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NM_000719.7(CACNA1C):c.1552C>T (p.Arg518Cys) AND Long qt syndrome 8

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
May 22, 2022
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV002250585.2

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]
Observations:
1

Condition(s)

Name:
Long qt syndrome 8
Identifiers:
MONDO: MONDO:0032756; MedGen: CN260585; OMIM: 618447

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV0025211573billion
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(May 22, 2022) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002767302Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(May 6, 2021) 		germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot provided1not 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

Novel Timothy syndrome mutation leading to increase in CACNA1C window current.

Boczek NJ, Miller EM, Ye D, Nesterenko VV, Tester DJ, Antzelevitch C, Czosek RJ, Ackerman MJ, Ware SM.

Heart Rhythm. 2015 Jan;12(1):211-9. doi: 10.1016/j.hrthm.2014.09.051. Epub 2014 Sep 28.

PubMed [citation]
PMID:
25260352
PMCID:
PMC4907369
See all PubMed Citations (8)

Details of each submission

From 3billion, SCV002521157.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (2)

Description

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:26253506). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.88; 3Cnet: 0.86). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000190642). A different missense change at the same codon (p.Arg518His) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000372313). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002767302.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with LQTS (MIM#618447) and Timothy syndrome (MIM#601005). Missense variants result in loss of channel inactivation and increased current (OMIM, PMID: 25260352). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated I-II cytoplasmic linker region (PMID: 30513141). (I) 0702 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. These alternative changes (p.Arg518Ser, p.Arg518His) have been reported as likely pathogenic and pathogenic, and have been observed in multiple patients with hypertrophic cardiomyopathy (HCM) and Long QT syndrome (LQTS) (ClinVar, LOVD, PMID: 30513141, 30025578, 32161207). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic and likely pathogenic, and has been observed in multiple patients with HCM, LQTS, congenital heart defects and sudden cardiac death (VCGS, LOVD, ClinVar, PMID: 30513141, 29071820, 30984024, 32161207). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected HEK293 cells have demonstrated both loss of function and gain of function effects on protein function, including slowed channel inactivation (PMID: 30513141). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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

Last Updated: Sep 29, 2024