Variant summary: CACNA1C c.5731G>C (p.Gly1911Arg) results in a non-conservative amino acid change located in the Voltage-gated calcium channel subunit alpha, C-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 249708 control chromosomes, predominantly at a frequency of 0.00056 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 56 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 a benign polymorphism found primarily in populations of East Asian origin. The variant, c.5731G>C, has been reported in the literature in individuals affected with Brugada Syndrome, long QT syndrome or sudden unexplained infant death (Allegue_2015, Hennessey_2014). However, one publication, Hennessey_2014, suggests the variant is inherited from the asymptomatic father, although his DNA was not available for analysis. In electrophysiological analyses, the variant was observed to cause a gain of function of CaV1.2 suggesting increased susceptibility for arrhythmias in certain clinical settings (Hennessey_2014). Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS - possibly benign.
ClinVar Genomic variation as it relates to human health
NM_000719.7(CACNA1C):c.5731G>C (p.Gly1911Arg)
Germline
Classification
Help
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.
(10)
Help
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.
Conflicting classifications of pathogenicity
Uncertain significance(8); Benign(1); Likely benign(1)
Uncertain significance(8); Benign(1); Likely benign(1)
10
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000719.7(CACNA1C):c.5731G>C (p.Gly1911Arg)
Variation ID: 191427 Accession: VCV000191427.23
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 12p13.33 12: 2686216 (GRCh38) [ NCBI UCSC ] 12: 2795382 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jun 8, 2015 May 1, 2024 Jan 19, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000719.7:c.5731G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000710.5:p.Gly1911Arg missense NM_001167623.2:c.5731G>C MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001161095.1:p.Gly1911Arg missense NM_001129827.2:c.5875G>C NP_001123299.1:p.Gly1959Arg missense NM_001129829.2:c.5854G>C NP_001123301.1:p.Gly1952Arg missense NM_001129830.3:c.5836G>C NP_001123302.2:p.Gly1946Arg missense NM_001129831.2:c.5815G>C NP_001123303.1:p.Gly1939Arg missense NM_001129832.2:c.5791G>C NP_001123304.1:p.Gly1931Arg missense NM_001129833.2:c.5788G>C NP_001123305.1:p.Gly1930Arg missense NM_001129834.2:c.5788G>C NP_001123306.1:p.Gly1930Arg missense NM_001129835.2:c.5788G>C NP_001123307.1:p.Gly1930Arg missense NM_001129836.2:c.5782G>C NP_001123308.1:p.Gly1928Arg missense NM_001129837.2:c.5755G>C NP_001123309.1:p.Gly1919Arg missense NM_001129838.2:c.5755G>C NP_001123310.1:p.Gly1919Arg missense NM_001129839.2:c.5749G>C NP_001123311.1:p.Gly1917Arg missense NM_001129840.2:c.5731G>C NP_001123312.1:p.Gly1911Arg missense NM_001129841.2:c.5731G>C NP_001123313.1:p.Gly1911Arg missense NM_001129842.2:c.5731G>C NP_001123314.1:p.Gly1911Arg missense NM_001129843.2:c.5731G>C NP_001123315.1:p.Gly1911Arg missense NM_001129844.2:c.5722G>C NP_001123316.1:p.Gly1908Arg missense NM_001129846.2:c.5698G>C NP_001123318.1:p.Gly1900Arg missense NM_001167624.3:c.5836G>C NP_001161096.2:p.Gly1946Arg missense NM_001167625.2:c.5911G>C NP_001161097.1:p.Gly1971Arg missense NM_199460.4:c.5980G>C NP_955630.3:p.Gly1994Arg missense NC_000012.12:g.2686216G>C NC_000012.11:g.2795382G>C NG_008801.2:g.720431G>C LRG_334:g.720431G>C LRG_334t1:c.5731G>C - Protein change
- G1911R, G1946R, G1959R, G1939R, G1994R, G1917R, G1952R, G1919R, G1930R, G1931R, G1900R, G1908R, G1928R, G1971R
- Other names
- -
- Canonical SPDI
- NC_000012.12:2686215:G:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00007
Exome Aggregation Consortium (ExAC) 0.00008
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| CACNA1C | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
2116 | 3091 | |
| CACNA1C-AS1 | - | - | - |
GRCh38 GRCh38 |
- | 857 |
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. |
|---|---|---|---|---|
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Dec 5, 2019 | RCV000171619.19 | |
| Likely benign (1) |
criteria provided, single submitter
|
Jan 19, 2024 | RCV000226828.17 | |
| Benign (1) |
criteria provided, single submitter
|
Oct 18, 2023 | RCV000617712.10 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Apr 29, 2019 | RCV000855639.8 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Feb 11, 2018 | RCV000852446.8 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Sep 4, 2023 | RCV000988770.9 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Sep 20, 2021 | RCV002478546.8 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Timothy syndrome
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001138627.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
|
Uncertain significance
(Dec 05, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003830333.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Likely benign
(Jan 19, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Long QT syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000285599.10
First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024 |
|
|
|
Uncertain significance
