NM_152296.5(ATP1A3):c.410C>T (p.Ser137Phe) AND Dystonia 12

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 13, 2019
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:: RCV001234241.10

Allele description [Variation Report for NM_152296.5(ATP1A3):c.410C>T (p.Ser137Phe)]

NM_152296.5(ATP1A3):c.410C>T (p.Ser137Phe)

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.410C>T (p.Ser137Phe)

HGVS:

NC_000019.10:g.41986177G>A
NG_008015.1:g.13054C>T
NM_001256213.2:c.443C>T
NM_001256214.2:c.449C>T
NM_152296.5:c.410C>TMANE SELECT
NP_001243142.1:p.Ser148Phe
NP_001243143.1:p.Ser150Phe
NP_689509.1:p.Ser137Phe
LRG_1186t1:c.410C>T
LRG_1186:g.13054C>T
LRG_1186p1:p.Ser137Phe
NC_000019.9:g.42490329G>A
NM_001256214.1:c.449C>T
NM_152296.4:c.410C>T
P13637:p.Ser137Phe

Protein change:

S137F

Links:

UniProtKB: P13637#VAR_068935; dbSNP: rs542652468

NCBI 1000 Genomes Browser:

rs542652468

Molecular consequence:

NM_001256213.2:c.443C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001256214.2:c.449C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_152296.5:c.410C>T - 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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MeSH
D012481 (1)
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001406877	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 13, 2019)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22842232, 26297560, 26410222, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001406877

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 13, 2019)

germline

clinical testing

PubMed (4)
[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

Citations

PubMed

De novo mutations in ATP1A3 cause alternating hemiplegia of childhood.

Heinzen EL, Swoboda KJ, Hitomi Y, Gurrieri F, Nicole S, de Vries B, Tiziano FD, Fontaine B, Walley NM, Heavin S, Panagiotakaki E; European Alternating Hemiplegia of Childhood (AHC) Genetics Consortium.; Biobanca e Registro Clinico per l'Emiplegia Alternante (I.B.AHC) Consortium.; European Network for Research on Alternating Hemiplegia (ENRAH) for Small and Medium-sized Enterpriese (SMEs) Consortium., Fiori S, Abiusi E, Di Pietro L, Sweney MT, Newcomb TM, Viollet L, Huff C, Jorde LB, et al.

Nat Genet. 2012 Sep;44(9):1030-4. doi: 10.1038/ng.2358. Epub 2012 Jul 29.

PubMed [citation]

PMID:: 22842232
PMCID:: PMC3442240

Faulty cardiac repolarization reserve in alternating hemiplegia of childhood broadens the phenotype.

Jaffer F, Avbersek A, Vavassori R, Fons C, Campistol J, Stagnaro M, De Grandis E, Veneselli E, Rosewich H, Gianotta M, Zucca C, Ragona F, Granata T, Nardocci N, Mikati M, Helseth AR, Boelman C, Minassian BA, Johns S, Garry SI, Scheffer IE, Gourfinkel-An I, et al.

Brain. 2015 Oct;138(Pt 10):2859-74. doi: 10.1093/brain/awv243. Epub 2015 Aug 21.

PubMed [citation]

PMID:: 26297560
PMCID:: PMC4671482

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001406877.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser137 amino acid residue in ATP1A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22842232). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individuals affected with alternating hemiplegia of childhood (PMID: 22842232, 26297560, 26410222). ClinVar contains an entry for this variant (Variation ID: 161122). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with phenylalanine at codon 137 of the ATP1A3 protein (p.Ser137Phe). The serine residue is moderately conserved and there is a large physicochemical difference between serine and phenylalanine.

#	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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