VCV000380972.42 - ClinVar

NM_001127222.2(CACNA1A):c.4043G>A (p.Arg1348Gln)

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.

(21)

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/Likely 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.4043G>A (p.Arg1348Gln)

Variation ID: 380972 Accession: VCV000380972.42

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.13 19: 13262780 (GRCh38) [ NCBI UCSC ] 19: 13373594 (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	Mar 8, 2017	Oct 20, 2024	Oct 13, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001127222.2:c.4043G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001120694.1:p.Arg1348Gln	missense
NM_001127221.2:c.4046G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001120693.1:p.Arg1349Gln	missense
NM_000068.4:c.4055G>A	NP_000059.3:p.Arg1352Gln	missense
NM_001174080.2:c.4046G>A	NP_001167551.1:p.Arg1349Gln	missense
NM_023035.3:c.4055G>A	NP_075461.2:p.Arg1352Gln	missense
NC_000019.10:g.13262780C>T
NC_000019.9:g.13373594C>T
NG_011569.1:g.248681G>A
LRG_7:g.248681G>A
LRG_7t1:c.4046G>A	LRG_7p1:p.Arg1349Gln

... more HGVS ... less HGVS

Protein change

R1349Q, R1352Q, R1348Q

Other names

p.R1349Q

Canonical SPDI

NC_000019.10:13262779:C:T

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

Unknown function

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: CA16607714 dbSNP: rs1057520918 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	3511	3819

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.
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Apr 1, 2023	RCV000435974.30
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Oct 22, 2015	RCV000624902.11
Developmental and epileptic encephalopathy, 42 Episodic ataxia type 2 Migraine, familial hemiplegic, 1 Spinocerebellar ataxia type 6	Pathogenic (1)	criteria provided, single submitter	Oct 31, 2018	RCV000763033.10
Developmental and epileptic encephalopathy, 42 Episodic ataxia type 2	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 13, 2023	RCV001078138.14
Spinocerebellar ataxia type 6	Pathogenic (1)	criteria provided, single submitter	-	RCV001251039.9
Developmental and epileptic encephalopathy, 42	Pathogenic/Likely pathogenic (8)	criteria provided, multiple submitters, no conflicts	Sep 2, 2022	RCV000787277.19
Developmental and epileptic encephalopathy, 52 Episodic ataxia type 2 Migraine, familial hemiplegic, 1 Spinocerebellar ataxia type 6	Pathogenic (1)	criteria provided, single submitter	Mar 20, 2022	RCV002227161.9
Episodic ataxia type 2	Pathogenic (1)	criteria provided, single submitter	Apr 19, 2023	RCV003333066.2
Episodic ataxia type 2 Migraine, familial hemiplegic, 1 Spinocerebellar ataxia type 6	not provided (1)	no classification provided	-	RCV003223404.10

