Variant: NM_175914.5:c.901A>T

CA409108146

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 73e76dda-7da9-4a74-9b6c-89545ea9b76a

HGVS expressions

NM_175914.5:c.901A>T
NC_000020.11:g.44424092A>T
CM000682.2:g.44424092A>T
NC_000020.10:g.43052732A>T
CM000682.1:g.43052732A>T
NC_000020.9:g.42486146A>T
NG_009818.1:g.73292A>T
ENST00000316099.10:c.967A>T
ENST00000619550.5:n.941A>T
ENST00000316099.9:c.967A>T
ENST00000316099.8:c.967A>T
ENST00000316673.8:c.901A>T
ENST00000372920.1:c.*734A>T
ENST00000415691.2:c.967A>T
ENST00000443598.6:c.967A>T
ENST00000457232.5:c.901A>T
ENST00000609795.5:c.901A>T
ENST00000619550.4:c.892A>T
NM_000457.4:c.967A>T
NM_001030003.2:c.901A>T
NM_001030004.2:c.901A>T
NM_001258355.1:c.946A>T
NM_001287182.1:c.892A>T
NM_001287183.1:c.892A>T
NM_001287184.1:c.892A>T
NM_175914.4:c.901A>T
NM_178849.2:c.967A>T
NM_178850.2:c.967A>T
NM_001030003.3:c.901A>T
NM_001030004.3:c.901A>T
NM_001258355.2:c.946A>T
NM_001287182.2:c.892A>T
NM_001287184.2:c.892A>T
NM_178849.3:c.967A>T
NM_178850.3:c.967A>T
NM_000457.5:c.967A>T
NM_000457.6:c.967A>T
NM_001287183.2:c.892A>T

Likely Pathogenic

• Met criteria codes: PM2_Supporting PS3_Supporting PS2 PP4 PP3 PM1_Supporting

• 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 HNF4A Version 1.0.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.901A>T variant in the Hepatocyte nuclear factor 4 alpha, HNF4A, causes an amino acid change of isoleucine to phenylalanine at codon 301 (p.(Ile301Phe)) of NM_175914.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is located within the ligand binding domain (codons 300-350) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant was identified as a de novo occurrence with confirmed parental relationships in 1 individual with a clinical picture consistent with HNF4A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF1A) (PS2; PMID:15830177). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.976, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Functional studies demonstrated the p.Ile301Phe protein has DNA binding below 60% of wild type, indicating that this variant impacts protein function (PS3_Supporting; PMID:23485969). 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 one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMIDs: 27236918, 15830177). In summary, c.901A>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0, approved 11/16/2022): PS2, PS3_Supporting, PM2_Supporting, PM1_Supporting, PP3, PP4.

Met criteria codes

• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
• PS3_Supporting: Functional studies demonstrated the p.Ile301Phe protein has DNA binding below 40% of wild type, indicating that this variant impacts protein function (PS3_Supporting; [PMID:23485969]).
• PS2: This variant was identified as a de novo occurrence with confirmed parental relationships in 1 individual with a clinical picture highly specific for HNF4A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF1A) (PS2; PMID:15830177).
• 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; PMIDs: 17407387, 15830177).
• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.976, which is greater than the MDEP VCEP threshold of 0.70 (PP3).
• PM1_Supporting: This variant is located within the ligand binding domain (codons 300-350) of HNF4A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).

Not Met criteria codes

• PS4: only 1 family
• 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 (PMIDs: 27236918, 15830177).

Approved on: 2023-07-30

Published on: 2023-07-31