Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

HNF4A : monogenic diabetes

HGNC:5024 | MONDO_0015967
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Monogenic Diabetes EP
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12 5
McGlacken-Byrne SM et al. 2014 Jan (PMID:23796040); Flanagan SE et al. 2010 May (PMID:20164212);
Proband with predicted or proven null variant 1.5 0-2 10 1 1.5 1.5
Yamagata K et al. 1996 Dec 5 (PMID:8945471);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 6
Pearson ER et al. 2007 Apr (PMID:17407387);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count 1.5 1.5  
Candidate gene sequencing 16.71 3
Yamagata K et al. 1996 Dec 5 (PMID:8945471); Pearson ER et al. 2007 Apr (PMID:17407387);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 16.71    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 1
Drewes T et al. 1996 Mar (PMID:8622695);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Drewes T et al. 1996 Mar (PMID:8622695);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1 1 0.5
Han EH et al. 2012 Aug 30 (PMID:22952853);
Models Non-human model organism 2 0 - 4 4 1 1 1
Miura A et al. 2006 Feb 24 (PMID:16377800);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 3



Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 3 15 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
HNF4A was first reported in relation to autosomal dominant monogenic diabetes (more specifically in maturity onset diabetes of the young/ MODY) in 1996 (Yamagata et al., 1996 PMID: 8945471). HNF4A is a transcription factor expressed within the liver, kidney, and pancreas of humans (Drewes et al., 1996 PMID: 8622695). HNF4A has been shown to regulate the expression of HNF1A, another transcription factor that is associated with monogenic diabetes, providing a direct correlation between these monogenic diabetes associated genes (Thomas et al., 2001 PMID: 11590126). Numerous variants in HNF4A in relation to the development of monogenic diabetes ( or MODY and hyperinsulinemic hypoglycemia), including missense, frameshift, nonsense and deletions have been reported in humans. There are databases describing HNF4A variants of interest in monogenic diabetes, including: (1) the HNF4A database in LOVD (; and (2) The Diagnostic Mutation Database ( (Colclough et al., 2013 PMID: 23348805). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This gene-disease relationship has been studied for over 20 years, therefore a significant amount of case-level and segregation data is available, however the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is supported by expression studies, biochemical evidence, and animal models. HNF4A has been associated with multiple disease entities and/or phenotypes through autosomal dominant germline inheritance, including: (1) Fanconi renotubular syndrome 4, with maturity-onset diabetes of the young (MIM: 616026); (2) MODY, type I (MIM: 125850); (3) Susceptibility to Diabetes mellitus, noninsulin-dependent (MIM: 125853). The Fanconi renotubular syndrome 4 (FRST4) is associated with a single variant in HNF4A, p.Arg76Trp (aka p.Arg85Trp or Arg63Trp dependent on the transcript used, ref. Flanagan et al., 2010 PMID: 20164212, supplementary table 1) and has been shown to occur in at least 7 different probands (PMIDs: 22802087, 24285859, 25819479, 30005691, 28693455, 28458902, 27245055, 20164212). Renal abnormalities often accompany a diagnosis of MODY. Per the criteria outline by the ClinGen Lumping and Splitting Working Group, FRST4 and MODY1 show the same molecular mechanism and phenotypes consistent with a spectrum of MODY diagnosis, therefore they have been lumped into the disease entity, monogenic diabetes (MONDO:0015967). The susceptibility to diabetes mellitus, non-insulin dependent is not currently curated under this gene-disease relationship and will be evaluated independently. In summary, HNF4A is DEFINITIVELY associated with autosomal dominant monogenic diabetes. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Monogenic Diabetes Expert Panel on Feb 26, 2019.