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]
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Variant: NM_175914.5(HNF4A):c.403C>T (p.Gln135Ter)

CA409105749

450787 (ClinVar)

Gene: HNF4A
Condition: monogenic diabetes
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 3fb4a80e-d6d8-49b2-8b52-7ed16c23abe0

HGVS expressions

NM_175914.5:c.403C>T
NM_175914.5(HNF4A):c.403C>T (p.Gln135Ter)
NC_000020.11:g.44413777C>T
CM000682.2:g.44413777C>T
NC_000020.10:g.43042417C>T
CM000682.1:g.43042417C>T
NC_000020.9:g.42475831C>T
NG_009818.1:g.62977C>T
ENST00000316673.9:c.403C>T
ENST00000316099.10:c.469C>T
ENST00000619550.5:c.443C>T
ENST00000683148.1:n.445C>T
ENST00000683657.1:n.1593C>T
ENST00000316099.9:c.469C>T
ENST00000316099.8:c.469C>T
ENST00000316673.8:c.403C>T
ENST00000372920.1:c.*236C>T
ENST00000415691.2:c.469C>T
ENST00000443598.6:c.469C>T
ENST00000457232.5:c.403C>T
ENST00000609795.5:c.403C>T
ENST00000619550.4:c.394C>T
NM_000457.4:c.469C>T
NM_001030003.2:c.403C>T
NM_001030004.2:c.403C>T
NM_001258355.1:c.448C>T
NM_001287182.1:c.394C>T
NM_001287183.1:c.394C>T
NM_001287184.1:c.394C>T
NM_175914.4:c.403C>T
NM_178849.2:c.469C>T
NM_178850.2:c.469C>T
NM_001030003.3:c.403C>T
NM_001030004.3:c.403C>T
NM_001258355.2:c.448C>T
NM_001287182.2:c.394C>T
NM_001287184.2:c.394C>T
NM_178849.3:c.469C>T
NM_178850.3:c.469C>T
NM_000457.5:c.469C>T
NM_000457.6:c.469C>T
NM_001287183.2:c.394C>T

Pathogenic

Met criteria codes 3
PVS1 PM2_Supporting PP1
Not Met criteria codes 1
PS4

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.403C>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, results in a premature termination at codon 135 (p.(Gln135Ter)) of NM_175914.5. This variant, located in biologically-relevant exon 4 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). It was identified in at least three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (ClinVar ID:450787, internal lab contributor). Additionally, the variant segregated with diabetes, with three informative meioses in one family with MODY (PP1; internal lab contributor). In summary, c.403C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specidication version 2.0.0, approved 10/11/23): PVS1, PP1,1 PM2_Supporting.
Met criteria codes
PVS1
This variant, located in biologically-relevant exon 4 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805).
PM2_Supporting
This variant is absent in gnomAD v2.1.1 (PM2_Supporting).
PP1
This variant segregated with diabetes, with three informative meioses in one family with MODY (PP1; internal lab contributor).
Not Met criteria codes
PS4
This variant was identified in at least three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (ClinVar ID:450787, internal lab contributor).
Approved on: 2024-04-06
Published on: 2024-04-06
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