VCV000194928.54 - ClinVar

NM_001127222.2(CACNA1A):c.3040G>A (p.Glu1014Lys)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Uncertain significance(2); Benign(4); Likely benign(2)

8 out of 15 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001127222.2(CACNA1A):c.3040G>A (p.Glu1014Lys)

Variation ID: 194928 Accession: VCV000194928.54

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.13 19: 13298593 (GRCh38) [ NCBI UCSC ] 19: 13409407 (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	Apr 20, 2025	Mar 1, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_001127222.2:c.3040G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001120694.1:p.Glu1014Lys	missense
NM_001127221.2:c.3043G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001120693.1:p.Glu1015Lys	missense
NM_000068.4:c.3052G>A	NP_000059.3:p.Glu1018Lys	missense
NM_001127222.1:c.3040G>A
NM_001174080.2:c.3043G>A	NP_001167551.1:p.Glu1015Lys	missense
NM_023035.3:c.3052G>A	NP_075461.2:p.Glu1018Lys	missense
NC_000019.10:g.13298593C>T
NC_000019.9:g.13409407C>T
NG_011569.1:g.212868G>A
LRG_7:g.212868G>A
LRG_7t1:c.3043G>A	LRG_7p1:p.Glu1015Lys

... more HGVS ... less HGVS

Protein change

E1015K, E1018K, E1014K

Other names

Canonical SPDI

NC_000019.10:13298592:C:T

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.

0.00120 (T)

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

1000 Genomes Project 0.00120

1000 Genomes Project 30x 0.00125

Exome Aggregation Consortium (ExAC) 0.00255

The Genome Aggregation Database (gnomAD), exomes 0.00356

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00375

The Genome Aggregation Database (gnomAD) 0.00390

Trans-Omics for Precision Medicine (TOPMed) 0.00427

Links

ClinGen: CA241161 dbSNP: rs16024 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	3835	4165

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 specified	Benign (3)	criteria provided, single submitter	Nov 17, 2016	RCV000175409.13
Inborn genetic diseases	Benign (1)	criteria provided, single submitter	Sep 26, 2024	RCV000210670.14
not provided	Conflicting classifications of pathogenicity (7)	criteria provided, conflicting classifications	Mar 1, 2025	RCV000432960.41
Intellectual disability	Uncertain significance (1)	no assertion criteria provided	Jan 1, 2019	RCV001251922.9
Developmental and epileptic encephalopathy, 42	Likely benign (1)	criteria provided, single submitter	Jun 12, 2017	RCV000660566.13
Developmental and epileptic encephalopathy, 42 Episodic ataxia type 2	Benign (1)	criteria provided, single submitter	Feb 4, 2025	RCV001080527.16
CACNA1A-related disorder	Benign (1)	no assertion criteria provided	May 9, 2024	RCV003985285.2

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.
Uncertain Significance (Jan 31, 2017) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000511435.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: Converted during submission to Uncertain significance.
Benign (Nov 17, 2016) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000512441.4 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Likely benign (Jun 12, 2017) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Developmental and epileptic encephalopathy, 42 Affected status: unknown Allele origin: paternal	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000782677.2 First in ClinVar: Jul 09, 2018 Last updated: Jul 21, 2018
Benign (Mar 08, 2019) C Contributing to aggregate classification	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000841258.2 First in ClinVar: Mar 08, 2017 Last updated: Jan 18, 2020	Publications: PubMed (4) PubMed: 20156848‚ 30167989‚ 24108129‚ 25356970
Benign (Feb 04, 2025) C Contributing to aggregate classification	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: SCV000656743.9 First in ClinVar: Dec 26, 2017 Last updated: Mar 04, 2025
Uncertain significance (Feb 08, 2017) C Contributing to aggregate classification	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000226886.6 First in ClinVar: Jun 29, 2015 Last updated: Apr 13, 2025	Publications: PubMed (1) PubMed: 24108129 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CACNA1A Number of individuals with the variant: 12 Zygosity: Single Heterozygote Sex: mixed
Likely benign (Mar 01, 2025) C Contributing to aggregate classification	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: SCV002543884.19 First in ClinVar: Jul 09, 2022 Last updated: Apr 20, 2025	Comment: CACNA1A: PP3, BS2 Number of individuals with the variant: 46
Benign (Sep 26, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000262956.8 First in ClinVar: Apr 09, 2016 Last updated: Jan 13, 2025	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Uncertain significance (Jan 01, 2019) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	Intellectual disability Affected status: yes Allele origin: unknown	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille Accession: SCV001427668.1 First in ClinVar: Aug 15, 2020 Last updated: Aug 15, 2020	Publications: PubMed (1) PubMed: 25741868
Likely benign (-) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001797577.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Benign (-) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001930745.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Benign (-) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001959707.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Likely benign (-) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001976273.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Benign (May 09, 2024) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	CACNA1A-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004794174.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Uncertain significance (-) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV001550606.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021
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Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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
New CACNA1A deletions are associated to migraine phenotypes.	Grieco GS	The journal of headache and pain	2018	PMID: 30167989
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.	Richards S	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868
Enhanced utility of family-centered diagnostic exome sequencing with inheritance model-based analysis: results from 500 unselected families with undiagnosed genetic conditions.	Farwell KD	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25356970
The E1015K variant in the synprint region of the CaV2.1 channel alters channel function and is associated with different migraine phenotypes.	Condliffe SB	The Journal of biological chemistry	2013	PMID: 24108129
Genetic and functional characterisation of the P/Q calcium channel in episodic ataxia with epilepsy.	Rajakulendran S	The Journal of physiology	2010	PMID: 20156848
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CACNA1A	-	-	-	-

Text-mined citations for rs16024 ...

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 Apr 28, 2025

ClinVar Genomic variation as it relates to human health

NM_001127222.2(CACNA1A):c.3040G>A (p.Glu1014Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs16024 ...