NM_152296.5(ATP1A3):c.2452G>A (p.Glu818Lys) AND Dystonia 12

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 27, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000234480.20

Allele description [Variation Report for NM_152296.5(ATP1A3):c.2452G>A (p.Glu818Lys)]

NM_152296.5(ATP1A3):c.2452G>A (p.Glu818Lys)

Gene:

ATP1A3:ATPase Na+/K+ transporting subunit alpha 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19q13.2

Genomic location:

Preferred name:

NM_152296.5(ATP1A3):c.2452G>A (p.Glu818Lys)

HGVS:

NC_000019.10:g.41970275C>T
NG_008015.1:g.28956G>A
NM_001256213.2:c.2485G>A
NM_001256214.2:c.2491G>A
NM_152296.5:c.2452G>AMANE SELECT
NP_001243142.1:p.Glu829Lys
NP_001243143.1:p.Glu831Lys
NP_689509.1:p.Glu818Lys
NP_689509.1:p.Glu818Lys
LRG_1186t1:c.2452G>A
LRG_1186:g.28956G>A
LRG_1186p1:p.Glu818Lys
NC_000019.9:g.42474427C>T
NM_001256214.1:c.2491G>A
NM_152296.3:c.2452G>A
NM_152296.4:c.2452G>A
P13637:p.Glu818Lys

Protein change:

E818K; GLU818LYS

Links:

UniProtKB: P13637#VAR_070772; OMIM: 182350.0014; dbSNP: rs587777771

NCBI 1000 Genomes Browser:

rs587777771

Molecular consequence:

NM_001256213.2:c.2485G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001256214.2:c.2491G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_152296.5:c.2452G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Dystonia 12 (DYT12)
Synonyms:: DYT-ATP1A3; Rapid-Onset Dystonia-Parkinsonism
Identifiers:: MONDO: MONDO:0007496; MedGen: C1868681; Orphanet: 71517; OMIM: 128235

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000195717	GeneReviews	no classification provided	not provided	germline	literature only
SCV000291489	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 27, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 24468074, 25056583, 25895915, 26453127, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000195717

GeneReviews

no classification provided

not provided

germline

literature only

SCV000291489

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 27, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only

Citations

PubMed

A novel recurrent mutation in ATP1A3 causes CAPOS syndrome.

Demos MK, van Karnebeek CD, Ross CJ, Adam S, Shen Y, Zhan SH, Shyr C, Horvath G, Suri M, Fryer A, Jones SJ, Friedman JM; FORGE Canada Consortium..

Orphanet J Rare Dis. 2014 Jan 28;9:15. doi: 10.1186/1750-1172-9-15.

PubMed [citation]

PMID:: 24468074
PMCID:: PMC3937150

Phenotypic overlap of alternating hemiplegia of childhood and CAPOS syndrome.

Rosewich H, Weise D, Ohlenbusch A, Gärtner J, Brockmann K.

Neurology. 2014 Aug 26;83(9):861-3. doi: 10.1212/WNL.0000000000000735. Epub 2014 Jul 23. No abstract available.

PubMed [citation]

PMID:: 25056583

See all PubMed Citations (5)

Details of each submission

From GeneReviews, SCV000195717.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000291489.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 818 of the ATP1A3 protein (p.Glu818Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome (PMID: 24468074, 25056583, 25895915, 26453127). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 156238). 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%. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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