Variant: NM_000545.8(HNF1A):c.34C>G (p.Leu12Val)

CA386952398

1675062 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 937315db-2908-4530-8c11-7e8f35c7d71d

Approved on: 2025-06-09

Published on: 2025-06-09

HGVS expressions

NM_000545.8:c.34C>G
NM_000545.8(HNF1A):c.34C>G (p.Leu12Val)
NC_000012.12:g.120978802C>G
CM000674.2:g.120978802C>G
NC_000012.11:g.121416605C>G
CM000674.1:g.121416605C>G
NC_000012.10:g.119900988C>G
NG_011731.2:g.5057C>G
ENST00000560968.6:c.34C>G
ENST00000257555.11:c.34C>G
ENST00000257555.10:c.34C>G
ENST00000400024.6:c.34C>G
ENST00000402929.5:n.169C>G
ENST00000535955.5:n.42+110C>G
ENST00000538626.2:n.152C>G
ENST00000538646.5:c.34C>G
ENST00000540108.1:c.34C>G
ENST00000541395.5:c.34C>G
ENST00000541924.5:c.34C>G
ENST00000543427.5:c.34C>G
ENST00000544413.2:c.34C>G
ENST00000544574.5:c.34C>G
ENST00000560968.5:c.177C>G
ENST00000615446.4:c.-258+91C>G
ENST00000617366.4:c.34C>G
NM_000545.5:c.34C>G
NM_000545.6:c.34C>G
NM_001306179.1:c.34C>G
NM_001306179.2:c.34C>G

Likely Pathogenic

• Met criteria codes: PM1_Supporting PM5_Supporting PP4_Moderate PM2_Supporting PP3

• 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 for HNF1A Version 2.1.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.34C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of leucine to valine at codon 12 (p.(Leu12Val)) of NM_000545.8. This variant is absent from gnomAD v2.1.1 (PM2_Supporting).  Additionally, this variant is located within the dimerization domain of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).  This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.861, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified in 2 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 (internal lab contributors). One of these individuals had a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and response to low-dose sulfonylurea) (PP4_Moderate; internal lab contributor).  Lastly, another missense variant at the same amino acid position, c.34C>T (p.Leu12Phe), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, this 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): PM2_Supporting, PM1_Supporting, PP3, PP4_Moderate, PM5_Supporting.

Met criteria codes

• PM1_Supporting: This variant is located within the dimerization domain of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).
• PM5_Supporting: Another missense variant at the same amino acid position, c.34C>T (p.Leu12Phe), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting).
• PP4_Moderate: This variant was identified in one individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and response to low-dose sulfonylurea) (PP4_Moderate; internal lab contributor).
• 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 0.861, which is greater than the MDEP threshold of 0.70 (PP3).

Not Met criteria codes

• PS4: This variant was identified in 2 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 (internal lab contributors).