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 computer assertion could be determined for this classification!

Variant: NM_175914.5(HNF4A):c.868C>T (p.Arg290Cys)

CA409108070

447524 (ClinVar)

Gene: HNF4A
Condition: monogenic diabetes
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: f865092a-203c-4229-8cf1-4453409017d7
Approved on: 2024-04-06
Published on: 2024-04-06

HGVS expressions

NM_175914.5:c.868C>T
NM_175914.5(HNF4A):c.868C>T (p.Arg290Cys)
NC_000020.11:g.44424059C>T
CM000682.2:g.44424059C>T
NC_000020.10:g.43052699C>T
CM000682.1:g.43052699C>T
NC_000020.9:g.42486113C>T
NG_009818.1:g.73259C>T
ENST00000316673.9:c.868C>T
ENST00000316099.10:c.934C>T
ENST00000619550.5:c.908C>T
ENST00000316099.9:c.934C>T
ENST00000316099.8:c.934C>T
ENST00000316673.8:c.868C>T
ENST00000372920.1:c.*701C>T
ENST00000415691.2:c.934C>T
ENST00000443598.6:c.934C>T
ENST00000457232.5:c.868C>T
ENST00000609795.5:c.868C>T
ENST00000619550.4:c.859C>T
NM_000457.4:c.934C>T
NM_001030003.2:c.868C>T
NM_001030004.2:c.868C>T
NM_001258355.1:c.913C>T
NM_001287182.1:c.859C>T
NM_001287183.1:c.859C>T
NM_001287184.1:c.859C>T
NM_175914.4:c.868C>T
NM_178849.2:c.934C>T
NM_178850.2:c.934C>T
NM_001030003.3:c.868C>T
NM_001030004.3:c.868C>T
NM_001258355.2:c.913C>T
NM_001287182.2:c.859C>T
NM_001287184.2:c.859C>T
NM_178849.3:c.934C>T
NM_178850.3:c.934C>T
NM_000457.5:c.934C>T
NM_000457.6:c.934C>T
NM_001287183.2:c.859C>T
More

Pathogenic

Met criteria codes 6
PM5 PP1_Strong PM2_Supporting PP4_Moderate PS4 PP3
Not Met criteria codes 2
PM1 BP4

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.868C>T variant in the hepatic nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of arginine to cysteine at codon 290 (p.(Arg290Cys)) of NM_175914.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.92, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in at least 10 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 32533152, 21683639, internal lab contributors). One of these individuals had a clinical history highly specific for HNF4A-monogenic diabetes (MODY probability calculator result >50%, negative genetic testing for HNF1A, and a family member with the variant with diazoxide-responsive neonatal hyperinsulinemic hypoglycemia) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes, with 20 informative meioses in 8 families (PP1_Strong; internal lab contributors). Another missense variant, c.869G>A p.Arg290His, has been interpreted as pathogenic by the ClinGen MDEP, and p.Arg290Cys has a greater Grantham distance (PM5). In summary, c.868C>T meets the criteria to be classified as Pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PP1_Strong, PS4, PP4_Moderate, PM5, PP3, PM2_Supporting.
Met criteria codes
PM5
Another missense variant, c.869G>A p.Arg290His, has been interpreted as pathogenic by the ClinGen MDEP, and p.Arg290Cys has a greater Grantham distance (PM5).
PP1_Strong
This variant segregated with diabetes, with 20 informative meioses in 8 families (PP1_Strong; internal lab contributors).
PM2_Supporting
This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
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 a family member with the variant with diazoxide-responsive neonatal hyperinsulinemic hypoglycemia) (PP4_Moderate; internal lab contributors).
PS4
This variant was identified in at least 10 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 32533152, 21683639, internal lab contributors).
PP3
This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.92, which is greater than the MDEP VCEP threshold of 0.70 (PP3).
Not Met criteria codes
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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