Variant: NM_175914.5(HNF4A):c.691C>T (p.Arg231Trp)

CA9870361

1186689 (ClinVar)

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 5ca9dcd8-781b-4769-9157-3e8fe159f595

Approved on: 2024-05-10

Published on: 2024-05-10

HGVS expressions

NM_175914.5:c.691C>T
NM_175914.5(HNF4A):c.691C>T (p.Arg231Trp)
NC_000020.11:g.44419741C>T
CM000682.2:g.44419741C>T
NC_000020.10:g.43048381C>T
CM000682.1:g.43048381C>T
NC_000020.9:g.42481795C>T
NG_009818.1:g.68941C>T
ENST00000316673.9:c.691C>T
ENST00000316099.10:c.757C>T
ENST00000619550.5:c.731C>T
ENST00000683148.1:n.733C>T
ENST00000683657.1:n.1881C>T
ENST00000316099.9:c.757C>T
ENST00000316099.8:c.757C>T
ENST00000316673.8:c.691C>T
ENST00000372920.1:c.*524C>T
ENST00000415691.2:c.757C>T
ENST00000443598.6:c.757C>T
ENST00000457232.5:c.691C>T
ENST00000609795.5:c.691C>T
ENST00000619550.4:c.682C>T
NM_000457.4:c.757C>T
NM_001030003.2:c.691C>T
NM_001030004.2:c.691C>T
NM_001258355.1:c.736C>T
NM_001287182.1:c.682C>T
NM_001287183.1:c.682C>T
NM_001287184.1:c.682C>T
NM_175914.4:c.691C>T
NM_178849.2:c.757C>T
NM_178850.2:c.757C>T
NM_001030003.3:c.691C>T
NM_001030004.3:c.691C>T
NM_001258355.2:c.736C>T
NM_001287182.2:c.682C>T
NM_001287184.2:c.682C>T
NM_178849.3:c.757C>T
NM_178850.3:c.757C>T
NM_000457.5:c.757C>T
NM_000457.6:c.757C>T
NM_001287183.2:c.682C>T

Likely Pathogenic

• Met criteria codes: PM2_Supporting PS4 PM5 PP4 PP3

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.691C>T variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of arginine to tryptophan at codon 231 (p.(Arg231Trp)) of NM_175914.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.927, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to one copy in the European non-Finnish subpopulation and zero copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Grpmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). Additionally, this variant was identified in at least 8 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; internal lab contributors). One of these individuals has a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF1A) (PP4; internal lab contributor). Another missense variant, c.692G>A (p.Arg231Gln), has been interpreted as pathogenic by the ClinGen MDEP, and p.Arg231Trp has a greater grantham distance (PM5). In summary, c.691C>T 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): PS4, PM5, PP3, PP4, PM2_Supporting.

Met criteria codes

• PM2_Supporting: This variant has an incomputable gnomAD v2.1.1 Grpmax filtering allele frequency due to one copy in the European non-Finnish subpopulation and zero copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Grpmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting).
• PS4: This variant was identified in at least 8 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; internal lab contributors).
• PM5: Another missense variant, c.692G>A (p.Arg231Gln), has been interpreted as pathogenic by the ClinGen MDEP, and p.Arg231Trp has a greater grantham distance (PM5).
• 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 0.927, which is greater than the MDEP VCEP threshold of 0.70 (PP3).