rs121908212

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_001127222.2(CACNA1A):c.1994C>T(p.Thr665Met) 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T665T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 30)

Consequence

CACNA1A
NM_001127222.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:18O:3

Conservation

PhyloP100: 9.85

Publications

56 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 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_001127222.2

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.976

PP5

Variant 19-13303877-G-A is Pathogenic according to our data. Variant chr19-13303877-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 8488.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.1994C>T	p.Thr665Met	missense_variant	Exon 16 of 47	ENST00000360228.11	NP_001120694.1
CACNA1A	NM_001127221.2 link	c.1997C>T	p.Thr666Met	missense_variant	Exon 16 of 47	ENST00000638009.2	NP_001120693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1A	ENST00000360228.11 link	c.1994C>T	p.Thr665Met	missense_variant	Exon 16 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638009.2 link	c.1997C>T	p.Thr666Met	missense_variant	Exon 16 of 47	1	NM_001127221.2	ENSP00000489913.1
CACNA1A	ENST00000638029.1 link	c.1997C>T	p.Thr666Met	missense_variant	Exon 16 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7 link	c.2000C>T	p.Thr667Met	missense_variant	Exon 16 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1 link	c.1997C>T	p.Thr666Met	missense_variant	Exon 16 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1 link	c.1997C>T	p.Thr666Met	missense_variant	Exon 16 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1 link	c.1997C>T	p.Thr666Met	missense_variant	Exon 16 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1 link	c.1856C>T	p.Thr619Met	missense_variant	Exon 15 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1 link	c.1997C>T	p.Thr666Met	missense_variant	Exon 16 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1 link	c.1997C>T	p.Thr666Met	missense_variant	Exon 16 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1 link	c.1997C>T	p.Thr666Met	missense_variant	Exon 16 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1 link	c.2000C>T	p.Thr667Met	missense_variant	Exon 16 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1 link	c.1997C>T	p.Thr666Met	missense_variant	Exon 16 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000637276.1 link	c.1997C>T	p.Thr666Met	missense_variant	Exon 16 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2 link	n.1997C>T		non_coding_transcript_exon_variant	Exon 16 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1 link	n.1994C>T		non_coding_transcript_exon_variant	Exon 16 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18Other:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Aug 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 21, 2023

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has been identified in individuals with familial hemiplegic migraine (FHM) and/or cerebellar ataxia, and segregates with disease in multiple families. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID:10024348, 22190617, 9488686)

Apr 02, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate that the variant leads to loss-of-function for the P/Q-type channel activity, which significantly alters channel inactivation kinetics resulting in defective voltage-dependent gating to support calcium influx (Kraus et al., 1998; Barrett et al., 2005; Tao et al., 2012); Not observed 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: 30180405, 28717674, 10024348, 22136990, 24270521, 25274239, 22190617, 9488686, 22969264, 22000314, 25266619, 24498617, 27290639, 11971066, 11814735, 28169007, 18279427, 15795222, 12056940, 10987655, 8898206, 9915947, 12756131, 28856914, 29915382, 29486580, 31824404, 31692161, 14718690, 11439943, 31935766, 30063100, 31115040, 30027842)

Jan 30, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP1, PP3, PM2_moderate, PS3, PS4_moderate

Migraine, familial hemiplegic, 1

Pathogenic:4Other:1

UniProtKB/Swiss-Prot

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

May 05, 2021

Institute of Human Genetics Munich, TUM University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 30, 2016

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 28, 2021

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 24, 2005

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Episodic ataxia type 2

Pathogenic:2

Oct 08, 2015

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Developmental and epileptic encephalopathy, 42

Pathogenic:2

Jun 17, 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.1997C>T (p.Thr666Met) 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 247906 control chromosomes. c.1997C>T has been reported in the literature in multiple individuals affected with Familial Hemiplegic Migraine (example, Ducros_2001, Garcia-Baro-Huarte_2014). These data indicate that the variant is very likely to be associated with disease. At least two publication reports experimental evidence evaluating an impact on protein function (example, Hans_1999). The most pronounced variant effect results in decreased density of functional channels and their unitary conductance consistent with a loss of function mechanism od disease. The following representative publications have been ascertained in the context of this evaluation (PMID: 11439943, 25266619, 10024348). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

May 20, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The observed missense variant c.1994C>T(p.Thr665Met) in CACNA1A gene has been reported previously in heterozygous state in multiple individuals with a wide clinical spectrum of symptoms including: Developmental and epileptic encephalopathy, migraines, hemiplegia, comas, progressive cognitive dysfunction, and progressive cerebellar ataxia (Li M, et al., 2019, Kierdaszuk B, et al., 2017). Experimental studies have shown that this missense change affects CACNA1A function (Hans M, et al., 1999). The c.1994C>T variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submissions).The amino acid Threonine at position 665 is changed to a Methionine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (SIFT and Mutation Taster) predict a damaging effect on protein structure and function for this variant. The amino acid change p.Thr665Met in CACNA1A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.

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

Pathogenic:1

Oct 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 666 of the CACNA1A protein (p.Thr666Met). This variant is present in population databases (rs121908212, gnomAD 0.008%). This missense change has been observed in individuals with hemiplegic migraine (PMID: 8898206, 11814735, 11971066, 24270521, 25274239, 28169007). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8488). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CACNA1A function (PMID: 9488686, 10024348). For these reasons, this variant has been classified as Pathogenic.

Inborn genetic diseases

Pathogenic:1

Mar 20, 2023

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1997C>T (p.T666M) alteration is located in exon 16 (coding exon 16) of the CACNA1A gene. This alteration results from a C to T substitution at nucleotide position 1997, causing the threonine (T) at amino acid position 666 to be replaced by a methionine (M). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been described in many individuals with a wide clinical spectrum of symptoms including: migraines, hemiplegia, comas, progressive cognitive dysfunction, and progressive cerebellar ataxia, in both the individual and familial forms (Ophoff, 1996; Wada, 2002; Kirchmann, 2006; Choi, 2012; García-Baró-Huarte, 2014; Kierdaszuk, 2017; Indelicato, 2019; Li, 2019; Sun, 2019; Ngo, 2020). In addition, this alteration has been referred to as the most common mutation found in CACNA1A, accounting for 40% of unrelated cases of CACNA1A-related familial hemiplegic migraine (Choi, 2012). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). In vitro studies showed defective voltage-dependent gating associated with the p.T666M pathogenic mutation (Barrett, 2005). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

Migraine, sporadic hemiplegic, with progressive cerebellar ataxia

Pathogenic:1

Jun 24, 2005

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

CACNA1A-related disorder

Pathogenic:1

Jun 18, 2024

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is not observed in the gnomAD v4.0.0 dataset. Predicted Consequence/Location: Missense variant Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 10024348, 22190617, 9488686). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.96 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.70 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000008488 /PMID: 8898206 /3billion dataset). The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 11814735). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

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

Pathogenic:1

May 01, 2024

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 classified as Pathogenic and reported on 08-01-2018 by GeneDx. 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 Dr. Philip Payne 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/.

Familial hemiplegic migraine

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Most common pathogenic variant with no evidence for founder effect

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0

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

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.98

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

0.0

.;.;.;.;H;.;.;H;.;.;.;.;H;.;.

PhyloP100

9.9

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

0.0

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

REVEL

Benign

0.0

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Vest4

0.96

ClinPred

1.0

GERP RS

3.5

Varity_R

0.77

gMVP

0.99

Mutation Taster

=8/92

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