rs121908247

chr19-13235693-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_001127222.2(CACNA1A):c.4988G>A(p.Arg1663Gln) 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:14 U:1 O:2
• Conservation: PhyloP100: 7.86

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 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001127222.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CACNA1A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 19-13235693-C-T is Pathogenic according to our data. Variant chr19-13235693-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 68432.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=7, Likely_pathogenic=3, Uncertain_significance=1, not_provided=2}. Variant chr19-13235693-C-T is described in Lovd as [Pathogenic]. Variant chr19-13235693-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1A	NM_001127222.2	c.4988G>A	p.Arg1663Gln	missense_variant	32/47	ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11	c.4988G>A	p.Arg1663Gln	missense_variant	32/47	1	NM_001127222.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:14 Uncertain:1 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:5 Other:1

Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 16, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 14, 2023	Published functional studies demonstrate a damaging effect by significantly impairing the function of the protein (PMID: 28742085); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28742085, 16325861, 24486772, 32429945, 32637629, 37555011, 33349592, 34068417) -
not provided, no classification provided	phenotyping only	GenomeConnect - Brain Gene Registry	-	Variant interpreted as Pathogenic and reported on 12-08-2021 by Lab or GTR ID 500031. 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. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 12, 2023	- -

Developmental and epileptic encephalopathy, 42 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Pediatric Department, Xiangya Hospital, Central South University	Jan 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -

Spinocerebellar ataxia type 6 Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000068432). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 28742085). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 16325861, 28742085). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -

Neurodevelopmental delay Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

-

- -

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 15, 2022

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects CACNA1A function (PMID: 28742085). 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. ClinVar contains an entry for this variant (Variation ID: 68432). This missense change has been observed in individual(s) with early onset ataxia (PMID: 16325861, 28742085). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1664 of the CACNA1A protein (p.Arg1664Gln). -

Ataxia _ Neurologic (child onset);na:Non-progressive congenital cerebellar ataxia Pathogenic:1

Pathogenic, no assertion criteria provided

research

Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea

Feb 11, 2019

- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 16, 2019

The p.R1664Q variant (also known as c.4991G>A), located in coding exon 32 of the CACNA1A gene, results from a G to A substitution at nucleotide position 4991. The arginine at codon 1664 is replaced by glutamine, an amino acid with highly similar properties. The variant disrupts the R2 position of the voltage sensing motif in the voltage sensing domain which is known to be crucial for proper gating (Bezanilla F. Nat. Rev. Mol. Cell Biol., 2008 Apr;9:323-32; Chamberlin A et al. J. Mol. Biol., 2015 Jan;427:131-45). In one study, this alteration was identified as a de novo occurrence in four individuals with severe early onset ataxia, global developmental delay, hypotonia, and ophthalmologic abnormalities. In addition, two studies performed in drosophilla showed that this alteration acts as a loss of function mutation and only partially rescues lethality (Oriel C et al. Int J Mol Sci, 2018 Jul;19:; Luo X et al. PLoS Genet., 2017 Jul;13:e1006905). In another study, this variant was identified to be de novo with early onset, non-fluctuating limb and trunk ataxia (Tonelli A et al. J. Neurol. Sci., 2006 Feb;241:13-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Chronic and progressive ataxia Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Mendelics

Nov 30, 2014

- -

Global developmental delay;C1853377:Enlarged cisterna magna Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

May 20, 2014

- -

Episodic ataxia type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 01, 2017

This mutation has been previously reported as disease-causing and was found four times in our laboratory as de novo findings in affected individuals. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	35
Dann	Pathogenic	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.81	D
Sift4G	Pathogenic	0.0	D;D;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.76
MutPred		0.87		.;.;Loss of methylation at R1664 (P = 0.021);Loss of methylation at R1664 (P = 0.021);Loss of methylation at R1664 (P = 0.021);.;.;Loss of methylation at R1664 (P = 0.021);.;.;.;Loss of methylation at R1664 (P = 0.021);Loss of methylation at R1664 (P = 0.021);.;Loss of methylation at R1664 (P = 0.021);.;.;.;.;.;
MVP		0.99
MPC		1.5
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.77
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.49		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121908247; hg19: chr19-13346507;