Activity

Filter

Cancel
Date Panel Item Activity
36 actions
Short QT syndrome v3.25 CACNA1C Ida Ertmanska commented on gene: CACNA1C: Comment on list classification: There are several individuals reported in literature with monoallelic CACNA1C variants and Short QT Syndrome (SQTS), or Brugada syndrome with SQTS. However, this association has been classified as Disputed in ClinGen. Some allele frequencies are too high in population databases, there is little functional evidence supporting the variant pathogenicity, and most variants are ranked as VUS according to ACMG criteria. There is no robust evidence linking SQTS to CACNA1C variants. Hence this gene should be demoted at the next GMS update. An expert-review tag was added as this is a proposed demotion of a Green gene.
Short QT syndrome v3.25 CACNA1C Ida Ertmanska edited their review of gene: CACNA1C: Changed phenotypes to: Brugada syndrome 3, OMIM:611875, Timothy syndrome, OMIM:601005, Long QT syndrome 8, OMIM:618447
Short QT syndrome v3.25 CACNA1C Ida Ertmanska Publications for gene: CACNA1C were set to 24291113; 16301704; 30027834; 30279520; 17224476; 28427417; 28490369; 29759541; 29697308
Short QT syndrome v3.24 CACNA1C Ida Ertmanska Tag Q3_26_expert_review tag was added to gene: CACNA1C.
Short QT syndrome v3.24 CACNA1C Ida Ertmanska Tag Q3_26_demote_amber tag was added to gene: CACNA1C.
Short QT syndrome v3.24 CACNA1C Ida Ertmanska edited their review of gene: CACNA1C: Changed rating: AMBER
Short QT syndrome v3.24 CACNA1C Ida Ertmanska changed review comment from: The association between CANCA1C and AD short QT syndrome has been classified as Disputed in ClinGen (Aug 2020, Short QT Syndrome Expert Panel). Evidence summary:
PMID 24291113 - de novo CACNA1C variant reported, the gnomAD MAF was regarded as too high for a rare condition such as SQTS; no other evidence supporting this variant’s impact.
PMIDs 17224476, 20817017 - 3 probands had Brugada syndrome with a relatively short QT interval - not isolated SQTS
PMID 28427417 - proband with hypertrophic cardiomyopathy without a convincing SQTS phenotype

PMID: 30571592 El-Battrawy et al., 2018
Long-term follow up of patients with CACNA1C variant G490R and SQTS (3 members of same family). 1 individual had no clinical symptoms, 1 had palpitations, and third individual had both palpitations and Atrial fibrillation. CACNA1C p.Gly490Arg variant is common in gnomAD (total AF = 0.0003994, with 4 homozygotes reported) - too common to cause AD disease. B/LB in ClinGen.

PMID: 39503779 Martínez-Barrios et al., 2024 - lit review
"Four rare missense variants have been reported in the CACNA1C gene associated with phenotypes, showing a reduction in the QT interval (p.Ala39Val, p.Gly490Arg, p.Lys800Thr and p.Arg1973Pro). Concretely, three variants were reported in cases diagnosed with BrS and stnQT (p.Ala39Val, p.Gly490Arg and p.Arg1973Pro) and one additional rare variant was reported in a patient diagnosed with ASD and stnQT (p.Lys800Thr). All these rare variants are currently classified as VUS, following ACMG recommendations."; to: The association between CACNA1C and AD short QT syndrome has been classified as Disputed in ClinGen (Aug 2020, Short QT Syndrome Expert Panel). Evidence summary:
PMID 24291113 - de novo CACNA1C variant reported, the gnomAD MAF was regarded as too high for a rare condition such as SQTS; no other evidence supporting this variant’s impact.
PMIDs 17224476, 20817017 - 3 probands had Brugada syndrome with a relatively short QT interval - not isolated SQTS
PMID 28427417 - proband with hypertrophic cardiomyopathy without a convincing SQTS phenotype

CACNA1C association with AD Brugada syndrome is also Disputed in ClinGen as of 2025: "Many reported variants in CACNA1C are too common in population databases, and functional studies have shown that both common and rare variants can produce similar effects [PMID: 17224476, 20817017]."