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 (Jul 25, 2014)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000612538.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (3) PubMed: 21183743‚ 19811514‚ 23831250
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Episodic ataxia type 2 Migraine, familial hemiplegic, 1 Spinocerebellar ataxia type 6 Developmental and epileptic encephalopathy, 42 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893508.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Nov 15, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Developmental and epileptic encephalopathy, 42 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001132540.1 First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019	Comment: 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 … (more) 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. (less) Clinical Features: Abnormality of brain morphology (present)
Pathogenic (Feb 20, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 42 Episodic ataxia type 2 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics Accession: SCV001167344.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020	Comment: 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 … (more) 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. (less) Clinical Features: Mild global developmental delay (present) , Generalized dystonia (present) , Oculogyric crisis (present) , Tetraparesis (present) Age: 0-9 years Sex: male Ethnicity/Population group: Indian Hindu Geographic origin: India Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Spinocerebellar ataxia type 6 Affected status: yes Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV001426438.1 First in ClinVar: Aug 10, 2020 Last updated: Aug 10, 2020
Pathogenic (Oct 22, 2015)	criteria provided, single submitter (Ambry exome assertion method (8-5-2015)) Method: clinical testing	Inborn genetic diseases Affected status: yes Allele origin: germline	Ambry Genetics Accession: SCV000741128.3 First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023	Publications: PubMed (8) PubMed: 19811514‚ 20097664‚ 21183743‚ 23831250‚ 25758715‚ 22249839‚ 25596066‚ 26814174 Observation 1: Number of individuals with the variant: 1 Clinical Features: Seizures (present) , Scoliosis (present) , Global developmental delay (present) , Muscular hypotonia (present) , Vertical nystagmus (present) , Chronic constipation (present) , High anterior … (more) Seizures (present) , Scoliosis (present) , Global developmental delay (present) , Muscular hypotonia (present) , Vertical nystagmus (present) , Chronic constipation (present) , High anterior hairline (present) , Neurogenic bladder (present) , Precocious puberty (present) , Status epilepticus (present) , Vesicoureteral reflux (present) , Retrognathia (present) , Myopia (disease) (present) , Failure to thrive (present) , Hypertelorism (present) , Sleep disturbance (present) , Epicanthus (present) , Microtia (present) , Posteriorly rotated ears (present) , Low-set ears (present) , Esotropia (present) , Abnormality of the dentition (present) , Paralysis (present) , Developmental regression (present) , Cerebral atrophy (present) , Cerebellar atrophy (present) , EEG abnormality (present) (less) Sex: female Ethnicity/Population group: Caucasian Observation 2: Number of individuals with the variant: 1 Clinical Features: Generalized hypotonia (present) , Global developmental delay (present) , Failure to thrive (present) , Nystagmus (present) , Frontal bossing (present) , Limited knee extension (present) … (more) Generalized hypotonia (present) , Global developmental delay (present) , Failure to thrive (present) , Nystagmus (present) , Frontal bossing (present) , Limited knee extension (present) , Hypoplasia of the corpus callosum (present) , Poor head control (present) (less) Sex: male Ethnicity/Population group: Caucasian Observation 3: Number of individuals with the variant: 1 Sex: male Ethnicity/Population group: Hispanic
Pathogenic (Oct 27, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000520000.6 First in ClinVar: Mar 08, 2017 Last updated: Mar 04, 2023	Comment: 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, … (more) 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) (less)
Pathogenic (Jul 19, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 42 Affected status: yes Allele origin: de novo	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001950113.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021	Comment: This variant was identified as de novo (maternity and paternity confirmed).
Pathogenic (Jan 09, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002064439.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022
Pathogenic (Mar 20, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 52 Episodic ataxia type 2 Migraine, familial hemiplegic, 1 Spinocerebellar ataxia type 6 Affected status: yes Allele origin: de novo	Wendy Chung Laboratory, Columbia University Medical Center Accession: SCV002506531.1 First in ClinVar: May 07, 2022 Last updated: May 07, 2022	Clinical Features: Hereditary episodic ataxia (present) , Status epilepticus (present) , Seizure (present) , Autistic behavior (present) , Migraine (present) , Neurodevelopmental delay (present)
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 42 (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India Accession: SCV002818455.1 First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023	Publications: PubMed (1) PubMed: 34102571 Age: 0-9 years Sex: male
Pathogenic (Sep 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 42 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV003835478.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023
Pathogenic (Apr 19, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Episodic ataxia type 2 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004041384.1 First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023
Pathogenic (Jul 26, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003813074.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Oct 13, 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: SCV001589925.4 First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024	Publications: PubMed (6) PubMed: 20097664‚ 21183743‚ 23831250‚ 26814174‚ 28007337‚ 31139143 Comment: 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). … (more) 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). 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. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Apr 01, 2023)	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: SCV004011031.12 First in ClinVar: Jul 16, 2023 Last updated: Oct 20, 2024	Comment: CACNA1A: PS2:Very Strong, PM2, PP2, PP3 Number of individuals with the variant: 1
Pathogenic (May 03, 2019)	no assertion criteria provided Method: clinical testing	Developmental and epileptic encephalopathy, 42 Affected status: yes Allele origin: de novo	Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust Accession: SCV000926208.1 First in ClinVar: Jul 14, 2019 Last updated: Jul 14, 2019
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Developmental and epileptic encephalopathy, 42 (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Génétique des Maladies du Développement, Hospices Civils de Lyon Accession: SCV001482311.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021
Pathogenic (Sep 21, 2022)	no assertion criteria provided Method: clinical testing	Developmental and epileptic encephalopathy, 42 Affected status: yes Allele origin: de novo	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein Accession: SCV004167601.1 First in ClinVar: Nov 25, 2023 Last updated: Nov 25, 2023
Pathogenic (Sep 26, 2023)	no assertion criteria provided Method: clinical testing	Developmental and epileptic encephalopathy, 42 Affected status: yes Allele origin: de novo	Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV005368743.1 First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024	Number of individuals with the variant: 1 Clinical Features: Oculomotor apraxia (present) , Motor delay (present) , Generalized hypotonia (present) , Abnormal cerebellum morphology (present) , Cerebral atrophy (present) , Bilateral tonic-clonic seizure (present) … (more) Oculomotor apraxia (present) , Motor delay (present) , Generalized hypotonia (present) , Abnormal cerebellum morphology (present) , Cerebral atrophy (present) , Bilateral tonic-clonic seizure (present) , Cerebral cortical atrophy (present) , Ischemic stroke (present) , Developmental regression (present) , Abnormal cerebral cortex morphology (present) , Cerebral ischemia (present) , Cerebellar vermis atrophy (present) , Loss of consciousness (present) , Cerebellar cortical atrophy (present) , Paraplegia (present) , Cerebellar gliosis (present) , Abnormal circulating ferritin concentration (present) (less) Age: 10-19 years Sex: female Tissue: Blood
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: de novo	GenomeConnect - Brain Gene Registry Accession: SCV002548532.3 First in ClinVar: Jul 18, 2022 Last updated: Jun 17, 2024	Comment: 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 … (more) 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. (less) Observation 1: Clinical Features: Macrocephaly (present) , Global developmental delay (present) , Nystagmus (present) , Seizure (present) , Esotropia (present) , Hypotonia (present) Indication for testing: Diagnostic Age: 0-9 years Sex: male Method: Exome Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2018-07-19 Testing laboratory interpretation: Pathogenic Observation 2: Clinical Features: Abnormality of eye movement (present) , Myopia (present) , Abnormality of coordination (present) , EEG abnormality (present) , Encephalopathy (present) , Generalized hypotonia (present) , … (more) Abnormality of eye movement (present) , Myopia (present) , Abnormality of coordination (present) , EEG abnormality (present) , Encephalopathy (present) , Generalized hypotonia (present) , Seizure (present) , Autistic behavior (present) , Motor stereotypies (present) , Abnormal aggressive, impulsive or violent behavior (present) , Short attention span (present) , Joint hypermobility (present) , Abnormal pattern of respiration (present) (less) Indication for testing: Diagnostic Age: 10-19 years Sex: male Method: Exome Sequencing Testing laboratory: Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Date variant was reported to submitter: 2018-08-06 Testing laboratory interpretation: Pathogenic
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Comment:

