19-13262780-C-T

Variant names:

• chr19-13262780-C-T
• rs1057520918
• NM_001127222.2:c.4043G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 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. 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. R1348W) has been classified 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:21 O:1
• Conservation: PhyloP100: 7.88
• Publications: 16 publications found

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]

CACNA1A Gene-Disease associations (from GenCC):

• episodic ataxia type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
• developmental and epileptic encephalopathy, 42

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• migraine, familial hemiplegic, 1

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• spinocerebellar ataxia type 6

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• benign paroxysmal torticollis of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial or sporadic hemiplegic migraine

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Lennox-Gastaut syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001127222.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-13262781-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 421023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 380972.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
CACNA1A	NM_001127222.2	c.4043G>A	p.Arg1348Gln	missense_variant	Exon 25 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.4043G>A	p.Arg1348Gln	missense_variant	Exon 25 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.4055G>A	p.Arg1352Gln	missense_variant	Exon 25 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.4049G>A	p.Arg1350Gln	missense_variant	Exon 25 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.4046G>A	p.Arg1349Gln	missense_variant	Exon 25 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.4046G>A	p.Arg1349Gln	missense_variant	Exon 25 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.4046G>A	p.Arg1349Gln	missense_variant	Exon 25 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.3905G>A	p.Arg1302Gln	missense_variant	Exon 24 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.4046G>A	p.Arg1349Gln	missense_variant	Exon 25 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.4055G>A	p.Arg1352Gln	missense_variant	Exon 25 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.4046G>A	p.Arg1349Gln	missense_variant	Exon 25 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.4049G>A	p.Arg1350Gln	missense_variant	Exon 25 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.4046G>A	p.Arg1349Gln	missense_variant	Exon 25 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.4046G>A	p.Arg1349Gln	missense_variant	Exon 25 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.4046G>A	p.Arg1349Gln	missense_variant	Exon 25 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.4046G>A		non_coding_transcript_exon_variant	Exon 25 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.4043G>A		non_coding_transcript_exon_variant	Exon 25 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 42 Pathogenic:9

May 03, 2019

Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 27, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CACNA1A c.4046G>A (p.Arg1349Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248992 control chromosomes. c.4046G>A has been reported in the literature in multiple individuals affected with CACNA1A-related conditions and were reported as de novo (example: Mercimek-Mahmutoglu_2015, Blumkin_2015, LeRoux_2021, Moreno-DeLuca_2021). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 25758715, 34102571, 33528536, 20097664). ClinVar contains an entry for this variant (Variation ID: 380972). Based on the evidence outlined above, the variant was classified as pathogenic. -

Sep 26, 2023

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 20, 2025

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS2_VSTR,PS4,PM2,PP2,PP3 -

Sep 02, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 15, 2018

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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. -

-

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 21, 2022

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:5

Jul 26, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 09, 2018

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1A: PS2:Very Strong, PM2, PP2, PP3 -

Oct 09, 2024

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 27, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 20, 2020

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

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 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CACNA1A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Spinocerebellar ataxia type 6 Pathogenic:1

-

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Episodic ataxia type 2 Pathogenic:1

Apr 19, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Oct 22, 2015

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Mar 20, 2022

Wendy Chung Laboratory, Boston Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

-

GenomeConnect - Brain Gene Registry

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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;.;.
PhyloP100		7.9
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
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1057520918; hg19: chr19-13373594; COSMIC: COSV100802498; COSMIC: COSV100802498;