PMID: 30571592 El-Battrawy et al., 2018
Long-term follow up of patients with CACNA1C variant G490R and SQTS (3 members of same family). 1 individual had no clinical symptoms, 1 had palpitations, and third individual had both palpitations and Atrial fibrillation. CACNA1C p.Gly490Arg variant is common in gnomAD (total AF = 0.0003994, with 4 homozygotes reported) - too common to cause AD disease. B/LB in ClinGen.

PMID: 34999275 Novelli et al., 2022
563 BrS probands underwent CACNA1C sequencing - identified 11 different rare variants in 9 patients. Most of these were classified as VUS according to ACMG criteria.
"CACNA1C is an infrequent but definitive cause of BrS typically associated with short QT."

PMID: 39503779 Martínez-Barrios et al., 2024 - lit review
"Four rare missense variants have been reported in the CACNA1C gene associated with phenotypes, showing a reduction in the QT interval (p.Ala39Val, p.Gly490Arg, p.Lys800Thr and p.Arg1973Pro). Concretely, three variants were reported in cases diagnosed with BrS and stnQT (p.Ala39Val, p.Gly490Arg and p.Arg1973Pro) and one additional rare variant was reported in a patient diagnosed with ASD and stnQT (p.Lys800Thr). All these rare variants are currently classified as VUS, following ACMG recommendations."
Short QT syndrome v3.24 CACNA1C Ida Ertmanska changed review comment from: The association between CANCA1C and AD short QT syndrome has been classified as Disputed in ClinGen (Aug 2020, Short QT Syndrome Expert Panel). Evidence summary:
PMID 24291113 - de novo CACNA1C variant reported, the gnomAD MAF was regarded as too high for a rare condition such as SQTS; no other evidence supporting this variant’s impact.
PMIDs 17224476, 20817017 - 3 probands had Brugada syndrome with a relatively short QT interval - not isolated SQTS
PMID 28427417 - proband with hypertrophic cardiomyopathy without a convincing SQTS phenotype

PMID: 30571592 El-Battrawy et al., 2018
Long-term follow up of patients with CACNA1C variant G490R and SQTS (3 members of same family). 1 individual had no clinical symptoms, 1 had palpitations, and third individual had both palpitations and Atrial fibrillation. CACNA1C p.Gly490Arg variant is common in gnomAD (total AF = 0.0003994, with 4 homozygotes reported) - too common to cause AD disease.

PMID: 39503779 Martínez-Barrios et al., 2024 - lit review
"Four rare missense variants have been reported in the CACNA1C gene associated with phenotypes, showing a reduction in the QT interval (p.Ala39Val, p.Gly490Arg, p.Lys800Thr and p.Arg1973Pro). Concretely, three variants were reported in cases diagnosed with BrS and stnQT (p.Ala39Val, p.Gly490Arg and p.Arg1973Pro) and one additional rare variant was reported in a patient diagnosed with ASD and stnQT (p.Lys800Thr). All these rare variants are currently classified as VUS, following ACMG recommendations."; to: The association between CANCA1C and AD short QT syndrome has been classified as Disputed in ClinGen (Aug 2020, Short QT Syndrome Expert Panel). Evidence summary:
PMID 24291113 - de novo CACNA1C variant reported, the gnomAD MAF was regarded as too high for a rare condition such as SQTS; no other evidence supporting this variant’s impact.
PMIDs 17224476, 20817017 - 3 probands had Brugada syndrome with a relatively short QT interval - not isolated SQTS
PMID 28427417 - proband with hypertrophic cardiomyopathy without a convincing SQTS phenotype

PMID: 30571592 El-Battrawy et al., 2018
Long-term follow up of patients with CACNA1C variant G490R and SQTS (3 members of same family). 1 individual had no clinical symptoms, 1 had palpitations, and third individual had both palpitations and Atrial fibrillation. CACNA1C p.Gly490Arg variant is common in gnomAD (total AF = 0.0003994, with 4 homozygotes reported) - too common to cause AD disease. B/LB in ClinGen.

PMID: 39503779 Martínez-Barrios et al., 2024 - lit review
"Four rare missense variants have been reported in the CACNA1C gene associated with phenotypes, showing a reduction in the QT interval (p.Ala39Val, p.Gly490Arg, p.Lys800Thr and p.Arg1973Pro). Concretely, three variants were reported in cases diagnosed with BrS and stnQT (p.Ala39Val, p.Gly490Arg and p.Arg1973Pro) and one additional rare variant was reported in a patient diagnosed with ASD and stnQT (p.Lys800Thr). All these rare variants are currently classified as VUS, following ACMG recommendations."
Short QT syndrome v3.24 CACNA1C Ida Ertmanska changed review comment from: The association between CANCA1C and AD short QT syndrome has been classified as Disputed in ClinGen (Aug 2020, Short QT Syndrome Expert Panel). Evidence summary:
PMID 24291113 - de novo CACNA1C variant reported, the gnomAD MAF was regarded as too high for a rare condition such as SQTS; no other evidence supporting this variant’s impact.
PMIDs 17224476, 20817017 - 3 probands had Brugada syndrome with a relatively short QT interval - not isolated SQTS
PMID 28427417 - proband with hypertrophic cardiomyopathy without a convincing SQTS phenotype

PMID: 30571592 El-Battrawy et al., 2018
Long-term follow up of patients with CACNA1C variant G490R and SQTS (3 members of same family). 1 individual had no clinical symptoms, 1 had palpitations, and third individual had both palpitations and Atrial fibrillation.

PMID: 39503779 Martínez-Barrios et al., 2024 - lit review
"Four rare missense variants have been reported in the CACNA1C gene associated with phenotypes, showing a reduction in the QT interval (p.Ala39Val, p.Gly490Arg, p.Lys800Thr and p.Arg1973Pro). Concretely, three variants were reported in cases diagnosed with BrS and stnQT (p.Ala39Val, p.Gly490Arg and p.Arg1973Pro) and one additional rare variant was reported in a patient diagnosed with ASD and stnQT (p.Lys800Thr). All these rare variants are currently classified as VUS, following ACMG recommendations."; to: The association between CANCA1C and AD short QT syndrome has been classified as Disputed in ClinGen (Aug 2020, Short QT Syndrome Expert Panel). Evidence summary:
PMID 24291113 - de novo CACNA1C variant reported, the gnomAD MAF was regarded as too high for a rare condition such as SQTS; no other evidence supporting this variant’s impact.
PMIDs 17224476, 20817017 - 3 probands had Brugada syndrome with a relatively short QT interval - not isolated SQTS
PMID 28427417 - proband with hypertrophic cardiomyopathy without a convincing SQTS phenotype

PMID: 30571592 El-Battrawy et al., 2018
Long-term follow up of patients with CACNA1C variant G490R and SQTS (3 members of same family). 1 individual had no clinical symptoms, 1 had palpitations, and third individual had both palpitations and Atrial fibrillation. CACNA1C p.Gly490Arg variant is common in gnomAD (total AF = 0.0003994, with 4 homozygotes reported) - too common to cause AD disease.

