NM_152296.5(ATP1A3):c.2452G>A (p.Glu818Lys) AND Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome

Clinical significance:Pathogenic (Last evaluated: Oct 1, 2021)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
5 submissions [Details]
Record status:
current
Accession:
RCV000144250.9

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
  • NM_152296.5:c.2452G>A
  • NP_001243142.1:p.Glu829Lys
  • NP_001243143.1:p.Glu831Lys
  • NP_689509.1:p.Glu818Lys
  • 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]
Observations:
1

Condition(s)

Name:
Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome (CAPOS)
Synonyms:
CEREBELLAR ATAXIA, AREFLEXIA, PES CAVUS, OPTIC ATROPHY, AND SENSORINEURAL HEARING LOSS; Cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorinural hearing loss; CAPOS syndrome
Identifiers:
MONDO: MONDO:0011038; MedGen: C1832466; Orphanet: 1171; OMIM: 601338

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000189408OMIMno assertion criteria providedPathogenic
(Aug 26, 2014)
germlineliterature only

PubMed (4)
[See all records that cite these PMIDs]

SCV000195717GeneReviewsno assertion criteria providedPathogenic
(May 4, 2014)
de novoliterature only

Citation Link,

SCV001429018Institute of Human Genetics, University of Leipzig Medical Centercriteria provided, single submitter
Pathogenic
(Jul 15, 2019)
de novoclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001760451Genomics England Pilot Project,Genomics Englandno assertion criteria provided
Pathogenicgermlineclinical testing

Citation Link,

SCV001976671Laboratory of Medical Genetics, National & Kapodistrian University of Athenscriteria provided, single submitter
Pathogenic
(Oct 1, 2021)
paternalclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedde novoyes1not providednot providednot providednot providedclinical testing, literature only
not providedpaternalyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS): a new syndrome.

Nicolaides P, Appleton RE, Fryer A.

J Med Genet. 1996 May;33(5):419-21.

PubMed [citation]
PMID:
8733056
PMCID:
PMC1050615

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
See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000189408.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (4)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From GeneReviews, SCV000195717.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature onlynot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1de novoyesnot providednot providednot providednot providednot providednot providednot provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001429018.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

This variant was identified as de novo (maternity and paternity confirmed).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1de novoyesnot providednot providednot provided1not providednot providednot provided

From Genomics England Pilot Project,Genomics England, SCV001760451.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV001976671.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

PM1, PM2, PP3, PP5

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1paternalyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 20, 2021

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