(Jun 24, 2013)
|
criteria provided, single submitter
Method: research
|
Not provided
Affected status: unknown
Allele origin:
unknown
|
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000055190.1 First in ClinVar: Jun 08, 2015 Last updated: Jun 08, 2015
Comments (2):
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for … (more)
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for details. (less)
Medical sequencing
|
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(Feb 11, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiomyopathy
Affected status: yes
Allele origin:
germline
|
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego
Accession: SCV000995138.1
First in ClinVar: Oct 12, 2019 Last updated: Oct 12, 2019 |
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(Apr 29, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697555.2
First in ClinVar: Dec 06, 2016 Last updated: Nov 08, 2019 |
Comment:
Variant summary: CACNA1C c.5731G>C (p.Gly1911Arg) results in a non-conservative amino acid change located in the Voltage-gated calcium channel subunit alpha, C-terminal domain of the encoded … (more)
Variant summary: CACNA1C c.5731G>C (p.Gly1911Arg) results in a non-conservative amino acid change located in the Voltage-gated calcium channel subunit alpha, C-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 249708 control chromosomes, predominantly at a frequency of 0.00056 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 56 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 a benign polymorphism found primarily in populations of East Asian origin. The variant, c.5731G>C, has been reported in the literature in individuals affected with Brugada Syndrome, long QT syndrome or sudden unexplained infant death (Allegue_2015, Hennessey_2014). However, one publication, Hennessey_2014, suggests the variant is inherited from the asymptomatic father, although his DNA was not available for analysis. In electrophysiological analyses, the variant was observed to cause a gain of function of CaV1.2 suggesting increased susceptibility for arrhythmias in certain clinical settings (Hennessey_2014). Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS - possibly benign. (less)
|
|
|
Uncertain significance
(Sep 20, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Timothy syndrome
Brugada syndrome 3 Long qt syndrome 8
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000611378.2
First in ClinVar: Nov 11, 2017 Last updated: Dec 31, 2022 |
|
|
|
Uncertain significance
(Sep 04, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Timothy syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812339.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
This sequence change in CACNA1C is predicted to replace glycine with arginine at codon 1911, p.(Gly1911Arg). The glycine residue is moderately conserved (100 vertebrates, UCSC), … (more)
This sequence change in CACNA1C is predicted to replace glycine with arginine at codon 1911, p.(Gly1911Arg). The glycine residue is moderately conserved (100 vertebrates, UCSC), and is located in the cytoplasmic region. There is a large physicochemical difference between glycine and arginine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.03% (11/19,536 alleles) in the East Asian population. This variant has been reported in multiple probands with cardiac phenotypes (PMID: 25184293, 26230511, 23861362). An in vitro functional study using Cav1.2 channel vectors expressed in HEK293T cells showed increased calcium ion production during cardiac action potential suggesting that this variant impacts protein function however limited controls were included in the assay (PMID: 25184293). Computational evidence is uninformative for the missense substitution (REVEL = 0.629). Based on the classification scheme RMH Modified ACMG Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: none. (less)
|
|
|
Benign
(Oct 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000737990.5
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)
|
|
|
Uncertain significance
(Feb 02, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000230669.5
First in ClinVar: Jun 29, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
Comment:
Comment:
This sequence change in CACNA1C is predicted to replace glycine with arginine at codon 1911, p.(Gly1911Arg). The glycine residue is moderately conserved (100 vertebrates, UCSC), and is located in the cytoplasmic region. There is a large physicochemical difference between glycine and arginine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.03% (11/19,536 alleles) in the East Asian population. This variant has been reported in multiple probands with cardiac phenotypes (PMID: 25184293, 26230511, 23861362). An in vitro functional study using Cav1.2 channel vectors expressed in HEK293T cells showed increased calcium ion production during cardiac action potential suggesting that this variant impacts protein function however limited controls were included in the assay (PMID: 25184293). Computational evidence is uninformative for the missense substitution (REVEL = 0.629). Based on the classification scheme RMH Modified ACMG Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: none.