PMID: 39503779 Martínez-Barrios et al., 2024 - lit review
"Four rare missense variants have been reported in the CACNA1C gene associated with phenotypes, showing a reduction in the QT interval (p.Ala39Val, p.Gly490Arg, p.Lys800Thr and p.Arg1973Pro). Concretely, three variants were reported in cases diagnosed with BrS and stnQT (p.Ala39Val, p.Gly490Arg and p.Arg1973Pro) and one additional rare variant was reported in a patient diagnosed with ASD and stnQT (p.Lys800Thr). All these rare variants are currently classified as VUS, following ACMG recommendations."
Short QT syndrome v3.24 CACNA1C Ida Ertmanska changed review comment from: The association between CANCA1C and AD short QT syndrome has been classified as Disputed in ClinGen (Aug 2020, Short QT Syndrome Expert Panel). Evidence summary:
PMID 24291113 - de novo CACNA1C variant reported, the gnomAD MAF was regarded as too high for a rare condition such as SQTS; no other evidence supporting this variant’s impact.
PMIDs 17224476, 20817017 - 3 probands had Brugada syndrome with a relatively short QT interval - not isolated SQTS
PMID 28427417 - proband with hypertrophic cardiomyopathy without a convincing SQTS phenotype; to: The association between CANCA1C and AD short QT syndrome has been classified as Disputed in ClinGen (Aug 2020, Short QT Syndrome Expert Panel). Evidence summary:
PMID 24291113 - de novo CACNA1C variant reported, the gnomAD MAF was regarded as too high for a rare condition such as SQTS; no other evidence supporting this variant’s impact.
PMIDs 17224476, 20817017 - 3 probands had Brugada syndrome with a relatively short QT interval - not isolated SQTS
PMID 28427417 - proband with hypertrophic cardiomyopathy without a convincing SQTS phenotype

PMID: 30571592 El-Battrawy et al., 2018
Long-term follow up of patients with CACNA1C variant G490R and SQTS (3 members of same family). 1 individual had no clinical symptoms, 1 had palpitations, and third individual had both palpitations and Atrial fibrillation.

