rs730880056

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM5PP2PP3_Moderate

The NM_000719.7(CACNA1C):c.2579G>A(p.Arg860Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,608 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R860P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:4

Conservation

PhyloP100: 8.08

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

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 NM_000719.7

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-2593260-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 190702.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, 0.859

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1C	NM_000719.7 linkuse as main transcript	c.2579G>A	p.Arg860Gln	missense_variant	19/47	ENST00000399655.6
CACNA1C	NM_001167623.2 linkuse as main transcript	c.2579G>A	p.Arg860Gln	missense_variant	19/47	ENST00000399603.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1C	ENST00000399603.6 linkuse as main transcript	c.2579G>A	p.Arg860Gln	missense_variant	19/47	5	NM_001167623.2		Q13936-37
CACNA1C	ENST00000399655.6 linkuse as main transcript	c.2579G>A	p.Arg860Gln	missense_variant	19/47	1	NM_000719.7		Q13936-12

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000121

AC:

AN:

248588

Hom.:

AF XY:

0.0000223

AC XY:

AN XY:

134824

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461408

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

726928

show subpopulations

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2021	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28616568, 29071820, 28600387) -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Timothy syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Mar 25, 2019

- -

Wolff-Parkinson-White pattern

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Jul 14, 2017

This variant was identified in an individual with Wolff-Parkinson-White syndrome -

Long QT syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 15, 2021

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. This variant disrupts the p.Arg860 amino acid residue in CACNA1C. Other variant(s) that disrupt this residue have been observed in individuals with CACNA1C-related conditions (PMID: 25633834; Invitae), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 190654). This missense change has been observed in individuals with clinical features of long QT syndrome (PMID: 28600387, 28616568, 29071820, 31408100; Invitae). This variant is present in population databases (rs730880056, ExAC 0.003%). This sequence change replaces arginine with glutamine at codon 860 of the CACNA1C protein (p.Arg860Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2020

The p.R860Q variant (also known as c.2579G>A), located in coding exon 19 of the CACNA1C gene, results from a G to A substitution at nucleotide position 2579. The arginine at codon 860 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in long QT syndrome (LQTS) cases; however, in some cases clinical details were limited and/or an additional cardiac variant was also detected (Mellor G et al. Circ Cardiovasc Genet, 2017 Jun;10:[Epub ahead of print]; Boles U et al. Int J Cardiol Heart Vasc, 2017 Jun;15:21-23; Seo SH et al. Ann Lab Med, 2018 Jan;38:54-58). Alternate amino acid substitutions at this codon, p.R860G and p.R860P, have also been associated with LQTS (Mellor GJ et al. Europace, 2019 Nov;21:1725-1732). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

CardioboostArm

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.23

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.062

T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.98

M_CAP

Pathogenic

0.56

MetaRNN

Pathogenic

0.86

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

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

0.74

PROVEAN

Uncertain

-2.9

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

0.65

Sift

Benign

0.057

T;T;D;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;D;T;D

Sift4G

Benign

0.13

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

1.0, 1.0, 0.77, 0.41, 0.88, 1.0, 1.0

.;D;D;P;B;P;D;D;D;P;D;D;D;D;D;D;.;D;D;.;D;.;D

Vest4

0.79

MVP

0.94

MPC

2.0

ClinPred

0.86

GERP RS

4.9

gMVP

0.80

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over