rs1057517711

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2PM5PP5_Very_Strong

The NM_000719.7(CACNA1C):c.1553G>A(p.Arg518His) variant causes a missense change. The variant allele was found at a frequency of 0.00000188 in 1,595,866 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R518S) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 6.79

Publications

22 publications found

Variant links:

Genes affected

CACNA1C (HGNC:1390): (calcium voltage-gated channel subunit alpha1 C) This gene encodes an alpha-1 subunit of a voltage-dependent calcium channel. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization. The alpha-1 subunit consists of 24 transmembrane segments and forms the pore through which ions pass into the cell. The calcium channel consists of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. There are multiple isoforms of each of these proteins, either encoded by different genes or the result of alternative splicing of transcripts. The protein encoded by this gene binds to and is inhibited by dihydropyridine. Alternative splicing results in many transcript variants encoding different proteins. Some of the predicted proteins may not produce functional ion channel subunits. [provided by RefSeq, Oct 2012]

CACNA1C Gene-Disease associations (from GenCC):

Timothy syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
long QT syndrome
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
long QT syndrome 8
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
Brugada syndrome
Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen
Brugada syndrome 3
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
intellectual disability
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
short QT syndrome
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, ClinGen

CACNA1C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-2566465-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3233417.Status of the report is no_assertion_criteria_provided, 0 stars.

PP5

Variant 12-2566466-G-A is Pathogenic according to our data. Variant chr12-2566466-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 372313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.1553G>A	p.Arg518His	missense_variant	Exon 12 of 47	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 link	c.1553G>A	p.Arg518His	missense_variant	Exon 12 of 47	ENST00000399603.6	NP_001161095.1	Q13936-37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399603.6 link	c.1553G>A	p.Arg518His	missense_variant	Exon 12 of 47	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6 link	c.1553G>A	p.Arg518His	missense_variant	Exon 12 of 47	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 link	c.1643G>A	p.Arg548His	missense_variant	Exon 12 of 50			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000406454.8 link	c.1553G>A	p.Arg518His	missense_variant	Exon 12 of 48	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 link	c.1553G>A	p.Arg518His	missense_variant	Exon 12 of 47	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 link	c.1718G>A	p.Arg573His	missense_variant	Exon 13 of 48			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000347598.9 link	c.1553G>A	p.Arg518His	missense_variant	Exon 12 of 49	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 link	c.1553G>A	p.Arg518His	missense_variant	Exon 12 of 47	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 link	c.1553G>A	p.Arg518His	missense_variant	Exon 12 of 48	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617.6 link	c.1553G>A	p.Arg518His	missense_variant	Exon 12 of 48	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 link	c.1643G>A	p.Arg548His	missense_variant	Exon 12 of 47			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 link	c.1643G>A	p.Arg548His	missense_variant	Exon 12 of 47			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 link	c.1643G>A	p.Arg548His	missense_variant	Exon 12 of 47			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 link	c.1643G>A	p.Arg548His	missense_variant	Exon 12 of 47			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399638.5 link	c.1553G>A	p.Arg518His	missense_variant	Exon 12 of 48	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 link	c.1628G>A	p.Arg543His	missense_variant	Exon 13 of 48	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 link	c.1553G>A	p.Arg518His	missense_variant	Exon 12 of 48	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 link	c.1553G>A	p.Arg518His	missense_variant	Exon 12 of 47	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 link	c.1553G>A	p.Arg518His	missense_variant	Exon 12 of 47	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 link	c.1553G>A	p.Arg518His	missense_variant	Exon 12 of 47	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 link	c.1553G>A	p.Arg518His	missense_variant	Exon 12 of 47	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 link	c.1628G>A	p.Arg543His	missense_variant	Exon 13 of 47			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 link	c.1553G>A	p.Arg518His	missense_variant	Exon 12 of 46	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 link	c.1553G>A	p.Arg518His	missense_variant	Exon 12 of 46	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 link	c.1553G>A	p.Arg518His	missense_variant	Exon 12 of 46	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 link	c.1553G>A	p.Arg518His	missense_variant	Exon 12 of 47	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 link	c.1553G>A	p.Arg518His	missense_variant	Exon 12 of 47	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399641.6 link	c.1553G>A	p.Arg518His	missense_variant	Exon 12 of 47	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000399644.5 link	c.1553G>A	p.Arg518His	missense_variant	Exon 12 of 47	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682835.1 link	c.1553G>A	p.Arg518His	missense_variant	Exon 12 of 47			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482.1 link	c.1544G>A	p.Arg515His	missense_variant	Exon 12 of 47			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 link	c.1553G>A	p.Arg518His	missense_variant	Exon 12 of 46			ENSP00000507309.1	Q13936-19
CACNA1C	ENST00000480911.6 link	n.*160G>A		non_coding_transcript_exon_variant	Exon 10 of 27	5		ENSP00000437936.2	F5H638
CACNA1C	ENST00000480911.6 link	n.*160G>A		3_prime_UTR_variant	Exon 10 of 27	5		ENSP00000437936.2	F5H638

