This ATP1A3 variant (rs80356533) is absent from a large population dataset and has been reported in ClinVar. It has been reported in the literature in at least four unrelated individuals with DYT12. Three bioinformatic tools queried predict that this substitution would be damaging, and the glutamate residue at this position is strongly evolutionarily conserved across the vertebrate species assessed. p.Glu277Lys showed reduced survival in an in vitro cell viability assay (quabain sensitivity) and reduced protein expression in transiently transfected HEK293T cells. Bioinformatic analysis predicts that this missense variant would not affect normal exon 8 splicing, although this has not been confirmed experimentally to our knowledge. This variant is apparently de novo in this individual. We consider c.829G>A to be pathogenic.
ClinVar Genomic variation as it relates to human health
NM_152296.5(ATP1A3):c.829G>A (p.Glu277Lys)
Germline
Classification
Help
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.
(6)
Help
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
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_152296.5(ATP1A3):c.829G>A (p.Glu277Lys)
Variation ID: 12911 Accession: VCV000012911.12
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19q13.2 19: 41985082 (GRCh38) [ NCBI UCSC ] 19: 42489234 (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 Dec 7, 2014 Sep 29, 2024 Jan 18, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_152296.5:c.829G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_689509.1:p.Glu277Lys missense NM_001256213.2:c.862G>A NP_001243142.1:p.Glu288Lys missense NM_001256214.2:c.868G>A NP_001243143.1:p.Glu290Lys missense NC_000019.10:g.41985082C>T NC_000019.9:g.42489234C>T NG_008015.1:g.14149G>A LRG_1186:g.14149G>A LRG_1186t1:c.829G>A LRG_1186p1:p.Glu277Lys P13637:p.Glu277Lys - Protein change
- E277K, E290K, E288K
- Other names
- -
- Canonical SPDI
- NC_000019.10:41985081:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| ATP1A3 | - | - |
GRCh38 GRCh37 |
1161 | 1182 | |
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. |
|---|---|---|---|---|
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
May 16, 2023 | RCV000013774.43 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 18, 2024 | RCV004719645.1 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jul 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Dystonia 12
Affected status: unknown
Allele origin:
germline
|
Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV002570400.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
This ATP1A3 variant (rs80356533) is absent from a large population dataset and has been reported in ClinVar. It has been reported in the literature in … (more)
This ATP1A3 variant (rs80356533) is absent from a large population dataset and has been reported in ClinVar. It has been reported in the literature in at least four unrelated individuals with DYT12. Three bioinformatic tools queried predict that this substitution would be damaging, and the glutamate residue at this position is strongly evolutionarily conserved across the vertebrate species assessed. p.Glu277Lys showed reduced survival in an in vitro cell viability assay (quabain sensitivity) and reduced protein expression in transiently transfected HEK293T cells. Bioinformatic analysis predicts that this missense variant would not affect normal exon 8 splicing, although this has not been confirmed experimentally to our knowledge. This variant is apparently de novo in this individual. We consider c.829G>A to be pathogenic. (less)
|
|
|
Pathogenic
(May 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Dystonia 12
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004040760.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
|
|
|
Pathogenic
(Apr 24, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Dystonia 12
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000544727.5
First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect ATP1A3 protein function (PMID: 15260953). This variant has … (more)
For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect ATP1A3 protein function (PMID: 15260953). This variant has been reported in individuals affected with rapid-onset dystonia-parkinsonism (RDP) as well as in an individual with alternating hemiplegia of childhood (AHC) (PMID: 15260953, 17282997, 20558373, 25439493). ClinVar contains an entry for this variant (Variation ID: 12911). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 277 of the ATP1A3 protein (p.Glu277Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. (less)
|
|
|
Pathogenic
(Jan 18, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV005325005.1
First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024 |
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (gnomAD); This variant is associated … (more)
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30363590, 25447930, 15260953, 25439493, 17282997, 29396171, 27835968, 30550795, 27577505, 24739246, 26417536, 22067897, 27313535, 31361359, 33451880, 26297560) (less)
|
|
|
Pathogenic
(Jun 10, 2010)
