VCV000008488.57 - ClinVar

NM_001127222.2(CACNA1A):c.1994C>T (p.Thr665Met)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(20)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001127222.2(CACNA1A):c.1994C>T (p.Thr665Met)

Variation ID: 8488 Accession: VCV000008488.57

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.13 19: 13303877 (GRCh38) [ NCBI UCSC ] 19: 13414691 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 22, 2013	Oct 20, 2024	Oct 30, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001127222.2:c.1994C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001120694.1:p.Thr665Met	missense
NM_001127221.2:c.1997C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001120693.1:p.Thr666Met	missense
NM_000068.4:c.1997C>T	NP_000059.3:p.Thr666Met	missense
NM_001174080.2:c.1997C>T	NP_001167551.1:p.Thr666Met	missense
NM_023035.2:c.1997C>T
NM_023035.3:c.1997C>T	NP_075461.2:p.Thr666Met	missense
NC_000019.10:g.13303877G>A
NC_000019.9:g.13414691G>A
NG_011569.1:g.207584C>T
LRG_7:g.207584C>T
LRG_7t1:c.1997C>T	LRG_7p1:p.Thr666Met

... more HGVS ... less HGVS

Protein change

T666M, T665M

Other names

Canonical SPDI

NC_000019.10:13303876:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA119650 UniProtKB/Swiss-Prot: VAR_001492 OMIM: 601011.0002 dbSNP: rs121908212 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CACNA1A		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	3521	3832

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Migraine, familial hemiplegic, 1	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Oct 28, 2021	RCV000009009.25
Migraine, sporadic hemiplegic, with progressive cerebellar ataxia	Pathogenic (1)	no assertion criteria provided	Jun 24, 2005	RCV000009010.17
Episodic ataxia type 2	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 8, 2015	RCV000504541.15
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Apr 21, 2023	RCV000516650.41
Developmental and epileptic encephalopathy, 42 Episodic ataxia type 2	Pathogenic (1)	criteria provided, single submitter	Oct 30, 2023	RCV000802118.15
Familial hemiplegic migraine	not provided (1)	no classification provided	-	RCV001533159.10
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Mar 20, 2023	RCV002415406.10
Developmental and epileptic encephalopathy, 42	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jun 17, 2023	RCV002051776.12
Episodic ataxia type 2 Migraine, familial hemiplegic, 1 Spinocerebellar ataxia type 6	not provided (1)	no classification provided	-	RCV003233067.9

