ClinVar Genomic variation as it relates to human health
NM_152296.5(ATP1A3):c.2452G>A (p.Glu818Lys)
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.2452G>A (p.Glu818Lys)
Variation ID: 156238 Accession: VCV000156238.53
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.2 19: 41970275 (GRCh38) [ NCBI UCSC ] 19: 42474427 (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 Nov 3, 2024 Oct 29, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_152296.5:c.2452G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_689509.1:p.Glu818Lys missense NM_001256213.2:c.2485G>A NP_001243142.1:p.Glu829Lys missense NM_001256214.2:c.2491G>A NP_001243143.1:p.Glu831Lys missense NC_000019.10:g.41970275C>T NC_000019.9:g.42474427C>T NG_008015.1:g.28956G>A LRG_1186:g.28956G>A LRG_1186t1:c.2452G>A LRG_1186p1:p.Glu818Lys P13637:p.Glu818Lys - Protein change
- E818K, E829K, E831K
- Other names
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- Canonical SPDI
- NC_000019.10:41970274:C:T
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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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- 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 | ||
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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
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. |
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| ATP1A3 | - | - |
GRCh38 GRCh37 |
1163 | 1184 | |
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 (8) |
criteria provided, multiple submitters, no conflicts
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Oct 29, 2024 | RCV000144250.25 | |
| Pathogenic (1) |
criteria provided, single submitter
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Jul 20, 2015 | RCV000195001.13 | |
| Pathogenic (1) |
criteria provided, single submitter
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Aug 29, 2014 | RCV000190725.13 | |
| Pathogenic (2) |
criteria provided, single submitter
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Nov 27, 2023 | RCV000234480.20 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 24, 2021 | RCV000314245.33 |
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
(Dec 24, 2021)
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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: SCV000329953.7
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate a damaging effect with reduced pump turnover rate and failure to rapidly regain the resting membrane potential following action potentials (Roenn … (more)
Published functional studies demonstrate a damaging effect with reduced pump turnover rate and failure to rapidly regain the resting membrane potential following action potentials (Roenn et al., 2019); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28483396, 24431296, 24468074, 20301294, 25056583, 26410222, 26400718, 26453127, 25895915, 27091223, 26795593, 29090527, 29184165, 29305691, 30409907, 29397530, 29915382, 30904181, 31410291, 31737037, 31942761, 32907636, 32135597, 28708278, 32576493, 29625811) (less)
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Pathogenic
(Jul 20, 2015)
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criteria provided, single submitter
Method: clinical testing
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Alternating hemiplegia of childhood 2
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000246633.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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Pathogenic
(Jul 15, 2019)
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criteria provided, single submitter
Method: clinical testing
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Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome
Affected status: yes
Allele origin:
de novo
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001429018.1
First in ClinVar: Aug 17, 2020 Last updated: Aug 17, 2020 |
Comment:
This variant was identified as de novo (maternity and paternity confirmed).
Number of individuals with the variant: 1
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Pathogenic
(Oct 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome
Affected status: yes
Allele origin:
paternal
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV001976671.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
Comment:
PM1, PM2, PP3, PP5
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Pathogenic
(May 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002521690.1
First in ClinVar: Jun 05, 2022 Last updated: Jun 05, 2022 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000156238). The variant has been previously reported as de novo or assumed (i.e. paternity and maternity not confirmed) de novo in at least two similarly affected unrelated individuals (PMID: 24468074,25895915, 3billion dataset). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID:24468074, 25056583, 25895915, 26453127) and to co-segregate with the disease in at least 5 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID:24468074). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Growth delay (present) , Irritability (present) , Generalized hypotonia (present) , Strabismus (present) , Rotary nystagmus (present) , Ophthalmoplegia (present) , Areflexia (present) , Acute … (more)
Growth delay (present) , Irritability (present) , Generalized hypotonia (present) , Strabismus (present) , Rotary nystagmus (present) , Ophthalmoplegia (present) , Areflexia (present) , Acute encephalopathy (present) (less)
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Pathogenic
(May 20, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002556419.2
First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022 |
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Pathogenic
(Aug 29, 2014)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000244166.7
First in ClinVar: Sep 14, 2015 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Progressive hearing impairment (present) , Visual loss (present) , Developmental regression (present) , Cerebellar ataxia (present) , Nystagmus (present) , Muscular hypotonia (present) , Gait … (more)
Progressive hearing impairment (present) , Visual loss (present) , Developmental regression (present) , Cerebellar ataxia (present) , Nystagmus (present) , Muscular hypotonia (present) , Gait ataxia (present) , Reduced tendon reflexes (present) , Head-banging (present) , Behavioral abnormality (present) , Recurrent pneumonia (present) , Seizures (present) , Nausea and vomiting (present) (less)
