The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • No ClinVar Id was directly found from the curated document


Variant: NM_175914.5:c.125G>T

CA409103809

Gene: HNF4A
Condition: monogenic diabetes
Inheritance Mode: Autosomal dominant inheritance
UUID: 0bf65934-36bc-4790-a026-1f4c62c0ece8
Approved on: 2023-08-18
Published on: 2023-08-18

HGVS expressions

NM_175914.5:c.125G>T
NC_000020.11:g.44406133G>T
CM000682.2:g.44406133G>T
NC_000020.10:g.43034773G>T
CM000682.1:g.43034773G>T
NC_000020.9:g.42468187G>T
NG_009818.1:g.55333G>T
ENST00000316099.10:c.191G>T
ENST00000619550.5:n.165G>T
ENST00000681977.1:n.167G>T
ENST00000682169.1:n.144G>T
ENST00000683148.1:n.167G>T
ENST00000683657.1:n.167G>T
ENST00000684046.1:n.167G>T
ENST00000684136.1:n.167G>T
ENST00000684476.1:n.148G>T
ENST00000316099.9:c.191G>T
ENST00000316099.8:c.191G>T
ENST00000316673.8:c.125G>T
ENST00000372920.1:c.282G>T
ENST00000415691.2:c.191G>T
ENST00000443598.6:c.191G>T
ENST00000457232.5:c.125G>T
ENST00000609262.5:c.116G>T
ENST00000609795.5:c.125G>T
ENST00000619550.4:c.116G>T
NM_000457.4:c.191G>T
NM_001030003.2:c.125G>T
NM_001030004.2:c.125G>T
NM_001258355.1:c.170G>T
NM_001287182.1:c.116G>T
NM_001287183.1:c.116G>T
NM_001287184.1:c.116G>T
NM_175914.4:c.125G>T
NM_178849.2:c.191G>T
NM_178850.2:c.191G>T
NM_001030003.3:c.125G>T
NM_001030004.3:c.125G>T
NM_001258355.2:c.170G>T
NM_001287182.2:c.116G>T
NM_001287184.2:c.116G>T
NM_178849.3:c.191G>T
NM_178850.3:c.191G>T
NM_000457.5:c.191G>T
NM_000457.6:c.191G>T
NM_001287183.2:c.116G>T
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Likely Pathogenic

Met criteria codes 5
PM2_Supporting PP3 PM1_Supporting PM5_Supporting PP4_Moderate

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HNF4A Version 1.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Monogenic Diabetes VCEP
The c.125G>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of glycine to valine at codon 42 (p.(Gly42Val)) of NM_175914.5. 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, and responsive to sulfonylurea) (PP4_Moderate; internal lab contributors). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.964, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is located within the DNA binding domain (codons 37-113 of HNF4A), 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). Another missense variant, c.124G>A p.Gly42Arg, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.125G>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 1.1.0 approved 8/11/2023): PP4_Moderate, PP3, PM1_Supporting, PM2_Supporting, PM5_Supporting.
Met criteria codes
PM2_Supporting
This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
PP3
This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.964, which is greater than the MDEP VCEP threshold of 0.70 (PP3).
PM1_Supporting
This variant is located within the DNA binding domain (codons 37-113 of HNF4A), which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).
PM5_Supporting
Another missense variant, c.124G>A p.Gly42Arg, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting).
PP4_Moderate
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, and responsive to sulfonylurea) (PP4_Moderate; internal lab contributors).
Curation History
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