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Oct 08, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Episodic ataxia, type 2 Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000593815.1 First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017
Pathogenic (Aug 30, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Migraine, familial hemiplegic, 1 Affected status: yes Allele origin: de novo	Center of Genomic medicine, Geneva, University Hospital of Geneva Accession: SCV000598107.1 First in ClinVar: May 27, 2017 Last updated: May 27, 2017	Age: 10-19 years Sex: female
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Unknown mechanism) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001446542.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Cerebellar ataxia (present) , Cerebellar ataxia (present) , Abnormal speech pattern (present) , Epileptic encephalopathy (present) Sex: female
Pathogenic (Oct 28, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Migraine, familial hemiplegic, 1 Affected status: yes Allele origin: de novo	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Accession: SCV001994820.1 First in ClinVar: Nov 06, 2021 Last updated: Nov 06, 2021
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Episodic ataxia type 2 Affected status: yes Allele origin: de novo	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India Accession: SCV002053927.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022
Pathogenic (Mar 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 42 Affected status: yes Allele origin: germline	3billion Accession: SCV002318456.1 First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022	Publications: PubMed (5) PubMed: 22190617‚ 11814735‚ 10024348‚ 9488686‚ 8898206 Comment: 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). … (more) 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). 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). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Cerebellar ataxia (present) , Cerebellar atrophy (present) , Global developmental delay (present) , Generalized hypotonia (present) , Strabismus (present)
Pathogenic (Jul 14, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001713791.1 First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021	Publications: PubMed (4) PubMed: 8898206‚ 9488686‚ 11971066‚ 22190617 Comment: PS3, PS4_Moderate, PM2, PP1, PP3 Number of individuals with the variant: 1
Pathogenic (May 05, 2021)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Migraine, familial hemiplegic, 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: maternal, germline	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV001150034.2 First in ClinVar: Feb 03, 2020 Last updated: Dec 24, 2022	Observation 1: Number of individuals with the variant: 1 Clinical Features: Myoclonus (present) , Dystonic disorder (present) , Nystagmus (present) , Cerebellar atrophy (present) , Cerebellar ataxia (present) Observation 2: Number of individuals with the variant: 1 Clinical Features: Seizure (present) , Nystagmus (present) , Dysarthria (present) , Migraine (present) , Cerebellar atrophy (present) , Cerebellar ataxia (present) , Episodic hemiplegia (present)
Pathogenic (Apr 02, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002512902.2 First in ClinVar: May 21, 2022 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (Jun 17, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 42 Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004020795.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Publications: PubMed (3) PubMed: 11439943‚ 25266619‚ 10024348 Comment: 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 … (more) 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. (less)
Pathogenic (Apr 21, 2023)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV000612511.6 First in ClinVar: Dec 19, 2017 Last updated: Jan 26, 2024	Publications: PubMed (19) PubMed: 25266619‚ 8898206‚ 10024348‚ 22000314‚ 22190617‚ 22969264‚ 9488686‚ 11814735‚ 9915947‚ 12756131‚ 11971066‚ 24498617‚ 18279427‚ 28856914‚ 31824404‚ 31692161‚ 29915382‚ 25274239‚ 33098801 Comment: 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 … (more) 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) (less)
Pathogenic (Oct 30, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Developmental and epileptic encephalopathy, 42 Episodic ataxia type 2 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000941934.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024	Publications: PubMed (8) PubMed: 8898206‚ 11814735‚ 11971066‚ 24270521‚ 25274239‚ 28169007‚ 9488686‚ 10024348 Comment: 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). … (more) 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. (less)
Pathogenic (Mar 20, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002717687.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (11) PubMed: 8898206‚ 11814735‚ 15795222‚ 16508934‚ 22969264‚ 25266619‚ 28169007‚ 29915382‚ 30063100‚ 31692161‚ 31824404 Comment: 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 … (more) 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. (less)
Pathogenic (May 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 42 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV005329541.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: 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 … (more) 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. (less) Clinical Features: Abnormality of the nervous system (present)
Pathogenic (Aug 01, 2021)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001248629.24 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 7
