NM_000719.7(CACNA1C):c.1553G>A (p.Arg518His) AND Cardiac arrhythmia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 5, 2022
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:: RCV002230228.1

Allele description [Variation Report for NM_000719.7(CACNA1C):c.1553G>A (p.Arg518His)]

NM_000719.7(CACNA1C):c.1553G>A (p.Arg518His)

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.1553G>A (p.Arg518His)

HGVS:

NC_000012.12:g.2566466G>A
NG_008801.2:g.600681G>A
NM_000719.7:c.1553G>AMANE SELECT
NM_001129827.2:c.1553G>A
NM_001129829.2:c.1553G>A
NM_001129830.3:c.1553G>A
NM_001129831.2:c.1553G>A
NM_001129832.2:c.1553G>A
NM_001129833.2:c.1553G>A
NM_001129834.2:c.1553G>A
NM_001129835.2:c.1553G>A
NM_001129836.2:c.1553G>A
NM_001129837.2:c.1553G>A
NM_001129838.2:c.1553G>A
NM_001129839.2:c.1553G>A
NM_001129840.2:c.1553G>A
NM_001129841.2:c.1553G>A
NM_001129842.2:c.1553G>A
NM_001129843.2:c.1553G>A
NM_001129844.2:c.1544G>A
NM_001129846.2:c.1553G>A
NM_001167623.2:c.1553G>A
NM_001167624.3:c.1553G>A
NM_001167625.2:c.1553G>A
NM_199460.4:c.1553G>A
NP_000710.5:p.Arg518His
NP_001123299.1:p.Arg518His
NP_001123301.1:p.Arg518His
NP_001123302.2:p.Arg518His
NP_001123303.1:p.Arg518His
NP_001123304.1:p.Arg518His
NP_001123305.1:p.Arg518His
NP_001123306.1:p.Arg518His
NP_001123307.1:p.Arg518His
NP_001123308.1:p.Arg518His
NP_001123309.1:p.Arg518His
NP_001123310.1:p.Arg518His
NP_001123311.1:p.Arg518His
NP_001123312.1:p.Arg518His
NP_001123313.1:p.Arg518His
NP_001123314.1:p.Arg518His
NP_001123315.1:p.Arg518His
NP_001123316.1:p.Arg515His
NP_001123318.1:p.Arg518His
NP_001161095.1:p.Arg518His
NP_001161096.2:p.Arg518His
NP_001161097.1:p.Arg518His
NP_955630.3:p.Arg518His
LRG_334t1:c.1553G>A
LRG_334t2:c.1553G>A
LRG_334:g.600681G>A
NC_000012.11:g.2675632G>A
NM_000719.6:c.1553G>A
NM_001129827.1:c.1553G>A
NM_001167624.2:c.1553G>A

Protein change:

R515H; ARG518HIS

Links:

OMIM: 114205.0017; dbSNP: rs1057517711

NCBI 1000 Genomes Browser:

rs1057517711

Molecular consequence:

NM_000719.7:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001129827.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001129829.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001129830.3:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001129831.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001129832.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001129833.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001129834.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001129835.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001129836.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001129837.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001129838.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001129839.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001129840.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001129841.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001129842.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001129843.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001129844.2:c.1544G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001129846.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167623.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167624.3:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167625.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_199460.4:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiac arrhythmia
Synonyms:: Cardiac rhythm disease
Identifiers:: EFO: EFO_0004269; MONDO: MONDO:0007263; MedGen: C0003811; Human Phenotype Ontology: HP:0011675

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002511564	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 5, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26253506, 32161207, 30172029 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002511564

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Apr 5, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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

High Prevalence of Late-Appearing T-Wave in Patients With Long QT Syndrome Type 8.

Fukuyama M, Ohno S, Ozawa J, Kato K, Makiyama T, Nakagawa Y, Horie M.

Circ J. 2020 Mar 25;84(4):559-568. doi: 10.1253/circj.CJ-19-1101. Epub 2020 Mar 12.

PubMed [citation]

PMID:: 32161207

See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002511564.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: CACNA1C c.1553G>A (p.Arg518His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 219196 control chromosomes. c.1553G>A has been reported in the literature in individuals affected with Arrhythmia. These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed that this variant disrupts the normal function. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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