rs786205753

Variant names:

• chr12-2593255-G-A
• rs786205753
• NM_000719.7:c.2573G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-2593255-G-A
• chr12-2593255-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 11P and 4B. PM1 PP3 PP5_Very_Strong BS2

The NM_000719.7(CACNA1C):​c.2573G>A​(p.Arg858His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. 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. R858C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 10.0
• Publications: 22 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000719.7
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822
• PP5: Variant 12-2593255-G-A is Pathogenic according to our data. Variant chr12-2593255-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 190653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.2573G>A	p.Arg858His	missense_variant	Exon 19 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.2573G>A	p.Arg858His	missense_variant	Exon 19 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.2573G>A	p.Arg858His	missense_variant	Exon 19 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.2573G>A	p.Arg858His	missense_variant	Exon 19 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.2663G>A	p.Arg888His	missense_variant	Exon 19 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.2573G>A	p.Arg858His	missense_variant	Exon 19 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.2573G>A	p.Arg858His	missense_variant	Exon 19 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.2738G>A	p.Arg913His	missense_variant	Exon 20 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.2573G>A	p.Arg858His	missense_variant	Exon 19 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.2573G>A	p.Arg858His	missense_variant	Exon 19 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.2573G>A	p.Arg858His	missense_variant	Exon 19 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.2573G>A	p.Arg858His	missense_variant	Exon 19 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.2663G>A	p.Arg888His	missense_variant	Exon 19 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.2663G>A	p.Arg888His	missense_variant	Exon 19 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.2663G>A	p.Arg888His	missense_variant	Exon 19 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.2663G>A	p.Arg888His	missense_variant	Exon 19 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.2573G>A	p.Arg858His	missense_variant	Exon 19 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.2648G>A	p.Arg883His	missense_variant	Exon 20 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.2573G>A	p.Arg858His	missense_variant	Exon 19 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.2573G>A	p.Arg858His	missense_variant	Exon 19 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.2573G>A	p.Arg858His	missense_variant	Exon 19 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.2573G>A	p.Arg858His	missense_variant	Exon 19 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.2573G>A	p.Arg858His	missense_variant	Exon 19 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.2648G>A	p.Arg883His	missense_variant	Exon 20 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.2573G>A	p.Arg858His	missense_variant	Exon 19 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.2573G>A	p.Arg858His	missense_variant	Exon 19 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.2573G>A	p.Arg858His	missense_variant	Exon 19 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.2573G>A	p.Arg858His	missense_variant	Exon 19 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.2573G>A	p.Arg858His	missense_variant	Exon 19 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.2573G>A	p.Arg858His	missense_variant	Exon 19 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.2573G>A	p.Arg858His	missense_variant	Exon 19 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.2573G>A	p.Arg858His	missense_variant	Exon 19 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.2564G>A	p.Arg855His	missense_variant	Exon 19 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.2573G>A	p.Arg858His	missense_variant	Exon 19 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*1180G>A		non_coding_transcript_exon_variant	Exon 17 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*1180G>A		3_prime_UTR_variant	Exon 17 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461334 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726868

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111740

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 25, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CACNA1C c.2573G>A; p.Arg858His variant (rs786205753) is reported in the literature in multiple individuals with long QT syndrome or episodes of syncope, arrhythmia, or sudden unexpected death (Fukuyama 2014, Gardner 2019, Hellenthal 2017, Mullally 2013). This variant has been observed to co-segregate with disease in several families, including a large five-generation kindred, although it has been noted in asymptomatic relatives, suggesting incomplete penetrance (Fukuyama 2014, Gardner 2019). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 858 is highly conserved, computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious, and functional analyses indicate an increased current density relative to wildtype protein (Fukuyama 2014). Based on available information, this variant is considered to be likely pathogenic. References: Fukuyama M et al. Long QT syndrome type 8: novel CACNA1C mutations causing QT prolongation and variant phenotypes. Europace. 2014 Dec;16(12):1828-37. Gardner RJM et al. Penetrance and expressivity of the R858H CACNA1C variant in a five-generation pedigree segregating an arrhythmogenic channelopathy. Mol Genet Genomic Med. 2019 Jan;7(1):e00476. Hellenthal N et al. Molecular autopsy of sudden unexplained deaths reveals genetic predispositions for cardiac diseases among young forensic cases. Europace. 2017 Nov 1;19(11):1881-1890. Mullally J et al. Risk of life-threatening cardiac events among patients with long QT syndrome and multiple mutations. Heart Rhythm. 2013 Mar;10(3):378-82. -

