Gene Validity Curation

KCNQ1 - hypertrophic cardiomyopathy

Gene: KCNQ1 (HGNC:6294)
Classification - 04/07/2020
Disease: hypertrophic cardiomyopathy (MONDO_0005045)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: NO Contradictory Evidence: NO
Expert Panel: Hypertrophic Cardiomyopathy EP
Evidence Summary: KCNQ1 has not yet been reported in relation to autosomal dominant hypertrophic cardiomyopathy in the literature. Many different variants have previously been reported in association with Long-QT syndrome, Jervell and Lange-Nielsen syndrome, and atrial fibrillation. Evidence supporting this gene-disease relationship is limited to a case where known pathogenic variants in other HCM causal genes, in particular MYBPC3, are present and segregate with the phenotype in the family. Evidence implicating KCNQ1 in sudden cardiac death and ventricular arrhythmias has been presented, but all seem to stem from another disease entity. No experimental evidence is present to support the relationship. In conclusion, no convincing evidence for or against a causal role for KCNQ1 in autosomal dominant hypertrophic cardiomyopathy has been reported. This gene-disease association is not supported by any relevant experimental evidence nor have any reports directly implicated the gene in humans.
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
Proband with predicted or proven null variant 1.5 0-2 10 1 0 0
D'Argenio V et al. 2014 Jan (PMID:24183960);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
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  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
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) 0
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4
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) 0

 


 

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 0 0 0 NO
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)
No Known Disease Relationship
04/07/2020
EXPERT CURATION (DATE)
No Known Disease Relationship
04/07/2020
EVIDENCE SUMMARY
KCNQ1 has not yet been reported in relation to autosomal dominant hypertrophic cardiomyopathy in the literature. Many different variants have previously been reported in association with Long-QT syndrome, Jervell and Lange-Nielsen syndrome, and atrial fibrillation. Evidence supporting this gene-disease relationship is limited to a case where known pathogenic variants in other HCM causal genes, in particular MYBPC3, are present and segregate with the phenotype in the family. Evidence implicating KCNQ1 in sudden cardiac death and ventricular arrhythmias has been presented, but all seem to stem from another disease entity. No experimental evidence is present to support the relationship. In conclusion, no convincing evidence for or against a causal role for KCNQ1 in autosomal dominant hypertrophic cardiomyopathy has been reported. This gene-disease association is not supported by any relevant experimental evidence nor have any reports directly implicated the gene in humans.