Sex: male
Ethnicity/Population group: Caucasian
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Pathogenic
(Nov 15, 2021)
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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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Revvity Omics, Revvity
Accession: SCV003811145.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Mar 01, 2020)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247063.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 3
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Pathogenic
(Mar 16, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV003841245.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Clinical Features:
Hearing impairment (present) , Delayed speech and language development (present) , Cerebellar ataxia (present) , Motor delay (present) , Areflexia (present) , Hereditary episodic ataxia … (more)
Hearing impairment (present) , Delayed speech and language development (present) , Cerebellar ataxia (present) , Motor delay (present) , Areflexia (present) , Hereditary episodic ataxia (present) , Poor motor coordination (present) (less)
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Pathogenic
(Nov 27, 2023)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000291489.8
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Oct 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome
Affected status: yes
Allele origin:
germline
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Department of Human Genetics, Hannover Medical School
Accession: SCV005382646.1
First in ClinVar: Nov 03, 2024 Last updated: Nov 03, 2024 |
Comment:
ACMG: PS3_Supporting, PS4_Moderate, PM1_Supporting, PM2_Supporting, PP1_Strong, PP2, PP3_Strong
Clinical Features:
Sensorineural hearing loss disorder (present) , Triggered by febrile illness (present) , Hyperkinetic movements (present) , Choreoathetosis (present)
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Pathogenic
(Aug 26, 2014)
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no assertion criteria provided
Method: literature only
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CEREBELLAR ATAXIA, AREFLEXIA, PES CAVUS, OPTIC ATROPHY, AND SENSORINEURAL HEARING LOSS
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000189408.5
First in ClinVar: Oct 01, 2014 Last updated: Jul 15, 2024 |
Comment on evidence:
In 10 patients from 3 unrelated families with cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS; 601338), including the original family … (more)
In 10 patients from 3 unrelated families with cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS; 601338), including the original family reported by Nicolaides et al. (1996), Demos et al. (2014) identified a heterozygous c.2452G-A transition in the ATP1A3 gene, resulting in a glu818-to-lys (E818K) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing of 2 of the families and confirmed by Sanger sequencing, was filtered against the dbSNP (builds 129 and 130) and 1000 Genomes Project databases and was not found in 1,834 controls. The mutation occurred de novo in the oldest affected generation of 1 family, but haplotype analysis could not rule out the possibility of a remote relationship between the other 2 families. All families were of Caucasian European descent. Functional studies of the E818K variant were not performed, but Demos et al. (2014) postulated a gain-of-function effect. In a German boy with CAPOS, Rosewich et al. (2014) identified a de novo heterozygous E818K mutation in the ATP1A3 gene. Functional studies were not performed. Tranebjaerg et al. (2018) reported that residue 818 of ATP1A3 is located at the cytoplasmic side of transmembrane helix-6, where it forms a salt bridge with the backbone carbonyl of arg930, a residue that stabilizes the C terminus. Tranebjaerg et al. (2018) expressed ATP1A3 with the E818K mutation in Xenopus laevis oocytes. Electrophysiologic analysis showed that the mutation disrupted the C terminus, caused opening of the C-terminal structure of ATP1A3, and affected sodium binding to and release from the binding site in the molecule. Molecular dynamic simulations confirmed that E818K opened the C-terminal pathway, allowing rapid entry of water molecules toward the ion-binding site. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome
Affected status: yes
Allele origin:
germline
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Genomics England Pilot Project, Genomics England
Accession: SCV001760451.1
First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021 |
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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: SCV000195717.3
First in ClinVar: Dec 07, 2014 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
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Phenotype-driven variant filtration strategy in exome sequencing toward a high diagnostic yield and identification of 85 novel variants in 400 patients with rare Mendelian disorders. | Marinakis NM | American journal of medical genetics. Part A | 2021 | PMID: 34008892 |
| The CAPOS mutation in ATP1A3 alters Na/K-ATPase function and results in auditory neuropathy which has implications for management. | Tranebjærg L | Human genetics | 2018 | PMID: 29305691 |
| ATP1A3-Related Neurologic Disorders. | Adam MP | - | 2018 | PMID: 20301294 |
| CAPOS syndrome and hemiplegic migraine in a novel pedigree with the specific ATP1A3 mutation. | Potic A | Journal of the neurological sciences | 2015 | PMID: 26453127 |
| CAOS-Episodic Cerebellar Ataxia, Areflexia, Optic Atrophy, and Sensorineural Hearing Loss: A Third Allelic Disorder of the ATP1A3 Gene. | Heimer G | Journal of child neurology | 2015 | PMID: 25895915 |
| Phenotypic overlap of alternating hemiplegia of childhood and CAPOS syndrome. | Rosewich H | Neurology | 2014 | PMID: 25056583 |
| A novel recurrent mutation in ATP1A3 causes CAPOS syndrome. | Demos MK | Orphanet journal of rare diseases | 2014 | PMID: 24468074 |
| Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS): a new syndrome. | Nicolaides P | Journal of medical genetics | 1996 | PMID: 8733056 |
Text-mined citations for rs587777771 ...
HelpRecord last updated Nov 25, 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.