Pro)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.924 (PP3). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; internal lab contributor). This variant was identified in two other individuals with diabetes, however the total number does not meet the MDEP cutoff for PS4_Moderate (PMIDs: 16249556, 18838325, 23771925). In summary, c.745C>T meets the criteria to be classified as a variant of unknown significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM2_Supporting, PM1_Supporting, PP3, PP4.

PP4

This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A) (internal lab contributor).

PP3

REVEL 0.924

PM2_Supporting

absent gnomAD

PM1_Supporting

This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP.

PS4

This variant was identified in three 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: 16249556, 23771925, internal lab contributor).

Approved on: 2022-04-13

Published on: 2022-07-12

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