ClinVar Genomic variation as it relates to human health
NM_000719.7(CACNA1C):c.1917C>A (p.Asn639Lys)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000719.7(CACNA1C):c.1917C>A (p.Asn639Lys)
Variation ID: 560694 Accession: VCV000560694.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12p13.33 12: 2581611 (GRCh38) [ NCBI UCSC ] 12: 2690777 (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 Sep 14, 2018 Feb 28, 2024 Jul 30, 2020 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000719.7:c.1917C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000710.5:p.Asn639Lys missense NM_001167623.2:c.1917C>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001161095.1:p.Asn639Lys missense NM_001129827.2:c.1917C>A NP_001123299.1:p.Asn639Lys missense NM_001129829.2:c.1917C>A NP_001123301.1:p.Asn639Lys missense NM_001129830.3:c.1917C>A NP_001123302.2:p.Asn639Lys missense NM_001129831.2:c.1917C>A NP_001123303.1:p.Asn639Lys missense NM_001129832.2:c.1917C>A NP_001123304.1:p.Asn639Lys missense NM_001129833.2:c.1917C>A NP_001123305.1:p.Asn639Lys missense NM_001129834.2:c.1917C>A NP_001123306.1:p.Asn639Lys missense NM_001129835.2:c.1917C>A NP_001123307.1:p.Asn639Lys missense NM_001129836.2:c.1917C>A NP_001123308.1:p.Asn639Lys missense NM_001129837.2:c.1917C>A NP_001123309.1:p.Asn639Lys missense NM_001129838.2:c.1917C>A NP_001123310.1:p.Asn639Lys missense NM_001129839.2:c.1917C>A NP_001123311.1:p.Asn639Lys missense NM_001129840.2:c.1917C>A NP_001123312.1:p.Asn639Lys missense NM_001129841.2:c.1917C>A NP_001123313.1:p.Asn639Lys missense NM_001129842.2:c.1917C>A NP_001123314.1:p.Asn639Lys missense NM_001129843.2:c.1917C>A NP_001123315.1:p.Asn639Lys missense NM_001129844.2:c.1908C>A NP_001123316.1:p.Asn636Lys missense NM_001129846.2:c.1917C>A NP_001123318.1:p.Asn639Lys missense NM_001167624.3:c.1917C>A NP_001161096.2:p.Asn639Lys missense NM_001167625.2:c.1917C>A NP_001161097.1:p.Asn639Lys missense NM_199460.4:c.1917C>A NP_955630.3:p.Asn639Lys missense NC_000012.12:g.2581611C>A NC_000012.11:g.2690777C>A NG_008801.2:g.615826C>A LRG_334:g.615826C>A LRG_334t1:c.1917C>A - Protein change
- N639K, N636K
- Other names
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- Canonical SPDI
- NC_000012.12:2581610:C: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.
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- 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 | ||
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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
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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 |
2050 | 2990 |
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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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) |
criteria provided, single submitter
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Feb 2, 2018 | RCV000678930.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 30, 2020 | RCV001302393.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 2, 2020 | RCV002272326.2 |
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
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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
(Feb 02, 2018)
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criteria provided, single submitter
Method: clinical testing
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Timothy syndrome
Affected status: yes
Allele origin:
unknown
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Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues
Accession: SCV000805141.1
First in ClinVar: Sep 14, 2018 Last updated: Sep 14, 2018 |
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Uncertain significance
(Jul 02, 2020)
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criteria provided, single submitter
Method: clinical testing
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Congenital long QT syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557381.1
First in ClinVar: Aug 08, 2022 Last updated: Aug 08, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as VUS-3A. Following criteria are met: 0103 - Loss of function and gain of function … (more)
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as VUS-3A. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to lysine (exon 14). (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). Note: this region has <30x coverage. (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. Moderate amino acid change, very high conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. Located in the intracellular region between subunits S4 and S5 of Domain II (PMID: 31004778). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. PMID: 31004778; p.(Asn639Thr) considered likely pathogenic in a female proband, her brother and mother with prolonged QT/?Timothy syndrome. Functional studies of CRISPR/Cas9-edited hiPSC-CMs had indicated an impact on the channel (increased action potential and slower voltage-dependent inactivation). (SP) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. ClinVar: VUS x1 (condition: Timothy syndrome) with an alternative nucleotide change (C>G) causing the same amino acid change also reported as a VUS x2 in ClinVar (conditions: Timothy syndrome, Not provided). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting Pathogenic, (I) – Information, (SB) – Supporting Benign (less)
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Uncertain significance
(Jul 30, 2020)
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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: SCV001491601.4
First in ClinVar: Mar 07, 2021 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces asparagine with lysine at codon 639 of the CACNA1C protein (p.Asn639Lys). The asparagine residue is highly conserved and there is a … (more)
This sequence change replaces asparagine with lysine at codon 639 of the CACNA1C protein (p.Asn639Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CACNA1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 560694). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. (less)
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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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Patient-independent human induced pluripotent stem cell model: A new tool for rapid determination of genetic variant pathogenicity in long QT syndrome. | Chavali NV | Heart rhythm | 2019 | PMID: 31004778 |
Text-mined citations for rs1057524804 ...
HelpRecord last updated Mar 05, 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.