Gene Validity Curation

CACNA1C - long QT syndrome

Gene: CACNA1C (HGNC:1390)
Classification - 04/24/2020
Disease: long QT syndrome (MONDO_0002442)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: NO Contradictory Evidence: NO
Expert Panel: Long QT Syndrome EP Contributors:
  • Long QT Syndrome
  • Long QT Syndrome GCEP
Evidence Summary: CACNA1C encodes for the alpha-1c subunit of the voltage-dependent L-type calcium channel which is important for the development of the action potential in human cardiomyocytes. Pathogenic variants in CACNA1C are the cause for Timothy Syndrome, a rare multi-organ disorder whose manifestations include QT prolongation and ventricular arrhythmias (PMID 15454078). Boczek at al. were the first to identify a variant in CACNA1C in a family with genotype-negative cardiac-specific typical LQTS (PMID 23677916). They performed exome sequencing of 3 members of the family and filtered the shared genetic variants identified using bioinformatics tools. Several other studies have provided additional genetic and experimental evidence to support the association of CACNA1C with typical LQTS, however, no segregation or case-control data is available and the overall level of evidence for this association was classified by the Working Group as moderate. Note: All LQTS genes were curated by 3 separate blinded teams. The evidence and scores reached by these 3 teams was reviewed by the LQTS Clinical Domain Working Group. The classification and summary presented here is the conclusion of this Working Group's analysis according to evidence available at time of publication. The scores presented here are the result of only one of the three curation teams' efforts. For a detailed discussion of this group's work and the scores of all 3 teams please see "Adler et al. An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome. Circulation 2020;141(6):418-428. doi: 10.1161/CIRCULATIONAHA.119.043132”
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
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 10
5
5
Wemhöner K et al. 2015 Mar (PMID:25633834); Boczek NJ et al. 2013 Jun (PMID:23677916); Fukuyama M et al. 2014 Dec (PMID:24728418);
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) 5
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
1.5
Non-patient cells 0.5 0 - 1 3 1.5
Wemhöner K et al. 2015 Mar (PMID:25633834); Boczek NJ et al. 2013 Jun (PMID:23677916); Fukuyama M et al. 2014 Dec (PMID:24728418);
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) 1.5

 


 

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 5 1.5 6.5 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)
Moderate
04/22/2020
EXPERT CURATION (DATE)
Moderate
04/24/2020
EVIDENCE SUMMARY
CACNA1C encodes for the alpha-1c subunit of the voltage-dependent L-type calcium channel which is important for the development of the action potential in human cardiomyocytes. Pathogenic variants in CACNA1C are the cause for Timothy Syndrome, a rare multi-organ disorder whose manifestations include QT prolongation and ventricular arrhythmias (PMID 15454078). Boczek at al. were the first to identify a variant in CACNA1C in a family with genotype-negative cardiac-specific typical LQTS (PMID 23677916). They performed exome sequencing of 3 members of the family and filtered the shared genetic variants identified using bioinformatics tools. Several other studies have provided additional genetic and experimental evidence to support the association of CACNA1C with typical LQTS, however, no segregation or case-control data is available and the overall level of evidence for this association was classified by the Working Group as moderate. Note: All LQTS genes were curated by 3 separate blinded teams. The evidence and scores reached by these 3 teams was reviewed by the LQTS Clinical Domain Working Group. The classification and summary presented here is the conclusion of this Working Group's analysis according to evidence available at time of publication. The scores presented here are the result of only one of the three curation teams' efforts. For a detailed discussion of this group's work and the scores of all 3 teams please see "Adler et al. An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome. Circulation 2020;141(6):418-428. doi: 10.1161/CIRCULATIONAHA.119.043132”