19-13262780-C-T

Position:

• chr19-13262780-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001127222.2(CACNA1A):​c.4043G>A​(p.Arg1348Gln) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20 O:1
• Conservation: PhyloP100: 7.88

Genes affected

CACNA1A (HGNC:1388): (calcium voltage-gated channel subunit alpha1 A) Voltage-dependent calcium channels mediate the entry of calcium ions into excitable cells, and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, and gene expression. Calcium channels are multisubunit complexes composed of alpha-1, beta, alpha-2/delta, and gamma subunits. The channel activity is directed by the pore-forming alpha-1 subunit, whereas, the others act as auxiliary subunits regulating this activity. The distinctive properties of the calcium channel types are related primarily to the expression of a variety of alpha-1 isoforms, alpha-1A, B, C, D, E, and S. This gene encodes the alpha-1A subunit, which is predominantly expressed in neuronal tissue. Mutations in this gene are associated with 2 neurologic disorders, familial hemiplegic migraine and episodic ataxia 2. This gene also exhibits polymorphic variation due to (CAG)n-repeats. Multiple transcript variants encoding different isoforms have been found for this gene. In one set of transcript variants, the (CAG)n-repeats occur in the 3' UTR, and are not associated with any disease. But in another set of variants, an insertion extends the coding region to include the (CAG)n-repeats which encode a polyglutamine tract. Expansion of the (CAG)n-repeats from the normal 4-18 to 21-33 in the coding region is associated with spinocerebellar ataxia 6. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a transmembrane_region Helical; Name=S4 of repeat III (size 18) in uniprot entity CAC1A_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001127222.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1A. . Gene score misZ: 5.7845 (greater than the threshold 3.09). Trascript score misZ: 3.9354 (greater than threshold 3.09). The gene has 137 curated pathogenic missense variants (we use a threshold of 10). The gene has 132 curated benign missense variants. GenCC has associacion of the gene with benign paroxysmal torticollis of infancy, developmental and epileptic encephalopathy, 42, undetermined early-onset epileptic encephalopathy, episodic ataxia type 2, familial or sporadic hemiplegic migraine, spinocerebellar ataxia type 6, Lennox-Gastaut syndrome, migraine, familial hemiplegic, 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 19-13262780-C-T is Pathogenic according to our data. Variant chr19-13262780-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 380972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13262780-C-T is described in Lovd as [Likely_pathogenic]. Variant chr19-13262780-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.4043G>A	p.Arg1348Gln	missense_variant	25/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.4043G>A	p.Arg1348Gln	missense_variant	25/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.4055G>A	p.Arg1352Gln	missense_variant	25/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.4049G>A	p.Arg1350Gln	missense_variant	25/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.4046G>A	p.Arg1349Gln	missense_variant	25/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.4046G>A	p.Arg1349Gln	missense_variant	25/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.4046G>A	p.Arg1349Gln	missense_variant	25/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.3905G>A	p.Arg1302Gln	missense_variant	24/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.4046G>A	p.Arg1349Gln	missense_variant	25/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.4055G>A	p.Arg1352Gln	missense_variant	25/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.4046G>A	p.Arg1349Gln	missense_variant	25/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.4049G>A	p.Arg1350Gln	missense_variant	25/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.4046G>A	p.Arg1349Gln	missense_variant	25/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.4046G>A	p.Arg1349Gln	missense_variant	25/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.4046G>A	p.Arg1349Gln	missense_variant	25/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:20 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 42 Pathogenic:8

Pathogenic, no assertion criteria provided	clinical testing	Undiagnosed Diseases Network, NIH	Sep 26, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 02, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Génétique des Maladies du Développement, Hospices Civils de Lyon	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 19, 2021	This variant was identified as de novo (maternity and paternity confirmed). -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	Sep 21, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust	May 03, 2019	- -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Nov 15, 2018	The heterozygous p.Arg1348Gln variant in CACNA1A was identified by our study in one individual with Early Infantile Epileptic Encephalopaty. The p.Arg1348Gln variant is pathogenic based off of multiple reports in ClinVar and the literature. -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 09, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 09, 2024	This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) In some published literature, this variant is referred to as c.4055G>A (p.R1352Q). In mouse models this variant is equivalent to p.R1252Q. This variant appears to occur de novo in multiple individuals with clinical features associated with a CACNA1A-related disorder. Computational tools yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 18597946) The variant is located in a region that is considered important for protein function and/or structure. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	CACNA1A: PS2:Very Strong, PM2, PP2, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2021	Published functional studies in the Tg5J mouse model, which harbors an equivalent variant, demonstrated a shift in both voltage activation and inactivation to lower voltage, suggesting that the Arg1349 residue is critical for sensing Ca(v)2.1 voltage changes (Miki et al., 2008; Knierim et al., 2011); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26814174, 28007337, 25596066, 21183743, 18597946, 23831250, 20097664, 28717674, 19811514, 30063100, 31139143, 32860008, 31785789) -

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1349 of the CACNA1A protein (p.Arg1349Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with CACNA1A-related conditions (PMID: 20097664, 21183743, 23831250, 26814174, 28007337, 31139143). In at least one individual the variant was observed to be de novo. This variant is also known as p.Arg1350Gln, p.R1352Q. ClinVar contains an entry for this variant (Variation ID: 380972). 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 CACNA1A protein function. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Feb 20, 2020	A heterozygous missense variant c.4043G>A in exon 25 of the CACNA1A gene that results in the amino acid substitution of Glutamine for Arginine at codon 1348 was detected. The observed variant has not been reported in the 1000 Genomes and ExAC databases. The observed variant lies in the Ion transport protein domain of the CACNA1A protein and has previously been reported (as Arg1350Gln) in patients affected with congenital cerebellar ataxia (Bahamonde et al.2015) and is a current de novo variant reported in multiple unrelated individuals affected with ataxia and developmental delay (ClinVar). The in silico prediction of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. -

Spinocerebellar ataxia type 6 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centogene AG - the Rare Disease Company

-

- -

Episodic ataxia type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 19, 2023

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 22, 2015

- -

Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1;C4479236:Developmental and epileptic encephalopathy, 52 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Wendy Chung Laboratory, Columbia University Medical Center

Mar 20, 2022

- -

Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1;C4310716:Developmental and epileptic encephalopathy, 42 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1 Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Brain Gene Registry

-

Variant reported in multiple GenomeConnect participants by multiple clinical testing laboratories. Variant interpreted as Pathogenic by all laboratories and reported most recently on 07-19-2018 by lab GeneDx and on 08-06-2018 by lab Greenwood Genetics Laboratories. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.49	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	5.1	.;.;.;.;H;.;.;.;.;.;.;.;H;.;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-4.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.98
MutPred		0.87		.;.;Loss of methylation at R1349 (P = 0.0318);Loss of methylation at R1349 (P = 0.0318);Loss of methylation at R1349 (P = 0.0318);.;Loss of methylation at R1349 (P = 0.0318);.;.;Loss of methylation at R1349 (P = 0.0318);Loss of methylation at R1349 (P = 0.0318);.;Loss of methylation at R1349 (P = 0.0318);.;Loss of methylation at R1349 (P = 0.0318);
MVP		1.0
MPC		2.4
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.82
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1057520918; hg19: chr19-13373594; COSMIC: COSV100802498; COSMIC: COSV100802498;