ClinVar Genomic variation as it relates to human health
NM_152296.5(ATP1A3):c.1838C>T (p.Thr613Met)
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.1838C>T (p.Thr613Met)
Variation ID: 12909 Accession: VCV000012909.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.2 19: 41978041 (GRCh38) [ NCBI UCSC ] 19: 42482193 (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 Dec 7, 2014 Feb 14, 2024 Jan 4, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_152296.5:c.1838C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_689509.1:p.Thr613Met missense NM_001256213.2:c.1871C>T NP_001243142.1:p.Thr624Met missense NM_001256214.2:c.1877C>T NP_001243143.1:p.Thr626Met missense NC_000019.10:g.41978041G>A NC_000019.9:g.42482193G>A NG_008015.1:g.21190C>T LRG_1186:g.21190C>T LRG_1186t1:c.1838C>T LRG_1186p1:p.Thr613Met P13637:p.Thr613Met - Protein change
- T613M, T626M, T624M
- Other names
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- Canonical SPDI
- NC_000019.10:41978040: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
Help
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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ATP1A3 | - | - |
GRCh38 GRCh37 |
1125 | 1146 |
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 (8) |
criteria provided, multiple submitters, no conflicts
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Jan 4, 2024 | RCV000013772.50 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 15, 2022 | RCV000726724.14 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 10, 2017 | RCV001004717.9 |
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. |
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Pathogenic
(Apr 27, 2018)
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criteria provided, single submitter
Method: clinical testing
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Dystonia 12
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001428887.1
First in ClinVar: Aug 17, 2020 Last updated: Aug 17, 2020 |
Number of individuals with the variant: 1
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Pathogenic
(Feb 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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Dystonia 12
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
maternal
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV002764804.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Dystonic disorder (present)
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Pathogenic
(Jan 04, 2024)
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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: SCV000827091.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 613 of the ATP1A3 protein (p.Thr613Met). … (more)
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 613 of the ATP1A3 protein (p.Thr613Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with rapid onset dystonia parkinsonism (RDP) (PMID: 15260953, 17282997, 17516473, 22534615, 24523486). 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. ClinVar contains an entry for this variant (Variation ID: 12909). 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 ATP1A3 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ATP1A3 function (PMID: 15260953). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 03, 2016)
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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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Eurofins Ntd Llc (ga)
Accession: SCV000702441.2
First in ClinVar: Apr 21, 2017 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(May 28, 2019)
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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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Mendelics
Accession: SCV001141094.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Pathogenic
(Aug 10, 2017)
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criteria provided, single submitter
Method: clinical testing
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Alternating hemiplegia of childhood 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Génétique des Maladies du Développement, Hospices Civils de Lyon
Accession: SCV001164184.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
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Pathogenic
(Jan 28, 2020)
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criteria provided, single submitter
Method: clinical testing
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Dystonia 12
Affected status: yes
Allele origin:
germline
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Centogene AG - the Rare Disease Company
Accession: SCV002059395.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
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Pathogenic
(May 15, 2022)
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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: SCV002520184.2
First in ClinVar: May 28, 2022 Last updated: Mar 04, 2023 |
Comment:
Functional studies indicate that T613M interferes with hydrogen bonding near the catalytic site (Rodacker et al., 2006, de Carvalho Aguiar et al., 2004).; In silico … (more)
Functional studies indicate that T613M interferes with hydrogen bonding near the catalytic site (Rodacker et al., 2006, de Carvalho Aguiar et al., 2004).; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11061257, 17595045, 22850527, 24842602, 15390049, 15260953, 12112218, 29801903, 24523486, 17516473, 30097153, 31061839, 31361359, 33326973, 32653672, Post2009[Article], 17282997, 22534615, 16632466) (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: not provided
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Dystonia 12
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics, University Hospital of Duesseldorf
Accession: SCV004171126.1
First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023 |
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Pathogenic
(Mar 01, 2007)
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no assertion criteria provided
Method: literature only
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DYSTONIA 12
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000034019.3
First in ClinVar: Apr 04, 2013 Last updated: Apr 21, 2017 |
Comment on evidence:
In a sporadic patient (Linazasoro et al., 2002) and affected members of a second family (Zaremba et al., 2004) with dystonia-12 (DYT12; 128235), de Carvalho … (more)
In a sporadic patient (Linazasoro et al., 2002) and affected members of a second family (Zaremba et al., 2004) with dystonia-12 (DYT12; 128235), de Carvalho Aguiar et al. (2004) identified a heterozygous 1838C-T transition in the ATP1A3 gene, resulting in a thr613-to-met (T613M) substitution in a highly conserved residue near the phosphorylation domain on the cytoplasmic face of the protein. The mutation was not identified in 500 northern European control chromosomes. Brashear et al. (2007) identified the T613M mutation in a family with DYT12 reported by Pittock et al. (2000). Rodacker et al. (2006) noted that T613 is universally conserved among Na+/K(+)-ATPases, H+/K(+)-ATPases, and Ca(2+)-ATPases. Using rat Atp1a1 (182310) for technical reasons, they presented evidence that the T613M substitution in ATP1A3 alters the affinity of ATP1A3 for Na+ and ATP and alters the conformation equilibrium in favor of the potassium-bound form. (less)
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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: SCV000041595.4
First in ClinVar: Apr 04, 2013 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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ATP1A3-Related Neurologic Disorders. | Adam MP | - | 2018 | PMID: 20301294 |
The expanding clinical and genetic spectrum of ATP1A3-related disorders. | Rosewich H | Neurology | 2014 | PMID: 24523486 |
New triggers and non-motor findings in a family with rapid-onset dystonia-parkinsonism. | Barbano RL | Parkinsonism & related disorders | 2012 | PMID: 22534615 |
ATP1A3 mutation in the first asian case of rapid-onset dystonia-parkinsonism. | Lee JY | Movement disorders : official journal of the Movement Disorder Society | 2007 | PMID: 17595045 |
Heterogeneity of presentation and outcome in the Irish rapid-onset dystonia-parkinsonism kindred. | McKeon A | Movement disorders : official journal of the Movement Disorder Society | 2007 | PMID: 17516473 |
The phenotypic spectrum of rapid-onset dystonia-parkinsonism (RDP) and mutations in the ATP1A3 gene. | Brashear A | Brain : a journal of neurology | 2007 | PMID: 17282997 |
Mutations Phe785Leu and Thr618Met in Na+,K+-ATPase, associated with familial rapid-onset dystonia parkinsonism, interfere with Na+ interaction by distinct mechanisms. | Rodacker V | The Journal of biological chemistry | 2006 | PMID: 16632466 |
Rapid-onset dystonia-parkinsonism: a fourth family consistent with linkage to chromosome 19q13. | Zaremba J | Movement disorders : official journal of the Movement Disorder Society | 2004 | PMID: 15390049 |
Mutations in the Na+/K+ -ATPase alpha3 gene ATP1A3 are associated with rapid-onset dystonia parkinsonism. | de Carvalho Aguiar P | Neuron | 2004 | PMID: 15260953 |
Possible sporadic rapid-onset dystonia-parkinsonism. | Linazasoro G | Movement disorders : official journal of the Movement Disorder Society | 2002 | PMID: 12112218 |
Rapid-onset dystonia-parkinsonism: a clinical and genetic analysis of a new kindred. | Pittock SJ | Neurology | 2000 | PMID: 11061257 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ATP1A3 | - | - | - | - |
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Text-mined citations for this variant ...
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.