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.

Comment:

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.

Comment:

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)

Comment:

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). 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. For these reasons, this variant has been classified as Pathogenic.

Comment:

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.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Unknown function			Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics Accession: SCV001167344.1

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
CACNA1A-associated epilepsy: Electroclinical findings and treatment response on seizures in 18 patients.	Le Roux M	European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society	2021	PMID: 34102571
The Clinical and Genetic Features of Co-occurring Epilepsy and Autism Spectrum Disorder in Chinese Children.	Long S	Frontiers in neurology	2019	PMID: 31139143
Missense mutations of CACNA1A are a frequent cause of autosomal dominant nonprogressive congenital ataxia.	Travaglini L	European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society	2017	PMID: 28007337
Eye movement disorders are an early manifestation of CACNA1A mutations in children.	Tantsis EM	Developmental medicine and child neurology	2016	PMID: 26814174
Prevalence of inherited neurotransmitter disorders in patients with movement disorders and epilepsy: a retrospective cohort study.	Mercimek-Mahmutoglu S	Orphanet journal of rare diseases	2015	PMID: 25758715
Paroxysmal tonic upward gaze as a presentation of de-novo mutations in CACNA1A.	Blumkin L	European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society	2015	PMID: 25596066
Possible effect of corticoids on hemiplegic attacks in severe hemiplegic migraine.	Sánchez-Albisua I	Pediatric neurology	2013	PMID: 23831250
Neuronal P/Q-type calcium channel dysfunction in inherited disorders of the CNS.	Rajakulendran S	Nature reviews. Neurology	2012	PMID: 22249839
Recurrent stroke due to a novel voltage sensor mutation in Cav2.1 responds to verapamil.	Knierim E	Stroke	2011	PMID: 21183743
Congenital ataxia, mental retardation, and dyskinesia associated with a novel CACNA1A mutation.	Blumkin L	Journal of child neurology	2010	PMID: 20097664
Sporadic hemiplegic migraine and delayed cerebral oedema after minor head trauma: a novel de novo CACNA1A gene mutation.	Malpas TJ	Developmental medicine and child neurology	2010	PMID: 19811514
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Text-mined citations for rs1057520918 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 19, 2024

ClinVar Genomic variation as it relates to human health

NM_001127222.2(CACNA1A):c.4043G>A (p.Arg1348Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1057520918 ...