Pathogenic (Jun 24, 2005)	no assertion criteria provided Method: literature only	MIGRAINE, FAMILIAL HEMIPLEGIC, 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000029223.8 First in ClinVar: Apr 04, 2013 Last updated: May 09, 2018	Publications: PubMed (6) PubMed: 8898206‚ 10987655‚ 9915947‚ 12056940‚ 12756131‚ 15795222 Comment on evidence: In families with hemiplegic migraine (FHM1; 141500), Ophoff et al. (1996) discovered a C-to-T transition in nucleotide 2272 of CACNL1A4, resulting in a thr666-to-met (T666M) … (more) In families with hemiplegic migraine (FHM1; 141500), Ophoff et al. (1996) discovered a C-to-T transition in nucleotide 2272 of CACNL1A4, resulting in a thr666-to-met (T666M) amino acid substitution. Friend et al. (1999) found this recurrent mutation in exon 16 in an Australian patient with familial hemiplegic migraine. Ducros et al. (1999) screened 16 families and 3 nonfamilial cases with hemiplegic migraine associated with progressive cerebellar ataxia (see 141500). They found the T666M mutation in 9 families and 1 nonfamilial case. The T666M mutation was absent in 12 probands belonging to pure HPM families whose disease appeared to be linked to CACNA1A. Terwindt et al. (2002) studied 27 patients with sporadic hemiplegic migraine and found the T666M mutation in a 78-year-old woman who had characteristic attacks starting at age 14 as well as interictal nystagmus, dysarthria, limb and gait ataxia, and cerebellar atrophy. Kors et al. (2003) reported the clinical symptoms of 5 families with hemiplegic migraine and the T666M mutation. Three of the families displayed cerebellar ataxia, 3 had loss of consciousness or coma associated with episodes, 1 had attacks with confusion but without hemiparesis, and 1 had progressive cognitive dysfunction. The authors emphasized the inter- and intrafamilial clinical heterogeneity. Barrett et al. (2005) found that CACNA1A channels with the T666M mutation were expressed and trafficked normally to the cell surface in transfected HEK293 cells. However, T666M mutant channels exhibited defective voltage-dependent gating to support calcium influx. (less)
Pathogenic (Jun 24, 2005)	no assertion criteria provided Method: literature only	MIGRAINE, SPORADIC HEMIPLEGIC, WITH PROGRESSIVE CEREBELLAR ATAXIA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000029225.8 First in ClinVar: Apr 04, 2013 Last updated: May 09, 2018	Publications: PubMed (6) PubMed: 8898206‚ 10987655‚ 9915947‚ 12056940‚ 12756131‚ 15795222 Comment on evidence: In families with hemiplegic migraine (FHM1; 141500), Ophoff et al. (1996) discovered a C-to-T transition in nucleotide 2272 of CACNL1A4, resulting in a thr666-to-met (T666M) … (more) In families with hemiplegic migraine (FHM1; 141500), Ophoff et al. (1996) discovered a C-to-T transition in nucleotide 2272 of CACNL1A4, resulting in a thr666-to-met (T666M) amino acid substitution. Friend et al. (1999) found this recurrent mutation in exon 16 in an Australian patient with familial hemiplegic migraine. Ducros et al. (1999) screened 16 families and 3 nonfamilial cases with hemiplegic migraine associated with progressive cerebellar ataxia (see 141500). They found the T666M mutation in 9 families and 1 nonfamilial case. The T666M mutation was absent in 12 probands belonging to pure HPM families whose disease appeared to be linked to CACNA1A. Terwindt et al. (2002) studied 27 patients with sporadic hemiplegic migraine and found the T666M mutation in a 78-year-old woman who had characteristic attacks starting at age 14 as well as interictal nystagmus, dysarthria, limb and gait ataxia, and cerebellar atrophy. Kors et al. (2003) reported the clinical symptoms of 5 families with hemiplegic migraine and the T666M mutation. Three of the families displayed cerebellar ataxia, 3 had loss of consciousness or coma associated with episodes, 1 had attacks with confusion but without hemiparesis, and 1 had progressive cognitive dysfunction. The authors emphasized the inter- and intrafamilial clinical heterogeneity. Barrett et al. (2005) found that CACNA1A channels with the T666M mutation were expressed and trafficked normally to the cell surface in transfected HEK293 cells. However, T666M mutant channels exhibited defective voltage-dependent gating to support calcium influx. (less)
not provided (-)	no classification provided Method: not provided	Familial hemiplegic migraine type 1 Affected status: not provided Allele origin: not provided	UniProtKB/Swiss-Prot Accession: SCV000090843.1 First in ClinVar: Oct 22, 2013 Last updated: Oct 22, 2013
not provided (-)	no classification provided Method: literature only	Familial hemiplegic migraine Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV001748978.2 First in ClinVar: Jul 10, 2021 Last updated: Oct 01, 2022	Publications: PubMed (2) PubMed: 20301562‚ 9915947 BookShelf: NBK1388 BookShelf: NBK1388 Comment: Most common pathogenic variant with no evidence for founder effect
not provided (-)	no classification provided Method: phenotyping only	Episodic ataxia type 2 Migraine, familial hemiplegic, 1 Spinocerebellar ataxia type 6 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: yes Allele origin: unknown	GenomeConnect - Brain Gene Registry Accession: SCV003931189.1 First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023	Comment: 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 … (more) 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/. (less) Clinical Features: Migraine with aura (present) , Congenital nystagmus (present) , Family history (present) Indication for testing: Diagnostic Age: 10-19 years Sex: male Method: Exome Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2018-08-01 Testing laboratory interpretation: Pathogenic
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Comment:

