ClinVar Genomic variation as it relates to human health
NM_000719.7(CACNA1C):c.3679G>A (p.Val1227Ile)
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(5); Benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000719.7(CACNA1C):c.3679G>A (p.Val1227Ile)
Variation ID: 234984 Accession: VCV000234984.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12p13.33 12: 2719827 (GRCh37) [ NCBI UCSC ] 12: 2610661 (GRCh38) [ 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 Jun 2, 2016 May 1, 2024 Dec 11, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000719.7:c.3679G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000710.5:p.Val1227Ile missense NM_001167623.2:c.3679G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001161095.1:p.Val1227Ile missense NM_001129827.2:c.3739G>A NP_001123299.1:p.Val1247Ile missense NM_001129829.2:c.3679G>A NP_001123301.1:p.Val1227Ile missense NM_001129830.3:c.3679G>A NP_001123302.2:p.Val1227Ile missense NM_001129831.2:c.3679G>A NP_001123303.1:p.Val1227Ile missense NM_001129832.2:c.3739G>A NP_001123304.1:p.Val1247Ile missense NM_001129833.2:c.3679G>A NP_001123305.1:p.Val1227Ile missense NM_001129834.2:c.3679G>A NP_001123306.1:p.Val1227Ile missense NM_001129835.2:c.3679G>A NP_001123307.1:p.Val1227Ile missense NM_001129836.2:c.3679G>A NP_001123308.1:p.Val1227Ile missense NM_001129837.2:c.3679G>A NP_001123309.1:p.Val1227Ile missense NM_001129838.2:c.3679G>A NP_001123310.1:p.Val1227Ile missense NM_001129839.2:c.3679G>A NP_001123311.1:p.Val1227Ile missense NM_001129840.2:c.3679G>A NP_001123312.1:p.Val1227Ile missense NM_001129841.2:c.3679G>A NP_001123313.1:p.Val1227Ile missense NM_001129842.2:c.3679G>A NP_001123314.1:p.Val1227Ile missense NM_001129843.2:c.3679G>A NP_001123315.1:p.Val1227Ile missense NM_001129844.2:c.3670G>A NP_001123316.1:p.Val1224Ile missense NM_001129846.2:c.3679G>A NP_001123318.1:p.Val1227Ile missense NM_001167624.3:c.3679G>A NP_001161096.2:p.Val1227Ile missense NM_001167625.2:c.3679G>A NP_001161097.1:p.Val1227Ile missense NM_199460.4:c.3739G>A NP_955630.3:p.Val1247Ile missense NC_000012.12:g.2610661G>A NC_000012.11:g.2719827G>A NG_008801.2:g.644876G>A LRG_334:g.644876G>A LRG_334t1:c.3679G>A - Protein change
- V1227I, V1247I, V1224I
- Other names
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- Canonical SPDI
- NC_000012.12:2610660: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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00005
The Genome Aggregation Database (gnomAD) 0.00006
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
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 |
2058 | 3008 |
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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Uncertain significance (1) |
no assertion criteria provided
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Mar 18, 2012 | RCV000223923.10 | |
Uncertain significance (1) |
no assertion criteria provided
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Jul 24, 2015 | RCV000415626.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 16, 2023 | RCV000463570.15 | |
Uncertain significance (1) |
no assertion criteria provided
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Dec 1, 2017 | RCV000656705.8 | |
Benign (1) |
criteria provided, single submitter
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Dec 11, 2023 | RCV000618584.10 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Oct 24, 2023 | RCV000725545.14 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 3, 2021 | RCV002478822.8 |
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. |
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Uncertain significance
(Dec 07, 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: SCV000337633.4
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
(Aug 16, 2023)
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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: SCV000553002.8
First in ClinVar: Apr 17, 2017 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 234984). In summary, the available evidence is currently insufficient to determine the role of this variant … (more)
ClinVar contains an entry for this variant (Variation ID: 234984). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1C protein function. This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. This variant is present in population databases (rs373124557, gnomAD 0.01%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1227 of the CACNA1C protein (p.Val1227Ile). (less)
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Uncertain significance
(Oct 24, 2023)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004563479.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The CACNA1C c.3679G>A; p.Val1227Ile variant (rs373124557), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 234984). This … (more)
The CACNA1C c.3679G>A; p.Val1227Ile variant (rs373124557), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 234984). This variant is found in the general population with an overall allele frequency of 0.0035% (10/282176 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.283). Due to limited information, the clinical significance of this variant is uncertain at this time. (less)
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Uncertain significance
(Nov 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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Timothy syndrome
Brugada syndrome 3 Long qt syndrome 8
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894756.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
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Benign
(Dec 11, 2023)
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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: SCV000737427.5
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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Uncertain significance
(May 20, 2020)
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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: SCV001805791.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as … (more)
In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge (less)
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Uncertain significance
(Mar 18, 2012)
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no assertion criteria provided
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280057.1
First in ClinVar: Jun 02, 2016 Last updated: Jun 02, 2016 |
Comment:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case … (more)
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Based on the data reviewed we consider this a variant of uncertain significance. This is a novel variant. It is not reported in dbSNP as a benign polymorphism nor is it reported in published literature in association with disease. This is a conservative amino acid change with a nonpolar Valine replaced by a nonpolar Leucine. Valine is not conserved at this position across species and there are no reported disease associated variants at nearby codons (Google, Gene Connection for the Heart Database, Mutadatabase). In silico analysis (PolyPhen) predicts the amino acid change to be benign. The reporting lab did not find this variant in 600 presumably healthy controls consisting of both Caucasian and African American ancestry. (less)
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Uncertain significance
(Jul 24, 2015)
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no assertion criteria provided
Method: clinical testing
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Short QT Syndrome 4
Affected status: no
Allele origin:
germline
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Knight Diagnostic Laboratories, Oregon Health and Sciences University
Study: CSER-NextGen
Accession: SCV000493714.1 First in ClinVar: Jan 23, 2017 Last updated: Jan 23, 2017 |
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Uncertain significance
(Dec 01, 2017)
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no assertion criteria provided
Method: clinical testing
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Timothy syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV000747830.1
First in ClinVar: Jun 30, 2018 Last updated: Jun 30, 2018 |
Comment:
The observed variant c.3679G>A (p.V1227I) is not reported in 1000 Genomes and has minor allele frequency of 0.00002479 in ExAC database. The in silico prediction … (more)
The observed variant c.3679G>A (p.V1227I) is not reported in 1000 Genomes and has minor allele frequency of 0.00002479 in ExAC database. The in silico prediction of the variant is benign by MutationTaster2 and tolerated by SIFT. (less)
Clinical Features:
Abnormal cardiovascular system morphology (present) , Duodenal atresia (present) , Annular pancreas (present) , Unilateral narrow palpebral fissure (present) , Abnormal pinna morphology (present) , … (more)
Abnormal cardiovascular system morphology (present) , Duodenal atresia (present) , Annular pancreas (present) , Unilateral narrow palpebral fissure (present) , Abnormal pinna morphology (present) , Low-set ears (present) , Intellectual disability, severe (present) , Common atrium (present) (less)
Sex: female
Ethnicity/Population group: Hindu/South Indian
Geographic origin: India
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on Illumina sequencing platform. Sequence obtained were aligned to the human reference genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variations in the targeted genes relevant to clinical indications.
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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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http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CACNA1C | - | - | - | - |
Text-mined citations for rs373124557 ...
HelpRecord last updated May 01, 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.