Variant: NM_000545.8(HNF1A):c.461T>C (p.Met154Thr)

CA386960242

1317657 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 5ca8d5ea-af99-4705-beaf-a5aa9967677e

Approved on: 2025-01-29

Published on: 2025-01-29

HGVS expressions

NM_000545.8:c.461T>C
NM_000545.8(HNF1A):c.461T>C (p.Met154Thr)
NC_000012.12:g.120988967T>C
CM000674.2:g.120988967T>C
NC_000012.11:g.121426770T>C
CM000674.1:g.121426770T>C
NC_000012.10:g.119911153T>C
NG_011731.2:g.15222T>C
ENST00000560968.6:c.461T>C
ENST00000257555.11:c.461T>C
ENST00000257555.10:c.461T>C
ENST00000400024.6:c.461T>C
ENST00000402929.5:n.596T>C
ENST00000535955.5:n.43-8524T>C
ENST00000538626.2:n.191-8524T>C
ENST00000538646.5:c.461T>C
ENST00000540108.1:c.327-4553T>C
ENST00000541395.5:c.461T>C
ENST00000541924.5:c.461T>C
ENST00000543427.5:c.461T>C
ENST00000544413.2:c.461T>C
ENST00000544574.5:c.73-7650T>C
ENST00000560968.5:c.604T>C
ENST00000615446.4:c.-257-7295T>C
ENST00000617366.4:c.461T>C
NM_000545.5:c.461T>C
NM_000545.6:c.461T>C
NM_001306179.1:c.461T>C
NM_001306179.2:c.461T>C

Likely Pathogenic

• Met criteria codes: PM1_Supporting PM5_Supporting PS4_Moderate PM2_Supporting PP3 PP4 PP1_Moderate

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.461T>C variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of methionine to threonine at codon 154 (p.(Met154Thr)) of NM_000545.8. 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). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.973, which is greater than the MDEP VCEP threshold of 0.70 (PP3). 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; internal lab contributors). This variant was identified in four unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID 27083284, internal lab contributors). Additionally, this variant segregated with diabetes with three informative meioses in three families (PP1_Moderate; PMID: 27083284, internal lab contributors). Another missense variant, c.460A>G p.Met154Val, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.461T>C 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): PS4_Moderate, PP1_Moderate, PM1_Supporting, PM2_Supporting, PM5_Supporting, PP3, PP4.

Met criteria codes

• 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).
• PM5_Supporting: Another missense variant, c.460A>G p.Met154Val, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting).
• PS4_Moderate: This variant was identified in four unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 27083284, internal lab contributors).
• 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 0.973, which is greater than the MDEP VCEP threshold of 0.70 (PP3).
• PP4: 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; internal lab contributors).
• PP1_Moderate: This variant segregated with diabetes with 3 informative meioses in 3 families (PP1_Moderate; PMID: 27083284, internal lab contributors).