Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_175914.5(HNF4A):c.778G>T (p.Asp260Tyr)

CA409107542

549555 (ClinVar)

Gene: HNF4A
Condition: monogenic diabetes
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 3fb9eb15-e6c5-41be-bbdb-c0a4ec44d279
Approved on: 2024-09-26
Published on: 2024-09-26

HGVS expressions

NM_175914.5:c.778G>T
NM_175914.5(HNF4A):c.778G>T (p.Asp260Tyr)
NC_000020.11:g.44419828G>T
CM000682.2:g.44419828G>T
NC_000020.10:g.43048468G>T
CM000682.1:g.43048468G>T
NC_000020.9:g.42481882G>T
NG_009818.1:g.69028G>T
ENST00000316673.9:c.778G>T
ENST00000316099.10:c.844G>T
ENST00000619550.5:c.818G>T
ENST00000683148.1:n.820G>T
ENST00000683657.1:n.1968G>T
ENST00000316099.9:c.844G>T
ENST00000316099.8:c.844G>T
ENST00000316673.8:c.778G>T
ENST00000372920.1:c.*611G>T
ENST00000415691.2:c.844G>T
ENST00000443598.6:c.844G>T
ENST00000457232.5:c.778G>T
ENST00000609795.5:c.778G>T
ENST00000619550.4:c.769G>T
NM_000457.4:c.844G>T
NM_001030003.2:c.778G>T
NM_001030004.2:c.778G>T
NM_001258355.1:c.823G>T
NM_001287182.1:c.769G>T
NM_001287183.1:c.769G>T
NM_001287184.1:c.769G>T
NM_175914.4:c.778G>T
NM_178849.2:c.844G>T
NM_178850.2:c.844G>T
NM_001030003.3:c.778G>T
NM_001030004.3:c.778G>T
NM_001258355.2:c.823G>T
NM_001287182.2:c.769G>T
NM_001287184.2:c.769G>T
NM_178849.3:c.844G>T
NM_178850.3:c.844G>T
NM_000457.5:c.844G>T
NM_000457.6:c.844G>T
NM_001287183.2:c.769G>T
More

Likely Pathogenic

Met criteria codes 5
PP3 PP1_Moderate PP4_Moderate PS4_Moderate PM2_Supporting

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 2.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Monogenic Diabetes VCEP
The c.778G>T variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, causes an amino acid change of aspartate to tyrosine at codon 260 (p.(Asp260Tyr)) 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 0.912, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in 5 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and antibody negative) (PP4_Moderate; internal lab contributors). This variant was segregated with diabetes, with three informative meioses in two families (PP1_Moderate; internal lab contributors). In summary, c.778G>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_moderate, PP1_moderate, PP4_moderate, PM2_supporting, PP3.
Met criteria codes
PP3
This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.912, which is greater than the MDEP VCEP threshold of 0.70 (PP3).
PP1_Moderate
This variant was segregated with diabetes, with three informative meioses in two families (PP1_Moderate; internal lab contributors).
PP4_Moderate
This variant was identified in an individual with a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and antibody negative) (PP4_Moderate; internal lab contributors).
PS4_Moderate
This variant was identified in 5 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors).
PM2_Supporting
This variant is absent from gnomAD v2.1.1 (PM2_Supporting). gnomAD v4.1.0, absent
Curation History
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