ClinVar Genomic variation as it relates to human health
NM_000719.7(CACNA1C):c.1468G>A (p.Gly490Arg)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(2); Benign(3); Likely benign(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000719.7(CACNA1C):c.1468G>A (p.Gly490Arg)
Variation ID: 17634 Accession: VCV000017634.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12p13.33 12: 2550020 (GRCh38) [ NCBI UCSC ] 12: 2659186 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 23, 2014 May 1, 2024 Feb 28, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000719.7:c.1468G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000710.5:p.Gly490Arg missense NM_001167623.2:c.1468G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001161095.1:p.Gly490Arg missense NM_001129827.2:c.1468G>A NP_001123299.1:p.Gly490Arg missense NM_001129829.2:c.1468G>A NP_001123301.1:p.Gly490Arg missense NM_001129830.3:c.1468G>A NP_001123302.2:p.Gly490Arg missense NM_001129831.2:c.1468G>A NP_001123303.1:p.Gly490Arg missense NM_001129832.2:c.1468G>A NP_001123304.1:p.Gly490Arg missense NM_001129833.2:c.1468G>A NP_001123305.1:p.Gly490Arg missense NM_001129834.2:c.1468G>A NP_001123306.1:p.Gly490Arg missense NM_001129835.2:c.1468G>A NP_001123307.1:p.Gly490Arg missense NM_001129836.2:c.1468G>A NP_001123308.1:p.Gly490Arg missense NM_001129837.2:c.1468G>A NP_001123309.1:p.Gly490Arg missense NM_001129838.2:c.1468G>A NP_001123310.1:p.Gly490Arg missense NM_001129839.2:c.1468G>A NP_001123311.1:p.Gly490Arg missense NM_001129840.2:c.1468G>A NP_001123312.1:p.Gly490Arg missense NM_001129841.2:c.1468G>A NP_001123313.1:p.Gly490Arg missense NM_001129842.2:c.1468G>A NP_001123314.1:p.Gly490Arg missense NM_001129843.2:c.1468G>A NP_001123315.1:p.Gly490Arg missense NM_001129844.2:c.1459G>A NP_001123316.1:p.Gly487Arg missense NM_001129846.2:c.1468G>A NP_001123318.1:p.Gly490Arg missense NM_001167624.3:c.1468G>A NP_001161096.2:p.Gly490Arg missense NM_001167625.2:c.1468G>A NP_001161097.1:p.Gly490Arg missense NM_199460.4:c.1468G>A NP_955630.3:p.Gly490Arg missense NC_000012.12:g.2550020G>A NC_000012.11:g.2659186G>A NG_008801.2:g.584235G>A LRG_334:g.584235G>A LRG_334t1:c.1468G>A - Protein change
- G490R, G487R
- Other names
- p.G490R:GGG>AGG
- Canonical SPDI
- NC_000012.12:2550019:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00040 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00036
1000 Genomes Project 0.00040
Trans-Omics for Precision Medicine (TOPMed) 0.00044
1000 Genomes Project 30x 0.00047
The Genome Aggregation Database (gnomAD), exomes 0.00067
Exome Aggregation Consortium (ExAC) 0.00081
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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CACNA1C | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
2059 | 3011 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (2) |
no assertion criteria provided
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Jan 30, 2007 | RCV000019201.38 | |
Benign/Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Oct 12, 2023 | RCV000170775.19 | |
not provided (1) |
no classification provided
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- | RCV000058286.12 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jun 17, 2021 | RCV000586094.20 | |
Benign (1) |
criteria provided, single submitter
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Aug 22, 2023 | RCV000334098.12 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 27, 2024 | RCV001085545.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 2, 2020 | RCV001256682.10 | |
Benign (1) |
criteria provided, single submitter
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Sep 6, 2017 | RCV000618330.11 | |
Likely benign (1) |
criteria provided, single submitter
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Feb 28, 2024 | RCV003944830.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Benign
(Apr 09, 2018)
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criteria provided, single submitter
Method: clinical testing
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not specified
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000271528.2
First in ClinVar: May 29, 2016 Last updated: Apr 03, 2017 |
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
Number of individuals with the variant: 2
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Likely benign
(Jan 27, 2024)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000285586.10
First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024 |
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Likely benign
(Feb 28, 2024)
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criteria provided, single submitter
Method: clinical testing
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CACNA1C-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004766319.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Uncertain significance
(Aug 26, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000334437.3
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Uncertain significance
(Mar 02, 2020)
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criteria provided, single submitter
Method: clinical testing
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Long QT syndrome 1
Affected status: yes
Allele origin:
germline
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Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV001433055.1
First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020 |
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Likely benign
(Jun 17, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000223330.12
First in ClinVar: May 23, 2015 Last updated: Apr 03, 2017 |
Comment:
Published functional studies demonstrate no damaging effect (Antzelevitch et al., 2007).; This variant is associated with the following publications: (PMID: 22581653, 17224476, 20301690, 20817017, 23414114, … (more)
