ClinVar Genomic variation as it relates to human health
NM_000702.4(ATP1A2):c.193C>T (p.Arg65Trp)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000702.4(ATP1A2):c.193C>T (p.Arg65Trp)
Variation ID: 12929 Accession: VCV000012929.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q23.2 1: 160123228 (GRCh38) [ NCBI UCSC ] 1: 160093018 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Aug 22, 2016 Feb 20, 2024 Dec 23, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000702.4:c.193C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000693.1:p.Arg65Trp missense NC_000001.11:g.160123228C>T NC_000001.10:g.160093018C>T NG_008014.1:g.12471C>T LRG_6:g.12471C>T - Protein change
- R65W
- Other names
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- Canonical SPDI
- NC_000001.11:160123227:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00006
Exome Aggregation Consortium (ExAC) 0.00009
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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ATP1A2 | - | - |
GRCh38 GRCh37 |
1199 | 1311 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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May 13, 2019 | RCV000013792.30 | |
Uncertain significance (2) |
criteria provided, single submitter
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Apr 14, 2020 | RCV000442150.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 23, 2023 | RCV001221618.4 |
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
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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
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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
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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. |
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Uncertain significance
(Dec 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial hemiplegic migraine
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001393674.4
First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 65 of the ATP1A2 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 65 of the ATP1A2 protein (p.Arg65Trp). This variant is present in population databases (rs121918619, gnomAD 0.01%). This missense change has been observed in individual(s) with familial hemiplegic migraine (PMID: 17877748). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12929). 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 not expected to disrupt ATP1A2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect ATP1A2 function (PMID: 34384358). This variant disrupts the p.Arg65 amino acid residue in ATP1A2. Other variant(s) that disrupt this residue have been observed in individuals with ATP1A2-related conditions (PMID: 35257835), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Aug 31, 2017)
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criteria provided, single submitter
Method: clinical testing
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Migraine, familial hemiplegic, 2
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001254125.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(May 13, 2019)
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criteria provided, single submitter
Method: clinical testing
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Migraine, familial hemiplegic, 2
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001367969.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in … (more)
This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP2,PP3. (less)
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Uncertain significance
(Apr 14, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000518163.6
First in ClinVar: Mar 08, 2017 Last updated: Mar 04, 2023 |
Comment:
Reported previously in three siblings with familial hemiplegic migraine (FHM), and was not present in another sibling who suffered from typical migraines without aura (Tonelli … (more)
Reported previously in three siblings with familial hemiplegic migraine (FHM), and was not present in another sibling who suffered from typical migraines without aura (Tonelli et al., 2007); 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: 17877748) (less)
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Pathogenic
(Dec 01, 2007)
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no assertion criteria provided
Method: literature only
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MIGRAINE, FAMILIAL HEMIPLEGIC, 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034039.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
In 3 affected members of a family with familial hemiplegic migraine-2 (FHM2; 602481), Tonelli et al. (2007) identified a heterozygous 193C-T transition in exon 4 … (more)
In 3 affected members of a family with familial hemiplegic migraine-2 (FHM2; 602481), Tonelli et al. (2007) identified a heterozygous 193C-T transition in exon 4 of the ATP1A2 gene, resulting in an arg65-to-trp (R65W) substitution in the cytoplasmic N-terminal portion of the protein, within the actuator domain (A domain). (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001552791.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The ATP1A2 p.Arg65Trp variant was identified in the literature in three siblings with hemiplegic migraines but was not identified in the fourth siblings who also … (more)
The ATP1A2 p.Arg65Trp variant was identified in the literature in three siblings with hemiplegic migraines but was not identified in the fourth siblings who also suffered from migraines (Tonelli_2007_PMID:17877748). The variant was identified in dbSNP (ID: rs121918619) and ClinVar (classified as a VUS by GeneDx). The variant was also identified in control databases in 17 of 282430 chromosomes at a frequency of 0.00006019 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 13 of 128770 chromosomes (freq: 0.000101), African in 2 of 24964 chromosomes (freq: 0.00008), East Asian in 1 of 19950 chromosomes (freq: 0.00005) and South Asian in 1 of 30616 chromosomes (freq: 0.000033), but was not observed in the Latino, Ashkenazi Jewish, European (Finnish) or Other populations. The p.Arg65 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Hemiplegic migraine type 2 with new mutation of the ATP1A2 gene in Japanese cases. | Oda I | Neuroscience research | 2022 | PMID: 35257835 |
Functional correlation of ATP1A2 mutations with phenotypic spectrum: from pure hemiplegic migraine to its variant forms. | Li Y | The journal of headache and pain | 2021 | PMID: 34384358 |
The genetic features of 24 patients affected by familial and sporadic hemiplegic migraine. | Gallanti A | Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology | 2011 | PMID: 21533730 |
Amino acid changes in the amino terminus of the Na,K-adenosine triphosphatase alpha-2 subunit associated to familial and sporadic hemiplegic migraine. | Tonelli A | Clinical genetics | 2007 | PMID: 17877748 |
Text-mined citations for rs121918619 ...
HelpRecord last updated May 19, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.