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1443646

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

716136

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33082

American (AMR)

AF:

0.00

AC:

AN:

42384

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25796

East Asian (EAS)

AF:

0.00

AC:

AN:

38834

South Asian (SAS)

AF:

0.00

AC:

AN:

82654

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52192

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1103170

Other (OTH)

AF:

0.00

AC:

AN:

59782

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41468

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Jul 26, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 17, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate reduction in current density combined with increased window current and loss of inactivation (PMID: 26253506); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27390944, 30984024, 30025578, 30027834, 35862440, 32161207, 30681346, 34079780, 35352813, 31110529, 31408100, 36252119, 34999275, 36578016, 37614386, 26253506, 31430211) -

Long qt syndrome 8

Pathogenic:1

Jan 11, 2024

Clinical Genetics Laboratory, Region Ostergotland

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS3, PM5, PM2, PP3 -

Timothy syndrome

Pathogenic:1

Sep 29, 2022

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Long QT syndrome

Pathogenic:1

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 518 of the CACNA1C protein (p.Arg518His). This variant is present in population databases (no rsID available, gnomAD 0.3%). This missense change has been observed in individuals with long QT syndrome or a complex phenotype of long QT syndrome and hypertrophic cardiomyopathy (PMID: 26253506, 30025578, 31408100, 32161207). ClinVar contains an entry for this variant (Variation ID: 372313). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CACNA1C protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CACNA1C function (PMID: 26253506). This variant disrupts the p.Arg518 amino acid residue in CACNA1C. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26253506; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Dec 20, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R518H pathogenic mutation (also known as c.1553G>A), located in coding exon 12 of the CACNA1C gene, results from a G to A substitution at nucleotide position 1553. The arginine at codon 518 is replaced by histidine, an amino acid with highly similar properties. This variant was identified in one or more individuals with mixed cardiac phenotypes, including long QT syndrome, hypertrophic cardiomyopathy, cardiac conduction defects, and congenital heart disease, and segregated with disease in at least one family (Boczek NJ et al. Circ Arrhythm Electrophysiol, 2015 Oct;8:1122-32; Bagnall RD et al. J. Am. Coll. Cardiol., 2018 Jul;72:419-429; Bonaventura J et al. Arch Med Sci, 2019 May;15:641-649; Mellor GJ et al. Europace, 2019 Aug; Fukuyama M et al. Circ J, 2020 03;84:559-568; external communication). In an assay testing CACNA1C function, this variant showed a functionally abnormal result (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 for CACNA1C-related long QT syndrome/Timothy syndrome; however, its clinical significance for CACNA1C-related neurodevelopmental disorder is uncertain. -

Cardiac arrhythmia

Pathogenic:1

Apr 05, 2022

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Hypertrophic cardiomyopathy 1

Pathogenic:1

Apr 19, 2017

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The CACNA1C Arg518His variant had been identified in a few probands with mixed phenotypes of Long QT, congenital heart defects and HCM (Boczek NJ, et al., 2015; Genedx, personal communication) and has been found to segregate in 2 families with varying phenotypes (Boczek NJ, et al., 2015). In vitro functional analysis using whole cell patch clamping confirmed the loss of current density and inactivation in combination with increased window and later voltage gated calcium channel current (Boczek NJ, et al., 2015), however this study may not necessarily reflect biological function and future studies will be useful to validate these findings. The variant is present a singleton event in the Exome Aggregation Consortium dataset (MAF= 0.00003230, http://exac.broadinstitute.org/). We identified this variant in a patient diagnosed with HCM in their adoloscence, the patient had a known family history of disease and a prolonged QT was noted when the patient was in his 40s. The probands affected son also harbours this variant. He was diagnosed with HCM at 2 months. Computational tools SIFT, PolyPhen-2 and MutationTaster predict this variant to have deleterious effect. In summary, based on a few proband's reported with similar phenotypes, strong segregation data, rarity in general population databases, as well supportive in silico tools in combination with a functional study suggestive of an affect on protein function, we classify the CACNA1C Arg518His as "likely pathogenic". -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

CardioboostArm

Uncertain

0.63

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.099

T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.98

M_CAP

Pathogenic

0.44

MetaRNN

Uncertain

0.73

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.93

MutationAssessor

Pathogenic

3.1

.;M;.;M;M;M;M;M;M;M;M;M;M;M;M;M;.;M;M;M;.;.;.

PhyloP100

6.8

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-2.8

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.79

Sift

Benign

0.075

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

Sift4G

Uncertain

0.060

T;T;D;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

1.0, 0.99, 0.52, 0.99

.;D;D;D;D;P;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.;D

Vest4

0.66

MVP

0.92

MPC

2.2

ClinPred

0.99

GERP RS

5.3

PromoterAI

0.024

Neutral

(source)

gMVP

0.92

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over