Gene Validity Curation

HNF1B - renal cysts and diabetes syndrome

Gene: HNF1B (HGNC:11630)
Classification - 12/10/2019
Disease: renal cysts and diabetes syndrome (MONDO_0007669)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Monogenic Diabetes EP
Evidence Summary: HNF1B was first reported in relation to autosomal dominant Renal Cysts and Diabetes Syndrome in 1997 (Horikawa et al., PMID: 9398836). This disease entity can include primary renal phenotypes and has also been referred to as MODY Type IV and Renal Cysts and Diabetes (RCAD). Numerous variants have been reported in humans per ClinVar. Evidence supporting this gene-disease relationship includes case-level and experimental data. Summary of case-level and experimental data: 18 points. Variants in this gene have been reported in at least 13 probands in 7 publications (PMIDS: 9398836, 12161522, 25705165, 25754277, 25441779, 15068978, 20378641). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is heterozygous loss of function. This gene-disease association is supported by expression studies, animal models, and in vitro functional assays. In summary, HNF1B is definitively associated with autosomal dominant Renal Cysts and Diabetes Syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.
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 3
5
5
Kanthimathi S et al. 2015 Jan (PMID:25441779); Heidet L et al. 2010 Jun (PMID:20378641);
Proband with predicted or proven null variant 1.5 0-2 10 4 6 6
Horikawa Y et al. 1997 Dec (PMID:9398836); Furuta H et al. 2002 Aug (PMID:12161522); Hogendorf A et al. 2015 (PMID:25754277); Bellanné-Chantelot C et al. 2004 Apr 6 (PMID:15068978);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 6
1
1
Kim EK et al. 2014 Dec (PMID:25705165); Bellanné-Chantelot C et al. 2004 Apr 6 (PMID:15068978);
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 0.5 0.5  
Candidate gene sequencing 2.41 1
Horikawa Y et al. 1997 Dec (PMID:9398836);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 2.41    
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
1.5
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 3 1.5
Fendler W et al. 2016 July (PMID:27059371); Fagerberg L et al. 2014 Feb (PMID:24309898); GTEx Consortium et al. 2013 Jun (PMID:23715323);
Functional Alteration Patient cells 1 0 - 2 2
0.5
Non-patient cells 0.5 0 - 1 1 0.5
Welters HJ et al. 2006 Jul (PMID:16837621);
Models Non-human model organism 2 0 - 4 4 2 4 4
Haumaitre C et al. 2005 Feb 1 (PMID:15668393); Wang L et al. 2004 Aug (PMID:15142986);
Cell culture model 1 0 - 2 1 1
Teo AK et al. 2016 Mar 8 (PMID:26876668);
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) 6

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
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
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 6 18 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
01/15/2020
EXPERT CURATION (DATE)
Definitive
12/10/2019
EVIDENCE SUMMARY
HNF1B was first reported in relation to autosomal dominant Renal Cysts and Diabetes Syndrome in 1997 (Horikawa et al., PMID: 9398836). This disease entity can include primary renal phenotypes and has also been referred to as MODY Type IV and Renal Cysts and Diabetes (RCAD). Numerous variants have been reported in humans per ClinVar. Evidence supporting this gene-disease relationship includes case-level and experimental data. Summary of case-level and experimental data: 18 points. Variants in this gene have been reported in at least 13 probands in 7 publications (PMIDS: 9398836, 12161522, 25705165, 25754277, 25441779, 15068978, 20378641). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is heterozygous loss of function. This gene-disease association is supported by expression studies, animal models, and in vitro functional assays. In summary, HNF1B is definitively associated with autosomal dominant Renal Cysts and Diabetes Syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.