rs786205747

Variant names:

• chr12-2566445-G-A
• rs786205747
• NM_000719.7:c.1532G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000719.7(CACNA1C):​c.1532G>A​(p.Arg511Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,443,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R511W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 9.99
• Publications: 7 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 6 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, 13 uncertain in NM_000719.7
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.876

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1532G>A	p.Arg511Gln	missense_variant	Exon 12 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1532G>A	p.Arg511Gln	missense_variant	Exon 12 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1532G>A	p.Arg511Gln	missense_variant	Exon 12 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.1532G>A	p.Arg511Gln	missense_variant	Exon 12 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1622G>A	p.Arg541Gln	missense_variant	Exon 12 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.1532G>A	p.Arg511Gln	missense_variant	Exon 12 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1532G>A	p.Arg511Gln	missense_variant	Exon 12 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1697G>A	p.Arg566Gln	missense_variant	Exon 13 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.1532G>A	p.Arg511Gln	missense_variant	Exon 12 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1532G>A	p.Arg511Gln	missense_variant	Exon 12 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1532G>A	p.Arg511Gln	missense_variant	Exon 12 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.1532G>A	p.Arg511Gln	missense_variant	Exon 12 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1622G>A	p.Arg541Gln	missense_variant	Exon 12 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1622G>A	p.Arg541Gln	missense_variant	Exon 12 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1622G>A	p.Arg541Gln	missense_variant	Exon 12 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1622G>A	p.Arg541Gln	missense_variant	Exon 12 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.1532G>A	p.Arg511Gln	missense_variant	Exon 12 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1607G>A	p.Arg536Gln	missense_variant	Exon 13 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1532G>A	p.Arg511Gln	missense_variant	Exon 12 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1532G>A	p.Arg511Gln	missense_variant	Exon 12 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1532G>A	p.Arg511Gln	missense_variant	Exon 12 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1532G>A	p.Arg511Gln	missense_variant	Exon 12 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1532G>A	p.Arg511Gln	missense_variant	Exon 12 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1607G>A	p.Arg536Gln	missense_variant	Exon 13 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1532G>A	p.Arg511Gln	missense_variant	Exon 12 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1532G>A	p.Arg511Gln	missense_variant	Exon 12 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1532G>A	p.Arg511Gln	missense_variant	Exon 12 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1532G>A	p.Arg511Gln	missense_variant	Exon 12 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1532G>A	p.Arg511Gln	missense_variant	Exon 12 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.1532G>A	p.Arg511Gln	missense_variant	Exon 12 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.1532G>A	p.Arg511Gln	missense_variant	Exon 12 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.1532G>A	p.Arg511Gln	missense_variant	Exon 12 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.1523G>A	p.Arg508Gln	missense_variant	Exon 12 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1532G>A	p.Arg511Gln	missense_variant	Exon 12 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*139G>A		non_coding_transcript_exon_variant	Exon 10 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*139G>A		3_prime_UTR_variant	Exon 10 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1443740 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 716220

African (AFR) AF: 0.00 AC: 0 AN: 33042

American (AMR) AF: 0.00 AC: 0 AN: 42510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25772

East Asian (EAS) AF: 0.00 AC: 0 AN: 38798

South Asian (SAS) AF: 0.00 AC: 0 AN: 82716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00000272 AC: 3 AN: 1103134

Other (OTH) AF: 0.00 AC: 0 AN: 59800

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Aug 28, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in four individuals from the same family with non-syndromic long QT syndrome, however two of these individuals also harbored a variant in an additional gene associated with long QT syndrome (Nakajima et al., 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; This variant is associated with the following publications: (PMID: 35862440) -

Long QT syndrome Uncertain:1

May 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 511 of the CACNA1C protein (p.Arg511Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 190641). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype Uncertain:1

Apr 17, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R511Q variant (also known as c.1532G>A), located in coding exon 12 of the CACNA1C gene, results from a G to A substitution at nucleotide position 1532. The arginine at codon 511 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in association with cardiomyopathy and long QT syndrome (Voka D et al. Genes (Basel), 2024 Jan;15:; Nakajima T et al. PLoS One, 2022 Jul;17:e0271796). 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 available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.088	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.88	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	1.0	D
MutationAssessor	Pathogenic	3.7	.;H;.;H;H;H;H;H;H;H;H;H;H;H;H;H;.;H;H;H;.;.;.
PhyloP100		10
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.6	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	0.87
Sift	Uncertain	0.0060	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	0.0070	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, 1.0, 0.92	.;D;D;D;D;P;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.;D
Vest4		0.67
MutPred		0.53		.;Gain of catalytic residue at K516 (P = 0.0016);Gain of catalytic residue at K516 (P = 0.0016);Gain of catalytic residue at K516 (P = 0.0016);Gain of catalytic residue at K516 (P = 0.0016);Gain of catalytic residue at K516 (P = 0.0016);Gain of catalytic residue at K516 (P = 0.0016);Gain of catalytic residue at K516 (P = 0.0016);Gain of catalytic residue at K516 (P = 0.0016);Gain of catalytic residue at K516 (P = 0.0016);Gain of catalytic residue at K516 (P = 0.0016);Gain of catalytic residue at K516 (P = 0.0016);Gain of catalytic residue at K516 (P = 0.0016);Gain of catalytic residue at K516 (P = 0.0016);Gain of catalytic residue at K516 (P = 0.0016);Gain of catalytic residue at K516 (P = 0.0016);Gain of catalytic residue at K516 (P = 0.0016);Gain of catalytic residue at K516 (P = 0.0016);Gain of catalytic residue at K516 (P = 0.0016);Gain of catalytic residue at K516 (P = 0.0016);Gain of catalytic residue at K516 (P = 0.0016);Gain of catalytic residue at K516 (P = 0.0016);Gain of catalytic residue at K516 (P = 0.0016);
MVP		0.97
MPC		2.2
ClinPred		1.0	D
GERP RS		5.3
PromoterAI		0.0044	Neutral
gMVP		0.92
Mutation Taster		=23/77	disease causing

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: rs786205747; hg19: chr12-2675611;