PMID: 39503779 Martínez-Barrios et al., 2024 - lit review
"Four rare missense variants have been reported in the CACNA1C gene associated with phenotypes, showing a reduction in the QT interval (p.Ala39Val, p.Gly490Arg, p.Lys800Thr and p.Arg1973Pro). Concretely, three variants were reported in cases diagnosed with BrS and stnQT (p.Ala39Val, p.Gly490Arg and p.Arg1973Pro) and one additional rare variant was reported in a patient diagnosed with ASD and stnQT (p.Lys800Thr). All these rare variants are currently classified as VUS, following ACMG recommendations."
Short QT syndrome v3.24 CACNA1C Ida Ertmanska reviewed gene: CACNA1C: Rating: RED; Mode of pathogenicity: None; Publications: 17224476, 20817017, 24291113, 28427417; Phenotypes: Brugada syndrome 3, OMIM:611875, Timothy syndrome, OMIM:601005, Long QT syndrome 8, OMIM:618447, Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures, OMIM:620029; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Short QT syndrome v3.24 CACNA1C Ida Ertmanska Tag disputed tag was added to gene: CACNA1C.
Short QT syndrome v2.14 CACNA1C Eleanor Williams Phenotypes for gene: CACNA1C were changed from Timothy syndrome, OMIM:601005; Timothy syndrome, MONDO:0010979; Long QT syndrome 8, OMIM:618447; long qt syndrome 8, MONDO:0032756; Brugada syndrome 3, OMIM:611875; Brugada syndrome 3, MONDO:0012742; CACNA1C-related disorder to Timothy syndrome, OMIM:601005; Timothy syndrome, MONDO:0010979; Long QT syndrome 8, OMIM:618447; long qt syndrome 8, MONDO:0032756; Brugada syndrome 3, OMIM:611875; Brugada syndrome 3, MONDO:0012742; Short QT; CACNA1C-related disorder
Short QT syndrome v2.13 CACNA1C Eleanor Williams Phenotypes for gene: CACNA1C were changed from Brugada syndrome 3 611875; syncope; brugada syndrome; scd; Brugada syndrome 3 (611875); short qt; Timothy syndrome (601005) to Timothy syndrome, OMIM:601005; Timothy syndrome, MONDO:0010979; Long QT syndrome 8, OMIM:618447; long qt syndrome 8, MONDO:0032756; Brugada syndrome 3, OMIM:611875; Brugada syndrome 3, MONDO:0012742; CACNA1C-related disorder
Short QT syndrome v2.12 CACNA1C Ivone Leong Tag for-review was removed from gene: CACNA1C.
Short QT syndrome v2.12 CACNA1C Ivone Leong changed review comment from: After NHSGenomic Medicine Service consideration, the rating of this gene has not been changed.; to: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed.
Short QT syndrome v2.12 CACNA1C Ivone Leong commented on gene: CACNA1C: After NHSGenomic Medicine Service consideration, the rating of this gene has not been changed.
Short QT syndrome v2.3 CACNA1C Ivone Leong Tag for-review tag was added to gene: CACNA1C.
Short QT syndrome v2.3 CACNA1C Zornitza Stark reviewed gene: CACNA1C: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Short QT syndrome v1.23 CACNA1C Ivone Leong reviewed gene: CACNA1C: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Short QT syndrome v1.20 CACNA1C Ivone Leong Source West Midlands, Oxford and Wessex GLH was added to CACNA1C.
Short QT syndrome v1.16 CACNA1C Ivone Leong Publications for gene: CACNA1C were set to 24291113; 16301704
Short QT syndrome v1.10 CACNA1C Rebecca Whittington commented on gene: CACNA1C: Timothy syndrome (601005); Brugada syndrome 3 (611875)
Short QT syndrome v1.9 CACNA1C Rebecca Whittington commented on gene: CACNA1C: Not associated with SQT
Short QT syndrome v1.8 CACNA1C Rebecca Whittington reviewed gene: CACNA1C: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Short QT syndrome v1.7 CACNA1C Ellen McDonagh Source South West GLH was added to CACNA1C.
Short QT syndrome v1.6 CACNA1C Ellen McDonagh reviewed gene: CACNA1C: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Short QT syndrome v1.5 CACNA1C Ellen McDonagh Source London South GLH was added to CACNA1C.
Short QT syndrome v1.4 CACNA1C James Eden reviewed gene: CACNA1C: Rating: GREEN; Mode of pathogenicity: ; Publications: 24291113, 16301704; Phenotypes: Brugada syndrome 3 (611875), Timothy syndrome (601005); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Short QT syndrome v1.3 CACNA1C Ellen McDonagh Source North West GLH was added to CACNA1C.
Added phenotypes Brugada syndrome 3 (611875); Timothy syndrome (601005) for gene: CACNA1C
Publications for gene CACNA1C were changed from 17224476; 28427417; 28490369; 29759541; 29697308 to 24291113; 16301704
Short QT syndrome v1.2 CACNA1C Oxford Medical Genetics Laboratory reviewed gene: CACNA1C: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Short QT syndrome v0.23 CACNA1C Louise Daugherty Added comment: Comment on publications: removed inclusion of PMID
Short QT syndrome v0.23 CACNA1C Louise Daugherty Publications for gene: CACNA1C were set to PMID: 17224476; 28427417; 28490369; 29759541; 29697308
Short QT syndrome v0.4 CACNA1C Sarah Leigh reviewed gene: CACNA1C: Rating: GREEN; Mode of pathogenicity: ; Publications: 30027834, 30279520; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Short QT syndrome v0.2 CACNA1C Sarah Leigh Source Emory Genetics Laboratory was added to CACNA1C.
Source Long QT syndrome (Version 1.5) was added to CACNA1C.
Source Expert Review Green was added to CACNA1C.
Source UKGTN was added to CACNA1C.
Source Brugada syndrome (Version 1.7) was added to CACNA1C.
Added phenotypes Brugada syndrome 3 611875 for gene: CACNA1C
Rating Changed from No List (delete) to Green List (high evidence)
Short QT syndrome v0.1 CACNA1C Jules Hancox gene: CACNA1C was added
gene: CACNA1C was added to Short QT syndrome. Sources: Literature
Mode of inheritance for gene: CACNA1C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CACNA1C were set to PMID: 17224476; 28427417; 28490369; 29759541; 29697308
Phenotypes for gene: CACNA1C were set to short qt; brugada syndrome; syncope; scd
Review for gene: CACNA1C was set to GREEN
Added comment: Encodes alpha subunit of L-type Ca channels. Mutations are loss of function and lead to a mixed short QT/Brugada phenotype
Sources: Literature