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]

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Variant: NM_000545.8(HNF1A):c.695T>C (p.Leu232Pro)

CA386965290

1756327 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 1add077c-7373-4275-8ea9-e3c18684d8d7

HGVS expressions

NM_000545.8:c.695T>C

NM_000545.8(HNF1A):c.695T>C (p.Leu232Pro)

NC_000012.12:g.120993688T>C

CM000674.2:g.120993688T>C

NC_000012.11:g.121431491T>C

CM000674.1:g.121431491T>C

NC_000012.10:g.119915874T>C

NG_011731.2:g.19943T>C

ENST00000257555.11:c.695T>C

ENST00000257555.10:c.695T>C

ENST00000400024.6:c.695T>C

ENST00000402929.5:n.830T>C

ENST00000535955.5:n.43-3803T>C

ENST00000538626.2:n.191-3803T>C

ENST00000538646.5:c.527-476T>C

ENST00000540108.1:c.*135T>C

ENST00000541395.5:c.695T>C

ENST00000541924.5:c.695T>C

ENST00000543427.5:c.633+62T>C

ENST00000544413.2:c.695T>C

ENST00000544574.5:c.73-2929T>C

ENST00000560968.5:n.838T>C

ENST00000615446.4:c.-257-2574T>C

ENST00000617366.4:c.586+109T>C

NM_000545.5:c.695T>C

NM_000545.6:c.695T>C

NM_001306179.1:c.695T>C

NM_001306179.2:c.695T>C

Likely Pathogenic

PM1_Supporting PM2_Supporting PP3 PP1_Moderate PS3_Supporting PP4_Moderate

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 1.2

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.695T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to proline at codon 232 (p.(Leu232Pro)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.936, which is greater than the MDEP VCEP threshold of 0.70 (PP3). It is also 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, functional studies demonstrated the p.Leu232Pro protein has DNA binding and transactivation below 40% of wild type, indicating that this variant impacts protein function (PS3_Supporting, internal lab contributor). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and 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: 29875428, internal lab contributors). 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, treated with low-dose sulfonylureas, and persistent C-peptide) (PP4_Moderate; internal lab contributor). This variant also segregated with diabetes/hepatic adenomas, with three informative meioses in two families (PP1_Moderate; PMID: 29875428, internal lab contributors). In summary, the c.695T>C variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PP1_Moderate, PP3, PP4_Moderate, PM1_Supporting, PM2_Supporting, PS3_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 in gnomAD v2.1.1 (PM2_Supporting).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.936, which is greater than the MDEP VCEP threshold of 0.70 (PP3).

PP1_Moderate

This variant segregated with diabetes/hyperglycemia and/or hepatic adenomas, with three informative meioses in two families with MODY (PP1; PMID: 29875428, internal lab contributors).

PS3_Supporting

Functional studies demonstrated the p.Leu232Pro protein has DNA binding and transactivation below 40% of wild type, indicating that this variant impacts protein function (PS3_Supporting, internal lab contributor).

PP4_Moderate

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, treated with low-dose sulfonylureas, and persistent C-peptide) (PP4_Moderate; internal lab contributor).

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: 29875428, internal lab contributors).

Approved on: 2023-08-14

Published on: 2023-08-14

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