chr12-2566466-G-A

Position:

• chr12-2566466-G-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PS1_Moderate PM1 PM2 PM5 PP2 PP5_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 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. R518C) 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 6.79

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
• PM1: In a topological_domain Cytoplasmic (size 122) in uniprot entity CAC1C_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000719.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• 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.
• PP5: Variant 12-2566466-G-A is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1553G>A	p.Arg518His	missense_variant	12/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1553G>A	p.Arg518His	missense_variant	12/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1553G>A	p.Arg518His	missense_variant	12/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.1553G>A	p.Arg518His	missense_variant	12/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1643G>A	p.Arg548His	missense_variant	12/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.1553G>A	p.Arg518His	missense_variant	12/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1553G>A	p.Arg518His	missense_variant	12/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1718G>A	p.Arg573His	missense_variant	13/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.1553G>A	p.Arg518His	missense_variant	12/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1553G>A	p.Arg518His	missense_variant	12/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1553G>A	p.Arg518His	missense_variant	12/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.1553G>A	p.Arg518His	missense_variant	12/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1643G>A	p.Arg548His	missense_variant	12/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1643G>A	p.Arg548His	missense_variant	12/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1643G>A	p.Arg548His	missense_variant	12/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1643G>A	p.Arg548His	missense_variant	12/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.1553G>A	p.Arg518His	missense_variant	12/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1628G>A	p.Arg543His	missense_variant	13/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1553G>A	p.Arg518His	missense_variant	12/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1553G>A	p.Arg518His	missense_variant	12/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1553G>A	p.Arg518His	missense_variant	12/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1553G>A	p.Arg518His	missense_variant	12/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1553G>A	p.Arg518His	missense_variant	12/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1628G>A	p.Arg543His	missense_variant	13/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1553G>A	p.Arg518His	missense_variant	12/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1553G>A	p.Arg518His	missense_variant	12/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1553G>A	p.Arg518His	missense_variant	12/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1553G>A	p.Arg518His	missense_variant	12/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1553G>A	p.Arg518His	missense_variant	12/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.1553G>A	p.Arg518His	missense_variant	12/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.1553G>A	p.Arg518His	missense_variant	12/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.1553G>A	p.Arg518His	missense_variant	12/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.1544G>A	p.Arg515His	missense_variant	12/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1553G>A	p.Arg518His	missense_variant	12/46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*160G>A		non_coding_transcript_exon_variant	10/27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*160G>A		3_prime_UTR_variant	10/27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 33

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: 2 AN: 1443646 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 716136

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: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 29, 2024	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 26, 2023	- -

Long qt syndrome 8 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Clinical Genetics Laboratory, Region Ostergotland

Jan 11, 2024

PS3, PM5, PM2, PP3 -

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

Labcorp Genetics (formerly Invitae), Labcorp

Oct 04, 2023

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). 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. 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; Invitae). 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

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 28, 2024

The c.1553G>A (p.R518H) alteration is located in exon 12 (coding exon 12) of the CACNA1C gene. This alteration results from a G to A substitution at nucleotide position 1553, causing the arginine (R) at amino acid position 518 to be replaced by a histidine (H). for CACNA1C-related long QT syndrome/Timothy syndrome; however, its clinical significance for CACNA1C-related neurodevelopmental disorder is uncertain. Based on data from gnomAD, the A allele has an overall frequency of 0.003% (1/31394) total alleles studied. The highest observed frequency was <0.001% of alleles. This variant was reported in multiple individuals with features consistent with CACNA1C-related long QT syndrome/Timothy syndrome (Fukuyama, 2020, Bagnall, 2018, external communication). This amino acid position is well conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). Based on internal structural analysis, this variant is anticipated to disrupt a region of known function (Wu, 2016, Mellor, 2019, Boczek, 2015, Korkosh, 2019). In an assay testing CACNA1C function, this variant showed a functionally abnormal result (Boczek, 2015). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Cardiac arrhythmia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Apr 05, 2022

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

Likely pathogenic, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Apr 19, 2017

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
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	30
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	D
M_CAP	Pathogenic	0.44	D
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	D
MutationAssessor	Pathogenic	3.1	.;M;.;M;M;M;M;M;M;M;M;M;M;M;M;M;.;M;M;M;.;.;.
PrimateAI	Pathogenic	0.81	D
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	D
GERP RS		5.3
gMVP		0.92

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: rs1057517711; hg19: chr12-2675632; COSMIC: COSV59732331;