Jul 15, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; Published in vitro functional studies showed that p.(R858H) results in a gain-of-function of the cardiac L-type calcium channel (PMID: 24728418); This variant is associated with the following publications: (PMID: 29016939, 23174487, 25184293, 24728418, 26707467, 30027834, 30345660, 23631430, 29046645, 30513141, 31395126, 31729605, 32161207, 34691145, 31408100, 32062134, 30530868) -

Jan 26, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PP1_Strong, PS4_Moderate, PM1, PM2_Supporting, PP2, PP3 -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:2

Jun 05, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R858H variant (also known as c.2573G>A), located in coding exon 19 of the CACNA1C gene, results from a G to A substitution at nucleotide position 2573. The arginine at codon 858 is replaced by histidine, an amino acid with highly similar properties. This variant was detected in multiple individuals who met clinical criteria for long QT syndrome (LQTS), or had features of LQTS such as QTc prolongation or syncope; some of these individuals were related (Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61; Mullally J et al. Heart Rhythm, 2013 Mar;10:378-82; Fukuyama M et al. Europace, 2014 Dec;16:1828-37; Hellenthal N et al. Europace, 2017 Nov;19:1881-1890; Gardner RJM et al. Mol Genet Genomic Med, 2019 01;7:e00476; Fukuyama M et al. Circ J, 2020 03;84:559-568). This variant was also detected in multiple sudden death cases, one of which had cardiac findings (Hellenthal N et al. Europace, 2017 Nov;19:1881-1890; Larsen MK et al. Int J Legal Med, 2020 Jan;134:111-121). In vitro functional studies suggest that this alteration may impact protein function; however, the clinical significance of these studies is undetermined (Fukuyama M et al. Europace, 2014 Dec;16:1828-37). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is expected to be causative of long QT syndrome (LQTS); however, its clinical significance for Timothy syndrome is unclear. -

Sep 14, 2022

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long qt syndrome 8 Pathogenic:1

Jun 05, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Long QT syndrome Pathogenic:1

Jan 28, 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 858 of the CACNA1C protein (p.Arg858His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 23174487, 23631430, 24728418, 29016939, 30345660). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 190653). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CACNA1C protein function. Experimental studies have shown that this missense change affects CACNA1C function (PMID: 24728418). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.092	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.82	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	1.1	D
MutationAssessor	Pathogenic	3.0	.;M;.;M;M;M;M;M;M;M;M;M;M;M;M;M;.;M;M;M;.;.;.
PhyloP100		10
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-4.3	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	0.78
Sift	Benign	0.035	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.022	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0, 0.86, 0.96	.;D;D;P;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;.;D;.;D
Vest4		0.74
MutPred		0.29		.;Gain of catalytic residue at M853 (P = 0.045);Gain of catalytic residue at M853 (P = 0.045);Gain of catalytic residue at M853 (P = 0.045);Gain of catalytic residue at M853 (P = 0.045);Gain of catalytic residue at M853 (P = 0.045);Gain of catalytic residue at M853 (P = 0.045);Gain of catalytic residue at M853 (P = 0.045);Gain of catalytic residue at M853 (P = 0.045);Gain of catalytic residue at M853 (P = 0.045);Gain of catalytic residue at M853 (P = 0.045);Gain of catalytic residue at M853 (P = 0.045);Gain of catalytic residue at M853 (P = 0.045);Gain of catalytic residue at M853 (P = 0.045);Gain of catalytic residue at M853 (P = 0.045);Gain of catalytic residue at M853 (P = 0.045);Gain of catalytic residue at M853 (P = 0.045);Gain of catalytic residue at M853 (P = 0.045);Gain of catalytic residue at M853 (P = 0.045);Gain of catalytic residue at M853 (P = 0.045);Gain of catalytic residue at M853 (P = 0.045);Gain of catalytic residue at M853 (P = 0.045);Gain of catalytic residue at M853 (P = 0.045);
MVP		0.95
MPC		2.1
ClinPred		1.0	D
GERP RS		4.9
gMVP		0.62
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs786205753; hg19: chr12-2702421; COSMIC: COSV59697881;