rs786205753

Positions:

• chr12-2593255-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1_Moderate PM1 PP2 PP3 PP5_Very_Strong

The ENST00000399655.6(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. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. 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 ENST00000399655.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PS1: Transcript ENST00000399655.6 (CACNA1C) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in ENST00000399655.6
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1C. . Gene score misZ 6.4654 (greater than the threshold 3.09). Trascript score misZ 7.2674 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures, Brugada syndrome, long QT syndrome, short QT syndrome, long qt syndrome 8, Timothy syndrome, Brugada syndrome 3.
• 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. Variant chr12-2593255-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.2573G>A	p.Arg858His	missense_variant	19/47	5	NM_001167623.2	ENSP00000382512
CACNA1C	ENST00000399655.6	c.2573G>A	p.Arg858His	missense_variant	19/47	1	NM_000719.7	ENSP00000382563

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

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 26, 2021	PS3, PP1_Strong, PS4_Moderate, PM1, PM2_Supporting, PP2, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2022	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) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 25, 2019	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. -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Long qt syndrome 8 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 05, 2019

- -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 20, 2023

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). Advanced 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 at Invitae 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. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 05, 2021

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 variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
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

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

LitVar

Other links and lift over

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