Variant: NM_000545.8(HNF1A):c.511C>G (p.Arg171Gly)

CA386960701

1384058 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 56f4a372-b3eb-41b7-be50-2ea2562d587e

HGVS expressions

NM_000545.8:c.511C>G
NM_000545.8(HNF1A):c.511C>G (p.Arg171Gly)
NC_000012.12:g.120989017C>G
CM000674.2:g.120989017C>G
NC_000012.11:g.121426820C>G
CM000674.1:g.121426820C>G
NC_000012.10:g.119911203C>G
NG_011731.2:g.15272C>G
ENST00000257555.11:c.511C>G
ENST00000257555.10:c.511C>G
ENST00000400024.6:c.511C>G
ENST00000402929.5:n.646C>G
ENST00000535955.5:n.43-8474C>G
ENST00000538626.2:n.191-8474C>G
ENST00000538646.5:c.511C>G
ENST00000540108.1:c.327-4503C>G
ENST00000541395.5:c.511C>G
ENST00000541924.5:c.511C>G
ENST00000543427.5:c.511C>G
ENST00000544413.2:c.511C>G
ENST00000544574.5:c.73-7600C>G
ENST00000560968.5:c.654C>G
ENST00000615446.4:c.-257-7245C>G
ENST00000617366.4:c.511C>G
NM_000545.5:c.511C>G
NM_000545.6:c.511C>G
NM_001306179.1:c.511C>G
NM_001306179.2:c.511C>G

Likely Pathogenic

• Met criteria codes: PM2_Supporting PM1_Supporting PP4_Moderate PP3 PS4_Moderate

• Not Met criteria codes: PS3

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.511C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to glycine at codon 171 (p.(Arg171Gly)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.888, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in 4 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMIDs: 26853433 and 31291970, 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 negative antibodies) (PP4_Moderate; internal lab contributors). Additionally, 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). In summary, c.511C>G 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, PP3, PP4, PM1_Supporting, PM2_Supporting.

Met criteria codes

• PM2_Supporting: Absent in gnomAD v2.1.1
• 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).
• PP4_Moderate: This variant was identified in an individual with a clinical history highly specific for HNF1A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; internal lab contributors).
• PP3: REVEL = 0.888
• PS4_Moderate: This variant was identified in 4 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMIDs: 26853433 and 31291970, internal lab contributors).

Not Met criteria codes

• PS3: PMID:26853433. Demonstrates >50% luciferase activity in a transactivation assay.

Approved on: 2024-01-28

Published on: 2024-01-28