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). 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). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

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)

Comment:

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.

Comment:

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)

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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/.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Monogenic variants in dystonia: an exome-wide sequencing study.	Zech M	The Lancet. Neurology	2020	PMID: 33098801
A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders.	Ngo KJ	Human mutation	2020	PMID: 31692161
Familial Hemiplegic Migraine With Progressive Cerebellar Ataxia Caused by a p.Thr666Met CACNA1A Gene Mutation in a Chinese Family.	Li M	Frontiers in neurology	2019	PMID: 31824404
The neuropsychiatric phenotype in CACNA1A mutations: a retrospective single center study and review of the literature.	Indelicato E	European journal of neurology	2019	PMID: 30063100
Targeted exome analysis identifies the genetic basis of disease in over 50% of patients with a wide range of ataxia-related phenotypes.	Sun M	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 29915382
Ten years of follow-up in a large family with familial hemiplegic migraine type 1: Clinical course and implications for treatment.	Indelicato E	Cephalalgia : an international journal of headache	2018	PMID: 28856914
Identification of the first in Poland CACNA1A gene mutation in familial hemiplegic migraine. Case report.	Kierdaszuk B	Neurologia i neurochirurgia polska	2017	PMID: 28169007
Repeated encephalopathy and hemicerebral atrophy in a patient with familial hemiplegic migraine type 1.	Tashiro Y	Internal medicine (Tokyo, Japan)	2014	PMID: 25274239
Phenotypic variability in a four generation family with a p.Thr666Met CACNA1A gene mutation.	García-Baró-Huarte M	Pediatric neurology	2014	PMID: 25266619
Rare clinical findings in a patient with sporadic hemiplegic migraine: FDG-PET provides diminished brain metabolism at 10-year follow-up.	Topakian R	Cephalalgia : an international journal of headache	2014	PMID: 24270521
Screening of CACNA1A and ATP1A2 genes in hemiplegic migraine: clinical, genetic, and functional studies.	Carreño O	Molecular genetics & genomic medicine	2013	PMID: 24498617
Familial hemiplegic migraine with prolonged coma and cerebellar atrophy: CACNA1A T666M mutation in a Korean family.	Choi KH	Journal of Korean medical science	2012	PMID: 22969264
Effects of familial hemiplegic migraine type 1 mutation T666M on voltage-gated calcium channel activities in trigeminal ganglion neurons.	Tao J	Journal of neurophysiology	2012	PMID: 22190617
Early-onset cerebellar atrophy associated with mutation in the CACNA1A gene.	Naik S	Pediatric neurology	2011	PMID: 22000314
Expansion of the phenotypic spectrum of the CACNA1A T666M mutation: a family with familial hemiplegic migraine type 1, cerebellar atrophy and mental retardation.	Freilinger T	Cephalalgia : an international journal of headache	2008	PMID: 18279427
The CACNA1A and ATP1A2 genes are not involved in dominantly inherited migraine with aura.	Kirchmann M	American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics	2006	PMID: 16508934
Gating deficiency in a familial hemiplegic migraine type 1 mutant P/Q-type calcium channel.	Barrett CF	The Journal of biological chemistry	2005	PMID: 15795222
Expanding the phenotypic spectrum of the CACNA1A gene T666M mutation: a description of 5 families with familial hemiplegic migraine.	Kors EE	Archives of neurology	2003	PMID: 12756131
Mutation analysis of the CACNA1A calcium channel subunit gene in 27 patients with sporadic hemiplegic migraine.	Terwindt G	Archives of neurology	2002	PMID: 12056940
Japanese cases of familial hemiplegic migraine with cerebellar ataxia carrying a T666M mutation in the CACNA1A gene.	Takahashi T	Journal of neurology, neurosurgery, and psychiatry	2002	PMID: 11971066
Wide clinical variability in a family with a CACNA1A T666m mutation: hemiplegic migraine, coma, and progressive ataxia.	Wada T	Pediatric neurology	2002	PMID: 11814735
The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel.	Ducros A	The New England journal of medicine	2001	PMID: 11439943
Detection of a novel missense mutation and second recurrent mutation in the CACNA1A gene in individuals with EA-2 and FHM.	Friend KL	Human genetics	1999	PMID: 10987655
Functional consequences of mutations in the human alpha1A calcium channel subunit linked to familial hemiplegic migraine.	Hans M	The Journal of neuroscience : the official journal of the Society for Neuroscience	1999	PMID: 10024348
Recurrence of the T666M calcium channel CACNA1A gene mutation in familial hemiplegic migraine with progressive cerebellar ataxia.	Ducros A	American journal of human genetics	1999	PMID: 9915947
Familial hemiplegic migraine mutations change alpha1A Ca2+ channel kinetics.	Kraus RL	The Journal of biological chemistry	1998	PMID: 9488686
Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4.	Ophoff RA	Cell	1996	PMID: 8898206
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Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_001127222.2(CACNA1A):c.1994C>T (p.Thr665Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121908212 ...