rs786205748

chr12-2566465-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PS1_Moderate PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000719.7(CACNA1C):c.1552C>T(p.Arg518Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as 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. R518S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 3.17

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 17 ACMG points.

• PS1: Transcript NM_000719.7 (CACNA1C) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-2566466-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, CACNA1C
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922
• PP5: Variant 12-2566465-C-T is Pathogenic according to our data. Variant chr12-2566465-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 190642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2566465-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1C	NM_000719.7	c.1552C>T	p.Arg518Cys	missense_variant	12/47	ENST00000399655.6
CACNA1C	NM_001167623.2	c.1552C>T	p.Arg518Cys	missense_variant	12/47	ENST00000399603.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1552C>T	p.Arg518Cys	missense_variant	12/47	5	NM_001167623.2
CACNA1C	ENST00000399655.6	c.1552C>T	p.Arg518Cys	missense_variant	12/47	1	NM_000719.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1443586 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 716098

Gnomad4 AFR exome AF: 0.00

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: 9.07e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long qt syndrome 8 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	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 -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	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. -

not provided Pathogenic:2

Likely pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Apr 14, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2019	Described in another individual with LQTS and a positive family history, though segregation data was not provided (Seo et al., 2018); Reported in ClinVar as pathogenic (ClinVar Variant ID# 190642; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Whole cell patch clamp studies revealed a complex phenotype, including loss of current density and inactivation in combination with increased window and late current (Boczek et al., 2015); This variant is associated with the following publications: (PMID: 27390944, 26253506, 30513141, 29071820, 30172029, 30345660, 31430211, 32161207) -

Timothy syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 29, 2022

- -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 16, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 518 of the CACNA1C protein (p.Arg518Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with long QT syndrome (LQTS), hypertrophic cardiomyopathy (HCM) and septal defects (CHD) (PMID: 26253506; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 190642). 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) performed at Invitae indicates that this missense variant is expected to disrupt CACNA1C protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CACNA1C function (PMID: 26253506). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 22, 2021

The p.R518C pathogenic mutation (also known as c.1552C>T), located in coding exon 12 of the CACNA1C gene, results from a C to T substitution at nucleotide position 1552. The arginine at codon 518 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple unrelated probands with mixed cardiac phenotypes, including long QT syndrome, hypertrophic cardiomyopathy, cardiac conduction defects, and congenital heart disease, and has been reported to segregate with disease in several families (Boczek NJ et al. Circ Arrhythm Electrophysiol, 2015 Oct;8:1122-32; Seo SH et al. Ann Lab Med, 2018 Jan;38:54-58; Korkosh VS et al. Front Physiol, 2019 Mar;10:335; Fukuyama M et al. Circ J, 2020 03;84:559-568; GeneDx pers comm; Invitae pers comm; Ambry internal data). Functional studies performed in vitro indicate that R518C leads to a decrease in peak channel current density but an increase in the late calcium current (Boczek NJ et al. Circ Arrhythm Electrophysiol, 2015 Oct;8:1122-32; Estes SI et al. Circ Genom Precis Med, 2019 08;12:e002534). Another pathogenic alteration, p.R518H, has been described in the same codon (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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
CardioboostArm	Uncertain	0.75
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.14	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.92	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
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	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.6	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	0.88
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	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	.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.;D
Vest4		0.73
MVP		0.99
MPC		2.6
ClinPred		1.0	D
GERP RS		4.4
gMVP		0.95

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: rs786205748; hg19: chr12-2675631; COSMIC: COSV59720873;