Published functional studies demonstrate no damaging effect (Antzelevitch et al., 2007).; This variant is associated with the following publications: (PMID: 22581653, 17224476, 20301690, 20817017, 23414114, 24183960, 25333069, 26707467, 27711072, 25974115, 30027834, 30847666, 26582918, 28807990, 30821013, 27535533) (less)
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Benign
(Aug 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Timothy syndrome
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV001138624.2
First in ClinVar: Jan 09, 2020 Last updated: Aug 25, 2023 |
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Likely benign
(Oct 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697541.2
First in ClinVar: Mar 17, 2018 Last updated: Nov 20, 2023 |
Comment:
Variant summary: CACNA1C c.1468G>A (p.Gly490Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging … (more)
Variant summary: CACNA1C c.1468G>A (p.Gly490Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00067 in 231558 control chromosomes (gnomAD). The observed variant frequency is approximately 67 fold of the estimated maximal expected allele frequency for a pathogenic variant in CACNA1C causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. This variant has been reported in individuals affected with Brugada syndrome, hypertrophic cardiomyopathy, and early repolarization syndrome, without strong evidence for causality (examples: Antzelevitch_2007, D'Argenio_2014, Chen_2021). Published functional studies demonstrate no damaging effect from this variant (Antzelevitch et al., 2007). The following publications have been ascertained in the context of this evaluation (PMID: 17224476, 24183960, 34222376). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign/likely benign (n=2) and VUS (n=2). Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Benign
(Sep 06, 2017)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000736439.5
First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024 |
Comment:
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more)
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Pathogenic
(Jan 30, 2007)
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no assertion criteria provided
Method: literature only
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BRUGADA SYNDROME 3
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000039489.2
First in ClinVar: Apr 04, 2013 Last updated: Mar 23, 2014 |
Comment on evidence:
In a 41-year-old male of Turkish descent with Brugada syndrome and a shortened QTc interval (BRGDA3; 611875), Antzelevitch et al. (2007) identified a heterozygous 1468G-A … (more)
In a 41-year-old male of Turkish descent with Brugada syndrome and a shortened QTc interval (BRGDA3; 611875), Antzelevitch et al. (2007) identified a heterozygous 1468G-A transition in exon 10 of the CACNA1C gene, predicted to result in a gly490-to-arg (G490R) substitution in the cytoplasmic linker between domains I and II within a highly conserved region of the protein. The proband also carried 2 polymorphisms in CACNA1C, P1820L and V1821M, which were found in 31 and 27 of 114 healthy controls, respectively. The G490R mutation was also found in his 2 daughters, who had QTc intervals of 360 and 370 ms, respectively; the daughter with the longer QTc interval also carried a known K897T polymorphism in the KCNH2 gene. Patch-clamp experiments in Chinese hamster ovary (CHO) cells demonstrated a marked reduction in current amplitude of mutant channels compared to wildtype, although voltage at peak current was unchanged; confocal microscopy revealed normal trafficking of channels containing G490R CaV1.2 subunits. The G490R mutation was not found in 640 ethnically matched control alleles. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001918320.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001968452.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Brugada syndrome
Affected status: unknown
Allele origin:
germline
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Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust
Accession: SCV000089806.3
First in ClinVar: Oct 22, 2013 Last updated: Jun 09, 2014 |
Comment:
This variant has been reported as associated with Brugada syndrome in the following publications (PMID:17224476;PMID:20817017). This is a literature report, and does not necessarily reflect … (more)
This variant has been reported as associated with Brugada syndrome in the following publications (PMID:17224476;PMID:20817017). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Brugada syndrome 3
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000188929.3
First in ClinVar: Sep 11, 2014 Last updated: Oct 01, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Brugada Syndrome. | Adam MP | - | 2022 | PMID: 20301690 |
Clinical and Functional Genetic Characterization of the Role of Cardiac Calcium Channel Variants in the Early Repolarization Syndrome. | Chen X | Frontiers in cardiovascular medicine | 2021 | PMID: 34222376 |
Disease variants in genomes of 44 centenarians. | Freudenberg-Hua Y | Molecular genetics & genomic medicine | 2014 | PMID: 25333069 |
DNA sequence capture and next-generation sequencing for the molecular diagnosis of genetic cardiomyopathies. | D'Argenio V | The Journal of molecular diagnostics : JMD | 2014 | PMID: 24183960 |
High prevalence of genetic variants previously associated with Brugada syndrome in new exome data. | Risgaard B | Clinical genetics | 2013 | PMID: 23414114 |
Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death. | Burashnikov E | Heart rhythm | 2010 | PMID: 20817017 |
Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. | Antzelevitch C | Circulation | 2007 | PMID: 17224476 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CACNA1C | - | - | - | - |
Text-mined citations for rs121912775 ...
HelpRecord last updated May 19, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.