Variant: NM_000545.6(HNF1A):c.790G>T (p.Val264Phe)

CA214327

36830 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 9700d1bf-b8e1-4a24-a0e2-79487ca358fe

Approved on: 2025-08-05

Published on: 2025-08-05

HGVS expressions

NM_000545.6:c.790G>T
NM_000545.6(HNF1A):c.790G>T (p.Val264Phe)
NC_000012.12:g.120994240G>T
CM000674.2:g.120994240G>T
NC_000012.11:g.121432043G>T
CM000674.1:g.121432043G>T
NC_000012.10:g.119916426G>T
NG_011731.2:g.20495G>T
ENST00000560968.6:c.750+40G>T
ENST00000257555.11:c.790G>T
ENST00000257555.10:c.790G>T
ENST00000400024.6:c.790G>T
ENST00000402929.5:n.925G>T
ENST00000535955.5:n.43-3251G>T
ENST00000538626.2:n.191-3251G>T
ENST00000538646.5:c.603G>T
ENST00000540108.1:c.*230G>T
ENST00000541395.5:c.790G>T
ENST00000541924.5:c.713+534G>T
ENST00000543427.5:c.633+614G>T
ENST00000544413.2:c.790G>T
ENST00000544574.5:c.73-2377G>T
ENST00000560968.5:c.893+40G>T
ENST00000615446.4:c.-257-2022G>T
ENST00000617366.4:c.586+661G>T
NM_000545.5:c.790G>T
NM_001306179.1:c.790G>T
NM_000545.8:c.790G>T
NM_001306179.2:c.790G>T

Likely Pathogenic

• Met criteria codes: PM1 PM2_Supporting PP4_Moderate PP3

• Not Met criteria codes: PS4 PP1

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 3.0.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.790G>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of valine to phenylalanine at codon 264 (p.(Val264Phe)) of NM_000545.8. This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.964, which is greater than the MDEP VCEP threshold of 0.70 (PP3). 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: 18003757, 36257325, internal lab contributors). At least 2 of these individuals did have a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and one had a low renal glucose threshold) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 36257325). In summary, c.790G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PM1, PM2_Supporting, PP3, PP4_Moderate.

Met criteria codes

• PM1: This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 and v4.1.0 (PM2_Supporting).
• PP4_Moderate: This variant was identified in two individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A and one case had low renal glucose theshold) (PP4_Moderate).
• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.964, which is greater than the MDEP VCEP threshold of 0.70 (PP3).

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: 18003757, 36257325, internal lab contributors).
• PP1: This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors).