ACMG classification criteria: PS4 moderate, PM2 moderate, PM5, PM6 strong, PP1 moderate, PP3 supporting
NM_152296.5(ATP1A3):c.2266C>T (p.Arg756Cys)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic/Likely pathogenic
Pathogenic (12); Likely pathogenic (3)
Pathogenic (12); Likely pathogenic (3)
15 out of 19 submissions contributed to this 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.
19
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_152296.5(ATP1A3):c.2266C>T (p.Arg756Cys)
Variation ID: 425189 Accession: VCV000425189.42
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19q13.2 19: 41970540 (GRCh38) [ NCBI UCSC ] 19: 42474692 (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 May 8, 2017 May 16, 2026 Oct 11, 2025 - HGVS
-
... more HGVS ... less HGVSNucleotide 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_001256214.1:c.2305C>T 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
- -
- Canonical SPDI
- NC_000019.10:41970539:G:A
-
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 |
1385 | 1411 | |
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/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
May 25, 2023 | RCV000488196.19 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jul 15, 2021 | RCV000501825.7 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 16, 2016 | RCV000624914.4 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Sep 24, 2023 | RCV000692668.16 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Oct 12, 2018 | RCV000850500.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
- | RCV003335375.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 1, 2024 | RCV004586737.2 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Nov 27, 2024 | RCV004737556.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 10, 2024 | RCV004787793.1 | |
|
Autosomal dominant ATP1A3-related disorders
|
Pathogenic (1) |
criteria provided, single submitter
|
Oct 11, 2025 | RCV006696393.1 |
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. |
Expand all rows
Collapse all rows
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Jun 15, 2016)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Alternating hemiplegia of childhood 2 |
Genetic Services Laboratory, University of Chicago
Accession: SCV000593519.1
First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Likely pathogenic
(Oct 12, 2018)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Alternating hemiplegia of childhood 2
Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome Dystonia 12 |
Baylor Genetics
Accession: SCV000992700.1
First in ClinVar: Sep 21, 2019 Last updated: Sep 21, 2019 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Jul 15, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Alternating hemiplegia of childhood 2 |
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:
show
ACMG classification criteria: PS4 moderate, PM2 moderate, PM5, PM6 strong, PP1 moderate, PP3 supporting (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Geographic origin: Brazil
|
|
|
Likely pathogenic
(Sep 30, 2016)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
CeGaT Center for Human Genetics Tuebingen
Accession: SCV000575190.6
First in ClinVar: May 08, 2017 Last updated: Dec 24, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Mar 25, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Dystonia 12 |
Baylor Genetics
Accession: SCV003836469.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(May 25, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
GeneDx
Accession: SCV001793155.2
First in ClinVar: Aug 20, 2021 Last updated: Jun 03, 2023 |
Comment:
show
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)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(-)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome
(Autosomal dominant inheritance)
|
Institute of Human Genetics, University Hospital of Duesseldorf
Accession: SCV004046815.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Observation: 1
Collection method: not provided
Allele origin: germline
Affected status: yes
Observation 1
Collection method: not provided
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Oct 10, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
ATP1A3-associated neurological disorder
(Autosomal dominant inheritance)
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Accession: SCV005398258.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
show
Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ATP1A3-associated neurological disorder (MONDO:0700002). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Incomplete penetrance has been observed for the dystonia-12 phenotype, several members of larger families have been reported as having a heterozygous pathogenic variant but no symptoms. (PMID: 20301294). (I) 0115 - Variants in this gene are known to have variable expressivity. ATP1A3-related disorders represent a clinical continuum (PMID: 35945798). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. This variant affects the third nucleotide of exon 17 and is therefore also considered a non-canonical splice site variant. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v4; 1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. This variant is also located in a splice region; however, in silico predictions for abnormal splicing are conflicting. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported nine times as pathogenic and three times as likely pathogenic (ClinVar) and has been reported in thirteen individuals with fever induced paroxysmal encephalopathy and weakness (PMID: 34342181). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Feb 16, 2016)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Inborn genetic diseases |
Ambry Genetics
Accession: SCV000741354.4
First in ClinVar: Apr 15, 2018 Last updated: Apr 13, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
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
|
|
|
Pathogenic
(Oct 23, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided
(Autosomal dominant inheritance)
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446978.2
First in ClinVar: Nov 28, 2020 Last updated: Apr 13, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Clinical Features:
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)
Sex: male
|
|
|
Pathogenic
(Jul 01, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Seizures |
Génétique des Maladies du Développement, Hospices Civils de Lyon
Accession: SCV005073728.2
First in ClinVar: Jul 15, 2024 Last updated: Apr 13, 2025 |
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Zygosity: 1 Single Heterozygote
Sex: male
|
|
|
Pathogenic
(Mar 29, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Revvity Omics, Revvity
Accession: SCV003811134.3
First in ClinVar: Mar 04, 2023 Last updated: Sep 06, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Nov 27, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
ATP1A3-related disorder |
3billion
Accession: SCV005904503.2
First in ClinVar: Apr 13, 2025 Last updated: Oct 25, 2025 |
Comment:
show
The variant is not observed in the gnomAD v4.1.0 dataset. Predicted Consequence/Location: Missense variant. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.98 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.99 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000425189 /PMID: 27634470 /3billion dataset). Different missense changes at the same codon (p.Arg756His, p.Arg756Leu, p.Arg756Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000161134, VCV001705555 /PMID: 22924536, 28647130 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Method: genome sequencing
|
|
|
Pathogenic
(Sep 24, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Dystonia 12 |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000820504.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 15, 2026 |
Comment:
show
For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 425189). 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. This variant is not present in population databases (gnomAD no frequency). 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). (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Oct 11, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Autosomal dominant ATP1A3-related disorders
(Autosomal dominant inheritance)
|
Variantyx, Inc.
Accession: SCV007595547.1
First in ClinVar: May 16, 2026 Last updated: May 16, 2026 |
Comment:
show
This is a nonsynonymous variant in the ATP1A3 gene (OMIM: 182350). Pathogenic variants in this gene have been associated with autosomal dominant ATP1A3-related disorders. This variant likely occurred de novo in the current proband and individuals reported in the published literature; however, the possibility of parental germline mosaicism cannot be excluded (PMID: 30862413, 34765691, 27634470) (PS2_Very_Strong). Multiple computational algorithms predict a deleterious effect for this variant (REVEL score: 0.981) (PP3). This variant is absent from control populations (https://gnomad.broadinstitute.org/) (PM2). Based on the current evidence, this variant is classified as pathogenic for autosomal dominant ATP1A3-related disorders. (less)
Observation: 1
Collection method: clinical testing
Allele origin: de novo
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: de novo
Affected status: yes
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
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 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Study: VKGL Data-share Consensus
Accession: SCV001952062.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Mar 20, 2024)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
ATP1A3-related condition |
PreventionGenetics, part of Exact Sciences
Accession: SCV005361779.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
show
The ATP1A3 c.2305C>T variant is predicted to result in the amino acid substitution p.Arg769Cys. This variant was reported in several individuals with de novo inheritance with ATP1A3-associated disease (Hully et al 2016. PubMed ID: 27726050; Dard et al 2015. PubMed ID: 26400718; Kanemasa et al 2016. PubMed ID: 27634470). An alternate nucleotide change affecting the same amino acid (p.Arg769His), has been reported to be pathogenic (Rosewich et al 2014. PubMed ID: 24523486; Viollet et al 2015. PubMed ID: 25996915; Brashear et al 2012. PubMed ID: 22924536). A hypothesis that changes at this amino acid residue provide a unique phenotype of fever-induced paroxysmal weakness and encephalopathy (FIPWE) has been postulated (Yano et al 2017. PubMed ID: 28647130). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
not provided
(-)
N
Not contributing to aggregate classification
|
no classification provided
|
Dystonia 12 |
GeneReviews
Accession: SCV002559236.2
First in ClinVar: Aug 15, 2022 Last updated: Oct 01, 2022 |
Observation: 1
Collection method: literature only
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: literature only
Allele origin: germline
Affected status: unknown
|
|
Comment:
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 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)
Comment:
Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ATP1A3-associated neurological disorder (MONDO:0700002). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Incomplete penetrance has been observed for the dystonia-12 phenotype, several members of larger families have been reported as having a heterozygous pathogenic variant but no symptoms. (PMID: 20301294). (I) 0115 - Variants in this gene are known to have variable expressivity. ATP1A3-related disorders represent a clinical continuum (PMID: 35945798). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. This variant affects the third nucleotide of exon 17 and is therefore also considered a non-canonical splice site variant. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v4; 1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. This variant is also located in a splice region; however, in silico predictions for abnormal splicing are conflicting. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported nine times as pathogenic and three times as likely pathogenic (ClinVar) and has been reported in thirteen individuals with fever induced paroxysmal encephalopathy and weakness (PMID: 34342181). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
The variant is not observed in the gnomAD v4.1.0 dataset. Predicted Consequence/Location: Missense variant. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.98 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.99 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000425189 /PMID: 27634470 /3billion dataset). Different missense changes at the same codon (p.Arg756His, p.Arg756Leu, p.Arg756Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000161134, VCV001705555 /PMID: 22924536, 28647130 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 425189). 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. This variant is not present in population databases (gnomAD no frequency). 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).
Comment:
This is a nonsynonymous variant in the ATP1A3 gene (OMIM: 182350). Pathogenic variants in this gene have been associated with autosomal dominant ATP1A3-related disorders. This variant likely occurred de novo in the current proband and individuals reported in the published literature; however, the possibility of parental germline mosaicism cannot be excluded (PMID: 30862413, 34765691, 27634470) (PS2_Very_Strong). Multiple computational algorithms predict a deleterious effect for this variant (REVEL score: 0.981) (PP3). This variant is absent from control populations (https://gnomad.broadinstitute.org/) (PM2). Based on the current evidence, this variant is classified as pathogenic for autosomal dominant ATP1A3-related disorders.
Comment:
The ATP1A3 c.2305C>T variant is predicted to result in the amino acid substitution p.Arg769Cys. This variant was reported in several individuals with de novo inheritance with ATP1A3-associated disease (Hully et al 2016. PubMed ID: 27726050; Dard et al 2015. PubMed ID: 26400718; Kanemasa et al 2016. PubMed ID: 27634470). An alternate nucleotide change affecting the same amino acid (p.Arg769His), has been reported to be pathogenic (Rosewich et al 2014. PubMed ID: 24523486; Viollet et al 2015. PubMed ID: 25996915; Brashear et al 2012. PubMed ID: 22924536). A hypothesis that changes at this amino acid residue provide a unique phenotype of fever-induced paroxysmal weakness and encephalopathy (FIPWE) has been postulated (Yano et al 2017. PubMed ID: 28647130). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| ATP1A3-Related Disorder. | Adam MP | - | 2024 | PMID: 20301294 |
| Alternating hemiplegia of childhood: a distinct clinical entity and ATP1A3-related disorders: A narrative review. | Pavone P | Medicine | 2022 | PMID: 35945798 |
| Long-Term Follow-Up of a Patient with a De Novo p.Arg769Cys Mutation in the ATP1A3 Gene. | Chouksey A | Movement disorders clinical practice | 2021 | PMID: 34765691 |
| Variants of ATP1A3 in residue 756 cause a separate phenotype of relapsing encephalopathy with cerebellar ataxia (RECA)-Report of two cases and literature review. | Biela M | Molecular genetics & genomic medicine | 2021 | PMID: 34342181 |
| Relapsing encephalopathy with cerebellar ataxia are caused by variants involving p.Arg756 in ATP1A3. | Sabouraud P | European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society | 2019 | PMID: 30862413 |
| 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 |
| 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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Record last updated May 23, 2026
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.