Variant: NM_175914.5:c.270C>G

CA409104248

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 3fda7f99-c9d4-425e-8244-656486bc5225

Approved on: 2024-11-26

Published on: 2025-01-03

HGVS expressions

NM_175914.5:c.270C>G
NC_000020.11:g.44407426C>G
CM000682.2:g.44407426C>G
NC_000020.10:g.43036066C>G
CM000682.1:g.43036066C>G
NC_000020.9:g.42469480C>G
NG_009818.1:g.56626C>G
ENST00000316673.9:c.270C>G
ENST00000316099.10:c.336C>G
ENST00000619550.5:c.310C>G
ENST00000681977.1:c.312C>G
ENST00000682169.1:c.289C>G
ENST00000683148.1:n.312C>G
ENST00000683657.1:n.1460C>G
ENST00000684046.1:c.312C>G
ENST00000684136.1:c.322C>G
ENST00000684476.1:c.293C>G
ENST00000316099.9:c.336C>G
ENST00000316099.8:c.336C>G
ENST00000316673.8:c.270C>G
ENST00000372920.1:c.*103C>G
ENST00000415691.2:c.336C>G
ENST00000443598.6:c.336C>G
ENST00000457232.5:c.270C>G
ENST00000609262.5:c.261C>G
ENST00000609795.5:c.270C>G
ENST00000619550.4:c.261C>G
NM_000457.4:c.336C>G
NM_001030003.2:c.270C>G
NM_001030004.2:c.270C>G
NM_001258355.1:c.315C>G
NM_001287182.1:c.261C>G
NM_001287183.1:c.261C>G
NM_001287184.1:c.261C>G
NM_175914.4:c.270C>G
NM_178849.2:c.336C>G
NM_178850.2:c.336C>G
NM_001030003.3:c.270C>G
NM_001030004.3:c.270C>G
NM_001258355.2:c.315C>G
NM_001287182.2:c.261C>G
NM_001287184.2:c.261C>G
NM_178849.3:c.336C>G
NM_178850.3:c.336C>G
NM_000457.5:c.336C>G
NM_000457.6:c.336C>G
NM_001287183.2:c.261C>G

Likely Pathogenic

• Met criteria codes: PS2_Moderate PP3 PM1 PP4_Moderate PM2_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 for HNF4A Version 2.0.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.270C>G variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of cysteine to tryptophan at codon 90 (p.(Cys90Trp)) of NM_175914.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant resides in an amino acid that is necessary for Zinc-finger formation, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). Additionally, 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). This variant was identified in two 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 (ClinVar, internal lab contributors). One of these individuals had a clinical picture consistent with HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative diabetes antibodies), and this variant was detected as a de novo occurrence with unconfirmed parental relationships (PS2_Moderate, PP4_Moderate; internal lab contributors). In summary, c.270C>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 2.0.0, approved 10/11/2023): PP3, PP4_Moderate, PM2_Supporting, PM1, PS2_Moderate.

Met criteria codes

• PS2_Moderate: This variant was identified as a de novo occurrence with unconfirmed parental relationships in an individual with a clinical picture consistent with HNF4A-monogenic diabetes (MODY probability calculator result >50% and negative genetic testing for HNF1A) (PS2_Moderate; internal lab contributors).
• 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).
• PM1: This variant resides in an amino acid that is necessary for Zinc-finger formation, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1).
• PP4_Moderate: This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and negative antibodies) (PP4_Moderate; internal lab contributors).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

Not Met criteria codes

• PS4: This variant was identified in two 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 (ClinVar, internal lab contributors).