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NM_000719.7(CACNA1C):c.1552C>T (p.Arg518Cys) AND Cardiovascular phenotype

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Apr 22, 2021
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV002399602.2

Allele description [Variation Report for NM_000719.7(CACNA1C):c.1552C>T (p.Arg518Cys)]

NM_000719.7(CACNA1C):c.1552C>T (p.Arg518Cys)

Gene:
CACNA1C:calcium voltage-gated channel subunit alpha1 C [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
12p13.33
Genomic location:
Preferred name:
NM_000719.7(CACNA1C):c.1552C>T (p.Arg518Cys)
Other names:
p.R518C:CGC>TGC
HGVS:
  • NC_000012.12:g.2566465C>T
  • NG_008801.2:g.600680C>T
  • NM_000719.7:c.1552C>TMANE SELECT
  • NM_001129827.2:c.1552C>T
  • NM_001129829.2:c.1552C>T
  • NM_001129830.3:c.1552C>T
  • NM_001129831.2:c.1552C>T
  • NM_001129832.2:c.1552C>T
  • NM_001129833.2:c.1552C>T
  • NM_001129834.2:c.1552C>T
  • NM_001129835.2:c.1552C>T
  • NM_001129836.2:c.1552C>T
  • NM_001129837.2:c.1552C>T
  • NM_001129838.2:c.1552C>T
  • NM_001129839.2:c.1552C>T
  • NM_001129840.2:c.1552C>T
  • NM_001129841.2:c.1552C>T
  • NM_001129842.2:c.1552C>T
  • NM_001129843.2:c.1552C>T
  • NM_001129844.2:c.1543C>T
  • NM_001129846.2:c.1552C>T
  • NM_001167623.2:c.1552C>T
  • NM_001167624.3:c.1552C>T
  • NM_001167625.2:c.1552C>T
  • NM_199460.4:c.1552C>T
  • NP_000710.5:p.Arg518Cys
  • NP_000710.5:p.Arg518Cys
  • NP_001123299.1:p.Arg518Cys
  • NP_001123299.1:p.Arg518Cys
  • NP_001123301.1:p.Arg518Cys
  • NP_001123302.1:p.Arg518Cys
  • NP_001123302.2:p.Arg518Cys
  • NP_001123303.1:p.Arg518Cys
  • NP_001123304.1:p.Arg518Cys
  • NP_001123305.1:p.Arg518Cys
  • NP_001123306.1:p.Arg518Cys
  • NP_001123307.1:p.Arg518Cys
  • NP_001123308.1:p.Arg518Cys
  • NP_001123309.1:p.Arg518Cys
  • NP_001123310.1:p.Arg518Cys
  • NP_001123311.1:p.Arg518Cys
  • NP_001123312.1:p.Arg518Cys
  • NP_001123312.1:p.Arg518Cys
  • NP_001123313.1:p.Arg518Cys
  • NP_001123314.1:p.Arg518Cys
  • NP_001123315.1:p.Arg518Cys
  • NP_001123316.1:p.Arg515Cys
  • NP_001123318.1:p.Arg518Cys
  • NP_001161095.1:p.Arg518Cys
  • NP_001161096.2:p.Arg518Cys
  • NP_001161097.1:p.Arg518Cys
  • NP_955630.3:p.Arg518Cys
  • LRG_334t1:c.1552C>T
  • LRG_334t2:c.1552C>T
  • LRG_334t3:c.1552C>T
  • LRG_334t4:c.1552C>T
  • LRG_334:g.600680C>T
  • LRG_334p1:p.Arg518Cys
  • LRG_334p2:p.Arg518Cys
  • LRG_334p3:p.Arg518Cys
  • LRG_334p4:p.Arg518Cys
  • NC_000012.11:g.2675631C>T
  • NM_000719.6:c.1552C>T
  • NM_001129827.1:c.1552C>T
  • NM_001129830.1:c.1552C>T
  • NM_001129840.1:c.1552C>T
Protein change:
R515C; ARG518CYS
Links:
OMIM: 114205.0016; dbSNP: rs786205748
NCBI 1000 Genomes Browser:
rs786205748
Molecular consequence:
  • NM_000719.7:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129827.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129829.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129830.3:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129831.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129832.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129833.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129834.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129835.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129836.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129837.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129838.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129839.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129840.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129841.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129842.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129843.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129844.2:c.1543C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129846.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167623.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167624.3:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167625.2:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_199460.4:c.1552C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002704334Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Apr 22, 2021) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Identification and Functional Characterization of a Novel CACNA1C-Mediated Cardiac Disorder Characterized by Prolonged QT Intervals With Hypertrophic Cardiomyopathy, Congenital Heart Defects, and Sudden Cardiac Death.

Boczek NJ, Ye D, Jin F, Tester DJ, Huseby A, Bos JM, Johnson AJ, Kanter R, Ackerman MJ.

Circ Arrhythm Electrophysiol. 2015 Oct;8(5):1122-32. doi: 10.1161/CIRCEP.115.002745. Epub 2015 Aug 7.

PubMed [citation]
PMID:
26253506
PMCID:
PMC5094060

Application of Multigene Panel Sequencing in Patients with Prolonged Rate-corrected QT Interval and No Pathogenic Variants Detected in KCNQ1, KCNH2, and SCN5A.

Seo SH, Kim SY, Cho SI, Park H, Lee S, Choi JM, Kim MJ, Lee JS, Ahn KJ, Song MK, Bae EJ, Park SS, Seong MW.

Ann Lab Med. 2018 Jan;38(1):54-58. doi: 10.3343/alm.2018.38.1.54.

PubMed [citation]
PMID:
29071820
PMCID:
PMC5700148
See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV002704334.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

The p.R518C pathogenic mutation (also known as c.1552C>T), located in coding exon 12 of the CACNA1C gene, results from a C to T substitution at nucleotide position 1552. The arginine at codon 518 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple unrelated probands with mixed cardiac phenotypes, including long QT syndrome, hypertrophic cardiomyopathy, cardiac conduction defects, and congenital heart disease, and has been reported to segregate with disease in several families (Boczek NJ et al. Circ Arrhythm Electrophysiol, 2015 Oct;8:1122-32; Seo SH et al. Ann Lab Med, 2018 Jan;38:54-58; Korkosh VS et al. Front Physiol, 2019 Mar;10:335; Fukuyama M et al. Circ J, 2020 03;84:559-568; GeneDx pers comm; Invitae pers comm; Ambry internal data). Functional studies performed in vitro indicate that R518C leads to a decrease in peak channel current density but an increase in the late calcium current (Boczek NJ et al. Circ Arrhythm Electrophysiol, 2015 Oct;8:1122-32; Estes SI et al. Circ Genom Precis Med, 2019 08;12:e002534). Another pathogenic alteration, p.R518H, has been described in the same codon (Boczek NJ et al. Circ Arrhythm Electrophysiol, 2015 Oct;8:1122-32). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024