Gene Validity Classification Summary

Gene/Disease Pair:

HCN4 : Familial thoracic aortic aneurysm and aortic dissection

HGNC:16882 | OrphaNet: 91387 | OMIM:
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
0.0
0
Proband with predicted or proven null variant 1.5 0-2 10 1.5 1.5
Vermeer AM et al. 2016 May 17 (PMID:27173043); (Proband with dilated aorta asecendens and/or aortic root with predicted null : c.1920_1932dupCAGCGTGCTCACC; p.Ser695Ter )
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 3.5 3.5
Vermeer AM et al. 2016 May 17 (PMID:27173043); (7 unrelated probands with dilated aorta asecendens and/or aortic root. with 5 missense variants in HCN4. 7*0.5=3.5)
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 0.0 0
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 0.0
Segregation Evidence Evidence of segregation in one or more families LOD Score Examples 3 5 0-7 7 1.5 1.5
Vermeer AM et al. 2016 May 17 (PMID:27173043); (Three families together were assigned 1.5 based on segregation.)
2 4
1.5 3
1 1.5
   
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Scores PMIDs/Notes
Points/Study Max Points Tally
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12 0.0
Aggregate Variant Analysis 0-6 12 0.0
Total Genetic Evidence Points (Maximum 12) 6.5
Experimental Evidence
Evidence Category Evidence Type Guidelines Scores PMIDs/Notes
Default Range Max Points Tally
Function Biochemical Function 0.5 0 - 2 2 0.5 0.5
Liang X et al. 2013 Aug 2 (PMID:23743334); (Expression: Mice with nuclear localized LacZ or H2BGFP knocked into the endogenous HCN4 locus and analyzed reporter expression in the heart during development; At E12.5, HCN4-H2BGFP was expressed in endothelial cells of the aorta and pulmonary artery and co-expressed with PECAM, an endothelial cell marker.)
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 0.0
Non-patient cells 0.5 0 - 1
Models & Rescue Animal model 2 0 - 4 4 0.0
Cell culture model system 1 0 - 2
Rescue in animal model 2 0 - 4
Rescue in engineered equivalent 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 0.5

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 6.5 0.5 7 NO
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
CALCULATED CLASSIFICATION (DATE)
MODERATE
10/17/2016
EXPERT CURATION (DATE)
LIMITED
12/22/2016
Assertion made by the Aortopathy working group. 1 point subtracted due to absence of dissection and lack of longitudinal data on aortic growth. Recent gene - needs further data in support of clinically relevant aortic disease.