Variant: NM_175914.5(HNF4A):c.502T>C (p.Ser168Pro)

CA409106025

1744896 (ClinVar)

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 4cae4077-fb27-4f18-847d-4a8ca38ad6c0

Approved on: 2023-07-30

Published on: 2023-07-30

HGVS expressions

NM_175914.5:c.502T>C
NM_175914.5(HNF4A):c.502T>C (p.Ser168Pro)
NC_000020.11:g.44414582T>C
CM000682.2:g.44414582T>C
NC_000020.10:g.43043222T>C
CM000682.1:g.43043222T>C
NC_000020.9:g.42476636T>C
NG_009818.1:g.63782T>C
ENST00000316099.10:c.568T>C
ENST00000619550.5:n.542T>C
ENST00000683148.1:n.544T>C
ENST00000683657.1:n.1692T>C
ENST00000316099.9:c.568T>C
ENST00000316099.8:c.568T>C
ENST00000316673.8:c.502T>C
ENST00000372920.1:c.*335T>C
ENST00000415691.2:c.568T>C
ENST00000443598.6:c.568T>C
ENST00000457232.5:c.502T>C
ENST00000609795.5:c.502T>C
ENST00000619550.4:c.493T>C
NM_000457.4:c.568T>C
NM_001030003.2:c.502T>C
NM_001030004.2:c.502T>C
NM_001258355.1:c.547T>C
NM_001287182.1:c.493T>C
NM_001287183.1:c.493T>C
NM_001287184.1:c.493T>C
NM_175914.4:c.502T>C
NM_178849.2:c.568T>C
NM_178850.2:c.568T>C
NM_001030003.3:c.502T>C
NM_001030004.3:c.502T>C
NM_001258355.2:c.547T>C
NM_001287182.2:c.493T>C
NM_001287184.2:c.493T>C
NM_178849.3:c.568T>C
NM_178850.3:c.568T>C
NM_000457.5:c.568T>C
NM_000457.6:c.568T>C
NM_001287183.2:c.493T>C

Uncertain Significance

• Met criteria codes: PP1 PP4 PP3 PM2_Supporting

• Not Met criteria codes: PS4 PM1

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 1.0.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.502T>C variant in the Hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of serine to proline at codon 168 (p.( Ser168Pro)) of NM_175914.5. 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 0.95, 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 HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A) (PP4; internal lab contributor). This variant segregated with diabetes, with two informative meioses in two families with MODY (PP1; internal lab contributor). In summary, c.502T>C meets the criteria to be classified as VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0, approved 11/16/2022): PM2_Supporting, PP3, PP1, PP4.

Met criteria codes

• PP1: This variant segregated with diabetes, with two informative meioses in two families with MODY (PP1; internal lab contributor).
• PP4: This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A) (PP4; internal lab contributor).
• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.95, which is greater than the MDEP VCEP threshold of 0.70 (PP3).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

Not Met criteria codes

• PS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline