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.650C>G

CA386964769

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 2233aa14-19c6-44c8-a4b2-ff0ee3c413d1

HGVS expressions

NM_001306179.2:c.650C>G

NC_000012.12:g.120993643C>G

CM000674.2:g.120993643C>G

NC_000012.11:g.121431446C>G

CM000674.1:g.121431446C>G

NC_000012.10:g.119915829C>G

NG_011731.2:g.19898C>G

ENST00000257555.11:c.650C>G

ENST00000257555.10:c.650C>G

ENST00000400024.6:c.650C>G

ENST00000402929.5:n.785C>G

ENST00000535955.5:n.43-3848C>G

ENST00000538626.2:n.191-3848C>G

ENST00000538646.5:c.527-521C>G

ENST00000540108.1:c.*90C>G

ENST00000541395.5:c.650C>G

ENST00000541924.5:c.650C>G

ENST00000543427.5:c.633+17C>G

ENST00000544413.2:c.650C>G

ENST00000544574.5:c.73-2974C>G

ENST00000560968.5:n.793C>G

ENST00000615446.4:c.-257-2619C>G

ENST00000617366.4:c.586+64C>G

NM_000545.5:c.650C>G

NM_000545.6:c.650C>G

NM_001306179.1:c.650C>G

NM_000545.8:c.650C>G

Uncertain Significance

PM1_Supporting PM2_Supporting PP3

PS4 PP4

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.650C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of alanine to glycine at codon 217 (p.(Ala217Gly)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.753, which is greater than the MDEP threshold of 0.70 (PP3). Additionally, this variant is located within 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). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in an individual with diabetes; however, the calculated MODY probability is <50% (PMID: 18003757, internal lab contributor). In summary, c.650C>G 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_Supporting, PM2_Supporting.

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 (PM1_Supporting).

PM2_Supporting

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

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.753.

PS4

This variant was identified in one individual with a diabetes; however this number does not meet the MDEP cutoff for PS4_Moderate.

PP4

This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50% (PMID: 18003757, internal lab contributor).

Approved on: 2022-08-05

Published on: 2022-08-05

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.