|
no assertion criteria provided
Method: literature only
|
DYSTONIA 12
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000034021.3
First in ClinVar: Apr 04, 2013 Last updated: Apr 21, 2017 |
Comment on evidence:
In a patient with dystonia-12 (DYT12; 128235), de Carvalho Aguiar et al. (2004) identified a heterozygous 829G-A transition in exon 8 of the ATP1A3 gene, … (more)
In a patient with dystonia-12 (DYT12; 128235), de Carvalho Aguiar et al. (2004) identified a heterozygous 829G-A transition in exon 8 of the ATP1A3 gene, resulting in a glu277-to-lys (E277K) substitution in a highly conserved residue in the transmembrane domain of the protein. The mutation was not identified in 500 northern European control chromosomes. The patient had disease onset at age 20 years. Tarsy et al. (2010) identified the E277K mutation in a 29-year-old woman of African Caribbean descent with DYT12. She had onset at age 26 years of weakness and flexion of the left hand and ankle, which progressed rapidly over the next few years to become frank dystonia of the left arm and bulbar symptoms, including dysphagia, laryngeal dysfunction with task-specific dysphonia, and oropharyngeal dysmotility. She also had mild parkinsonism, with hypomimia and wide-based gait. Treatment with oral trihexyphenidyl and botulinum injection into selected laryngeal muscles resulted in clinical improvement. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Dystonia 12
Affected status: yes
Allele origin:
de novo
|
GeneReviews
Accession: SCV000041600.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect ATP1A3 protein function (PMID: 15260953). This variant has been reported in individuals affected with rapid-onset dystonia-parkinsonism (RDP) as well as in an individual with alternating hemiplegia of childhood (AHC) (PMID: 15260953, 17282997, 20558373, 25439493). ClinVar contains an entry for this variant (Variation ID: 12911). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 277 of the ATP1A3 protein (p.Glu277Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine.
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30363590, 25447930, 15260953, 25439493, 17282997, 29396171, 27835968, 30550795, 27577505, 24739246, 26417536, 22067897, 27313535, 31361359, 33451880, 26297560)
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:
This ATP1A3 variant (rs80356533) is absent from a large population dataset and has been reported in ClinVar. It has been reported in the literature in at least four unrelated individuals with DYT12. Three bioinformatic tools queried predict that this substitution would be damaging, and the glutamate residue at this position is strongly evolutionarily conserved across the vertebrate species assessed. p.Glu277Lys showed reduced survival in an in vitro cell viability assay (quabain sensitivity) and reduced protein expression in transiently transfected HEK293T cells. Bioinformatic analysis predicts that this missense variant would not affect normal exon 8 splicing, although this has not been confirmed experimentally to our knowledge. This variant is apparently de novo in this individual. We consider c.829G>A to be pathogenic.
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect ATP1A3 protein function (PMID: 15260953). This variant has been reported in individuals affected with rapid-onset dystonia-parkinsonism (RDP) as well as in an individual with alternating hemiplegia of childhood (AHC) (PMID: 15260953, 17282997, 20558373, 25439493). ClinVar contains an entry for this variant (Variation ID: 12911). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 277 of the ATP1A3 protein (p.Glu277Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine.
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30363590, 25447930, 15260953, 25439493, 17282997, 29396171, 27835968, 30550795, 27577505, 24739246, 26417536, 22067897, 27313535, 31361359, 33451880, 26297560)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| ATP1A3-Related Disorders: An Ever-Expanding Clinical Spectrum. | Salles PA | Frontiers in neurology | 2021 | PMID: 33868146 |
| Rapid-onset dystonia-parkinsonism with ATP1A3 mutation and left lower limb paroxysmal dystonia. | Nomura S | Brain & development | 2021 | PMID: 33451880 |
| ATP1A3-Related Neurologic Disorders. | Adam MP | - | 2018 | PMID: 20301294 |
| Identical ATP1A3 mutation causes alternating hemiplegia of childhood and rapid-onset dystonia parkinsonism phenotypes. | Boelman C | Pediatric neurology | 2014 | PMID: 25439493 |
| Case records of the Massachusetts General Hospital. Case 17-2010 - a 29-year-old woman with flexion of the left hand and foot and difficulty speaking. | Tarsy D | The New England journal of medicine | 2010 | PMID: 20558373 |
| 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 in the Na+/K+ -ATPase alpha3 gene ATP1A3 are associated with rapid-onset dystonia parkinsonism. | de Carvalho Aguiar P | Neuron | 2004 | PMID: 15260953 |
Text-mined citations for rs80356533 ...
HelpThese 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 10, 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.