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 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.
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. |
Comment:
Variant summary: CACNA1C c.5731G>C (p.Gly1911Arg) results in a non-conservative amino acid change located in the Voltage-gated calcium channel subunit alpha, C-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 249708 control chromosomes, predominantly at a frequency of 0.00056 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 56 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 a benign polymorphism found primarily in populations of East Asian origin. The variant, c.5731G>C, has been reported in the literature in individuals affected with Brugada Syndrome, long QT syndrome or sudden unexplained infant death (Allegue_2015, Hennessey_2014). However, one publication, Hennessey_2014, suggests the variant is inherited from the asymptomatic father, although his DNA was not available for analysis. In electrophysiological analyses, the variant was observed to cause a gain of function of CaV1.2 suggesting increased susceptibility for arrhythmias in certain clinical settings (Hennessey_2014). Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS - possibly benign.
Comment:
This sequence change in CACNA1C is predicted to replace glycine with arginine at codon 1911, p.(Gly1911Arg). The glycine residue is moderately conserved (100 vertebrates, UCSC), and is located in the cytoplasmic region. There is a large physicochemical difference between glycine and arginine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.03% (11/19,536 alleles) in the East Asian population. This variant has been reported in multiple probands with cardiac phenotypes (PMID: 25184293, 26230511, 23861362). An in vitro functional study using Cav1.2 channel vectors expressed in HEK293T cells showed increased calcium ion production during cardiac action potential suggesting that this variant impacts protein function however limited controls were included in the assay (PMID: 25184293). Computational evidence is uninformative for the missense substitution (REVEL = 0.629). Based on the classification scheme RMH Modified ACMG Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: none.
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 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Penetrance and expressivity of the R858H CACNA1C variant in a five-generation pedigree segregating an arrhythmogenic channelopathy. | Gardner RJM | Molecular genetics & genomic medicine | 2019 | PMID: 30345660 |
| Computational Cardiac Modeling Reveals Mechanisms of Ventricular Arrhythmogenesis in Long QT Syndrome Type 8: CACNA1C R858H Mutation Linked to Ventricular Fibrillation. | Bai J | Frontiers in physiology | 2017 | PMID: 29046645 |
| Pro-arrhythmogenic effects of CACNA1C G1911R mutation in human ventricular tachycardia: insights from cardiac multi-scale models. | Bai J | Scientific reports | 2016 | PMID: 27502440 |
| Genetic disruption of voltage-gated calcium channels in psychiatric and neurological disorders. | Heyes S | Progress in neurobiology | 2015 | PMID: 26386135 |
| Genetic Analysis of Arrhythmogenic Diseases in the Era of NGS: The Complexity of Clinical Decision-Making in Brugada Syndrome. | Allegue C | PloS one | 2015 | PMID: 26230511 |
| A CACNA1C variant associated with reduced voltage-dependent inactivation, increased CaV1.2 channel window current, and arrhythmogenesis. | Hennessey JA | PloS one | 2014 | PMID: 25184293 |
| Interpreting secondary cardiac disease variants in an exome cohort. | Ng D | Circulation. Cardiovascular genetics | 2013 | PMID: 23861362 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CACNA1C | - | - | - | - |
Text-mined citations for rs374528680 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 10, 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.