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.697G>C

CA16621927

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: a1a3324f-7f7f-4238-b15b-d936d569e7fb

HGVS expressions

NM_001306179.2:c.697G>C

NC_000012.12:g.120993690G>C

CM000674.2:g.120993690G>C

NC_000012.11:g.121431493G>C

CM000674.1:g.121431493G>C

NC_000012.10:g.119915876G>C

NG_011731.2:g.19945G>C

ENST00000257555.11:c.697G>C

ENST00000257555.10:c.697G>C

ENST00000400024.6:c.697G>C

ENST00000402929.5:n.832G>C

ENST00000535955.5:n.43-3801G>C

ENST00000538626.2:n.191-3801G>C

ENST00000538646.5:c.527-474G>C

ENST00000540108.1:c.*137G>C

ENST00000541395.5:c.697G>C

ENST00000541924.5:c.697G>C

ENST00000543427.5:c.633+64G>C

ENST00000544413.2:c.697G>C

ENST00000544574.5:c.73-2927G>C

ENST00000560968.5:c.840G>C

ENST00000615446.4:c.-257-2572G>C

ENST00000617366.4:c.586+111G>C

NM_000545.5:c.697G>C

NM_000545.6:c.697G>C

NM_001306179.1:c.697G>C

NM_000545.8:c.697G>C

Pathogenic

PP1_Strong PS3_Supporting PM1_Supporting PS4_Moderate PM2_Supporting PP4 PP3

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 for HNF1A Version 2.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.697G>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of valine to leucine at codon 233 (p.(Val233Leu)) of NM_000545.8. This variant segregated with diabetes/hyperglycemia, with 6 informative meioses in one family with (PP1_Strong; PMID: 28993341) and the variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.893, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Additionally, 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; PMID 28993341). 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) and is absent from gnomAD v2.1.1 (PM2_Supporting). Functional studies demonstrated the p.Val233Leu protein has transactivation below 40% of wildtype, indicating that this variant impacts protein function (PS3_Supporting; PMID: 15522234). Lastly, this variant was identified in 5 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMIDs: 12488961, 28993341, 24905847). In summary, c.697G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP1_Strong, PS4_Moderate, PP3, PP4, PM1_Supporting, PM2_Supporting, PS3_Supporting.

PP1_Strong

This variant segregated with diabetes/hyperglycemia, with 6 informative meioses in 1 family (PP1_Strong; PMID: 28993341).

PS3_Supporting

Functional studies demonstrated the p.Val233Leu protein has transactivation below 40% of wildtype, indicating that this variant impacts protein function (PMID: 15522234).

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).

PS4_Moderate

This variant was identified in 5 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMIDs: 12488961, 28993341, 24905847).

PM2_Supporting

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

PP4

This variant was identified in an individual with a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A) (PP4; PMID: 28993341).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.893, which is greater than the MDEP VCEP threshold of 0.70 (PP3).

Approved on: 2023-12-18

Published on: 2023-12-18

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.