rs121908225

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_001127222.2(CACNA1A):c.653C>T(p.Ser218Leu) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S218P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

CACNA1A
NM_001127222.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8O:2

Conservation

PhyloP100: 9.88

Publications

133 publications found

Variant links:

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

CACNA1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 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, 8 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 chr19-13365449-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1679531.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.936

PP5

Variant 19-13365448-G-A is Pathogenic according to our data. Variant chr19-13365448-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 8504.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 link	c.653C>T	p.Ser218Leu	missense_variant	Exon 5 of 47	ENST00000360228.11	NP_001120694.1
CACNA1A	NM_001127221.2 link	c.653C>T	p.Ser218Leu	missense_variant	Exon 5 of 47	ENST00000638009.2	NP_001120693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1A	ENST00000360228.11 link	c.653C>T	p.Ser218Leu	missense_variant	Exon 5 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638009.2 link	c.653C>T	p.Ser218Leu	missense_variant	Exon 5 of 47	1	NM_001127221.2	ENSP00000489913.1
CACNA1A	ENST00000638029.1 link	c.653C>T	p.Ser218Leu	missense_variant	Exon 5 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7 link	c.653C>T	p.Ser218Leu	missense_variant	Exon 5 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1 link	c.653C>T	p.Ser218Leu	missense_variant	Exon 5 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1 link	c.653C>T	p.Ser218Leu	missense_variant	Exon 5 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1 link	c.653C>T	p.Ser218Leu	missense_variant	Exon 5 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1 link	c.512C>T	p.Ser171Leu	missense_variant	Exon 4 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1 link	c.653C>T	p.Ser218Leu	missense_variant	Exon 5 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1 link	c.653C>T	p.Ser218Leu	missense_variant	Exon 5 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1 link	c.653C>T	p.Ser218Leu	missense_variant	Exon 5 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1 link	c.653C>T	p.Ser218Leu	missense_variant	Exon 5 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1 link	c.653C>T	p.Ser218Leu	missense_variant	Exon 5 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000637276.1 link	c.653C>T	p.Ser218Leu	missense_variant	Exon 5 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2 link	n.653C>T		non_coding_transcript_exon_variant	Exon 5 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1 link	n.653C>T		non_coding_transcript_exon_variant	Exon 5 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Episodic ataxia type 2

Pathogenic:2

May 12, 2016

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Lifecell International Pvt. Ltd

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A Heterozygous Missense variant c.653C>T in Exon 5 of the CACNA1A gene that results in the amino acid substitution p.Ser218Leu was identified. The observed variant has a minor allele frequency of 0.00% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic. (Variation ID: 8504) The variant has been previously reported by Kors EE, et al., 2001. Functional studies demonstrate a damaging gain of function effect (Damaj L et al., 2015) Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.

not provided

Pathogenic:2

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 29, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging gain of function effect (Kaja et al., 2015; Tottene et al., 2005); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18313928, 19520699, 19104150, 24498617, 23985897, 26208839, 29761117, 20186955, 19438926, 19242091, 22144569, 20071244, 25741235, 23115190, 24849341, 25716839, 21824570, 18581134, 11409427, 26814174, 22784462, 23673147, 28007337, 33023723, 29915382, 30649209, 15743764, 27476654, 33084218, 27535533)

Developmental and epileptic encephalopathy, 42

Pathogenic:2

May 28, 2021

Laboratoire de Génétique Moléculaire, CHU Bordeaux

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 15, 2023

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.653C>T (p.Ser218Leu) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248928 control chromosomes (gnomAD). c.653C>T has been reported in the literature in multiple individuals affected with Familial hemiplegic migraine (examples: Kors_2001, Stam_2009). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11409427, 19520699). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Migraine, familial hemiplegic, 1

Pathogenic:1Other:1

UniProtKB/Swiss-Prot

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Sep 12, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

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

Pathogenic:1

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 218 of the CACNA1A protein (p.Ser218Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial hemiplegic migraine (PMID: 11409427, 19520699). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8504). 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%. Experimental studies have shown that this missense change affects CACNA1A function (PMID: 15743764, 18581134). For these reasons, this variant has been classified as Pathogenic.

Familial hemiplegic migraine

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0

.;D;T;.;.;.;.;.;.;T;.;.;.;T;.

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D;D;D;D;D;D;D;.;D;D;D;D;D;D

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.94

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

0.0

.;M;.;.;M;.;.;M;.;.;.;.;M;.;.

PhyloP100

9.9

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

0.0

.;D;.;.;.;.;.;.;.;.;.;.;.;.;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;D;.;.;.;.;.;.;.;.;.;.;.;.;.

Sift4G

Pathogenic

0.0010

D;D;.;.;.;.;.;.;.;.;.;D;.;.;.

Vest4

0.93

ClinPred

0.99

GERP RS

5.5

Varity_R

0.91

gMVP

0.99

Mutation Taster

=7/93

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over