rs199473391

Variant names:

• chr12-2607117-G-A
• rs199473391
• NM_000719.7:c.3343G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-2607117-G-A
• chr12-2607117-G-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_000719.7(CACNA1C):​c.3343G>A​(p.Glu1115Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1115G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:2
• Conservation: PhyloP100: 9.60
• Publications: 26 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-AS3 (HGNC:40117): (CACNA1C antisense RNA 3)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888
• PP5: Variant 12-2607117-G-A is Pathogenic according to our data. Variant chr12-2607117-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 67554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.3343G>A	p.Glu1115Lys	missense_variant	Exon 26 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.3343G>A	p.Glu1115Lys	missense_variant	Exon 26 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.3343G>A	p.Glu1115Lys	missense_variant	Exon 26 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.3343G>A	p.Glu1115Lys	missense_variant	Exon 26 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.3493G>A	p.Glu1165Lys	missense_variant	Exon 27 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.3343G>A	p.Glu1115Lys	missense_variant	Exon 26 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.3343G>A	p.Glu1115Lys	missense_variant	Exon 26 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.3508G>A	p.Glu1170Lys	missense_variant	Exon 27 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.3403G>A	p.Glu1135Lys	missense_variant	Exon 27 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.3343G>A	p.Glu1115Lys	missense_variant	Exon 26 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.3343G>A	p.Glu1115Lys	missense_variant	Exon 26 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.3343G>A	p.Glu1115Lys	missense_variant	Exon 26 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.3433G>A	p.Glu1145Lys	missense_variant	Exon 26 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.3433G>A	p.Glu1145Lys	missense_variant	Exon 26 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.3433G>A	p.Glu1145Lys	missense_variant	Exon 26 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.3433G>A	p.Glu1145Lys	missense_variant	Exon 26 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.3343G>A	p.Glu1115Lys	missense_variant	Exon 26 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.3418G>A	p.Glu1140Lys	missense_variant	Exon 27 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.3403G>A	p.Glu1135Lys	missense_variant	Exon 27 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.3343G>A	p.Glu1115Lys	missense_variant	Exon 26 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.3343G>A	p.Glu1115Lys	missense_variant	Exon 26 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.3343G>A	p.Glu1115Lys	missense_variant	Exon 26 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.3343G>A	p.Glu1115Lys	missense_variant	Exon 26 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.3418G>A	p.Glu1140Lys	missense_variant	Exon 27 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.3343G>A	p.Glu1115Lys	missense_variant	Exon 26 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.3343G>A	p.Glu1115Lys	missense_variant	Exon 26 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.3343G>A	p.Glu1115Lys	missense_variant	Exon 26 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.3343G>A	p.Glu1115Lys	missense_variant	Exon 26 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.3343G>A	p.Glu1115Lys	missense_variant	Exon 26 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.3343G>A	p.Glu1115Lys	missense_variant	Exon 26 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.3343G>A	p.Glu1115Lys	missense_variant	Exon 26 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.3343G>A	p.Glu1115Lys	missense_variant	Exon 26 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.3334G>A	p.Glu1112Lys	missense_variant	Exon 26 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.3343G>A	p.Glu1115Lys	missense_variant	Exon 26 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*1950G>A		non_coding_transcript_exon_variant	Exon 24 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*1950G>A		3_prime_UTR_variant	Exon 24 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long qt syndrome 8 Pathogenic:2

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene. Loss-of-function variants are associated with neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures, AD (MIM#620029) (PMID: 34163037). Gain-of-function missense variants result in loss of channel inactivation and increased current, and are associated with long QT syndrome 8 (MIM#618447) and Timothy syndrome (MIM#601005, PMID: 25260352). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Parents with the same variant as their affected child have been observed to have a less severe phenotype (PMID: 34163037). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional DIII-S5/S6 pore-forming region. Glu1115 forms part of the calcium channel ion selectivity filter (PMID: 30172029). (SP) 0710 – Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. p.(Glu1115Gly) has been reported as a VUS by a clinical testing laboratory (ClinVar). (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been identified in six individuals with long QT syndrome and an individual with Brugada syndrome; however, it has been classified as a VUS in most cases (VCGS, ClinVar, PMIDs: 36007726, 30172029, 20817017). (SP) 0906 - Segregation evidence for this variant is inconclusive. This variant has been identified in both affected and unaffected family members (VCGS, PMIDs: 20817017, 36007726). (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Patch clamp functional studies indicate that this variant impairs the calcium ion selectivity of the channel, that results in an increased permeability to monovalent cations (PMIDs: 36007726, 30172029). However, patch clamp assays have been shown to be unreliable, therefore results from these studies are used with caution during variant classification. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Apr 22, 2025

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported in individuals with Brugada or long QT syndrome (PubMed: 20817017, 30172029, 36007726, internal cases of Victorian Clinical Genetics Services, The Royal Children’s Hospital). Functional studies suggested this change affected the protein function (PubMed:30172029, 36007726). This variant is absent from the general population, and the REVEL score indicates that the variant may have a deleterious effect on the original protein function. -

Timothy syndrome Pathogenic:1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Brugada syndrome -

Sep 29, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Dec 27, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in an individual with Brugada syndrome; also identified in one affected sibling who experienced sudden death and in the unaffected mother (PMID: 20817017); Identified in an adolescent with LQTS, sinus bradycardia, autism spectrum disorder, and seizures (PMID: 30172029); Published in vitro functional studies suggest a damaging effect including impaired calcium current and prolonged action potential duration (PMID: 30172029); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30662450, 30821013, 30172029, 36007726, 20817017) -

Long QT syndrome Pathogenic:1

Jun 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1115 of the CACNA1C protein (p.Glu1115Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of CACNA1C-related conditions (PMID: 20817017, 30172029, 30662450; Invitae). ClinVar contains an entry for this variant (Variation ID: 67554). 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: 30172029). For these reasons, this variant has been classified as Pathogenic. -

Brugada syndrome Other:1

-

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported as associated with Brugada syndrome in the following publications (PMID:20817017). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.68	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.89	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	Uncertain	2.7	.;.;.;.;.;.;.;.;.;.;.;M;M;.;.;.;.;.;.;.;.;.;.
PhyloP100		9.6
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.8	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	0.95
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	0.0010	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, 0.99, 1.0, 1.0	.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.;D
Vest4		0.84
MutPred		0.76		.;.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at S1132 (P = 0);Gain of catalytic residue at S1132 (P = 0);.;.;.;.;.;.;.;.;.;.;
MVP		0.98
MPC		2.3
ClinPred		0.99	D
GERP RS		4.9
gMVP		1.0
Mutation Taster		=0/100	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: rs199473391; hg19: chr12-2716283; COSMIC: COSV59750786; COSMIC: COSV59750786;