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

CA386965290

1756327 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

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

Approved on: 2023-08-14

Published on: 2023-08-14

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

• Met criteria codes: PS3_Supporting PP3 PP4_Moderate PP1_Moderate PM2_Supporting PM1_Supporting

• Not Met criteria codes: PS4

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

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.

Met criteria codes

• 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).
• 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).
• 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).
• 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).
• PM2_Supporting: This variant is absent in gnomAD v2.1.1 (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).

Not Met criteria codes

• 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).