ClinVar Genomic variation as it relates to human health
NM_152296.5(ATP1A3):c.2266C>T (p.Arg756Cys)
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_152296.5(ATP1A3):c.2266C>T (p.Arg756Cys)
Variation ID: 425189 Accession: VCV000425189.34
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.2 19: 41970540 (GRCh38) [ NCBI UCSC ] 19: 42474692 (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 May 8, 2017 Jul 15, 2024 Jul 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_152296.5:c.2266C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_689509.1:p.Arg756Cys missense NM_001256213.2:c.2299C>T NP_001243142.1:p.Arg767Cys missense NM_001256214.2:c.2305C>T NP_001243143.1:p.Arg769Cys missense NC_000019.10:g.41970540G>A NC_000019.9:g.42474692G>A NG_008015.1:g.28691C>T LRG_1186:g.28691C>T LRG_1186t1:c.2266C>T LRG_1186p1:p.Arg756Cys - Protein change
- R756C, R767C, R769C
- Other names
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- Canonical SPDI
- NC_000019.10:41970539:G:A
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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.
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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
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. |
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ATP1A3 | - | - |
GRCh38 GRCh37 |
1128 | 1149 |
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
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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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Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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May 25, 2023 | RCV000488196.17 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 15, 2021 | RCV000501825.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 16, 2016 | RCV000624914.3 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Sep 24, 2023 | RCV000692668.10 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 12, 2018 | RCV000850500.2 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV003335375.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 1, 2024 | RCV004586737.1 |
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. |
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Likely pathogenic
(Jun 15, 2016)
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criteria provided, single submitter
Method: clinical testing
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Alternating hemiplegia of childhood 2
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000593519.1
First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017 |
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Likely pathogenic
(Oct 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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Alternating hemiplegia of childhood 2
Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome Dystonia 12
Affected status: yes
Allele origin:
germline
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Baylor Genetics
Accession: SCV000992700.1
First in ClinVar: Sep 21, 2019 Last updated: Sep 21, 2019 |
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446978.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Strabismus (present) , Dysarthria (present) , Motor delay (present) , Dystonic disorder (present) , Multiple joint contractures (present) , Myopathy (present) , Generalized dystonia (present) … (more)
Strabismus (present) , Dysarthria (present) , Motor delay (present) , Dystonic disorder (present) , Multiple joint contractures (present) , Myopathy (present) , Generalized dystonia (present) , Abnormal vestibulo-ocular reflex (present) , Cerebral palsy (present) (less)
Sex: male
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Pathogenic
(Jul 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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Alternating hemiplegia of childhood 2
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002512690.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
ACMG classification criteria: PS4 moderate, PM2 moderate, PM5, PM6 strong, PP1 moderate, PP3 supporting
Geographic origin: Brazil
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Likely pathogenic
(Sep 30, 2016)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV000575190.6
First in ClinVar: May 08, 2017 Last updated: Dec 24, 2022 |
Number of individuals with the variant: 2
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Pathogenic
(Feb 16, 2016)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000741354.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Muscular hypotonia (present) , Ketosis (present) , Cerebellar ataxia (present) , Gait disturbance (present) , Incoordination (present)
Sex: male
Ethnicity/Population group: Caucasian
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Pathogenic
(Mar 25, 2022)
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criteria provided, single submitter
Method: clinical testing
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Dystonia 12
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV003836469.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
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Pathogenic
(May 25, 2023)
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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: SCV001793155.2
First in ClinVar: Aug 20, 2021 Last updated: Jun 03, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29396171, 8496742, 27726050, 22842232, 34765691, 34761051, 34975730, 26400718, 24436111, 19652145, 24123283, 23483595, 27091223, 26297560, 25895915, 26410222, 28293679, 16632466, 22534615, 24739246, 24468074, 29184165, 25656163, 15260953, 24996492, 25359261, 22850527, 29397530, 28647130, 27634470, 27268479, 29346770, 29066118, 30862413, 31269555, 31737037, 32637629, 31216405, 31175295) (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: not provided
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Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, University Hospital of Duesseldorf
Accession: SCV004046815.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
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Pathogenic
(Mar 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003811134.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Sep 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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Dystonia 12
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000820504.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 425189). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral … (more)
ClinVar contains an entry for this variant (Variation ID: 425189). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 756 of the ATP1A3 protein (p.Arg756Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with rapid onset of ataxia, encephalopathy, dystonia, and weakness following a febrile illness (PMID: 26400718, 27268479, 27634470, 27726050, 29066118, 29397530). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jul 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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Seizures
Affected status: yes
Allele origin:
unknown
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Génétique des Maladies du Développement, Hospices Civils de Lyon
Accession: SCV005073728.1
First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024 |
Sex: male
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001739883.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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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: SCV001952062.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Dystonia 12
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV002559236.2
First in ClinVar: Aug 15, 2022 Last updated: Oct 01, 2022 |
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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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Childhood Rapid-Onset Ataxia: Expanding the Phenotypic Spectrum of ATP1A3 Mutations. | Schirinzi T | Cerebellum (London, England) | 2018 | PMID: 29397530 |
A de novo p.Arg756Cys mutation in ATP1A3 causes a distinct phenotype with prolonged weakness and encephalopathy triggered by fever. | Nakamura Y | Brain & development | 2018 | PMID: 29066118 |
ATP1A3-Related Neurologic Disorders. | Adam MP | - | 2018 | PMID: 20301294 |
Mosaicism in ATP1A3-related disorders: not just a theoretical risk. | Hully M | Neurogenetics | 2017 | PMID: 27726050 |
De novo p.Arg756Cys mutation of ATP1A3 causes an atypical form of alternating hemiplegia of childhood with prolonged paralysis and choreoathetosis. | Kanemasa H | BMC neurology | 2016 | PMID: 27634470 |
Childhood-onset ATP1A3-related conditions: Report of two new cases of phenotypic spectrum. | Nicita F | Parkinsonism & related disorders | 2016 | PMID: 27268479 |
Relapsing encephalopathy with cerebellar ataxia related to an ATP1A3 mutation. | Dard R | Developmental medicine and child neurology | 2015 | PMID: 26400718 |
Alternating Hemiplegia of Childhood: Retrospective Genetic Study and Genotype-Phenotype Correlations in 187 Subjects from the US AHCF Registry. | Viollet L | PloS one | 2015 | PMID: 25996915 |
The expanding clinical and genetic spectrum of ATP1A3-related disorders. | Rosewich H | Neurology | 2014 | PMID: 24523486 |
Genotype-phenotype correlations in alternating hemiplegia of childhood. | Sasaki M | Neurology | 2014 | PMID: 24431296 |
ATP1A3 mutations in infants: a new rapid-onset dystonia-Parkinsonism phenotype characterized by motor delay and ataxia. | Brashear A | Developmental medicine and child neurology | 2012 | PMID: 22924536 |
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Text-mined citations for rs1064797245 ...
HelpRecord last updated Jul 23, 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.