rs80356533
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_152296.5(ATP1A3):c.829G>A(p.Glu277Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
ATP1A3
NM_152296.5 missense
NM_152296.5 missense
Scores
8
4
2
Clinical Significance
Conservation
PhyloP100: 7.79
Genes affected
ATP1A3 (HGNC:801): (ATPase Na+/K+ transporting subunit alpha 3) The protein encoded by this gene belongs to the family of P-type cation transport ATPases, and to the subfamily of Na+/K+ -ATPases. Na+/K+ -ATPase is an integral membrane protein responsible for establishing and maintaining the electrochemical gradients of Na and K ions across the plasma membrane. These gradients are essential for osmoregulation, for sodium-coupled transport of a variety of organic and inorganic molecules, and for electrical excitability of nerve and muscle. This enzyme is composed of two subunits, a large catalytic subunit (alpha) and a smaller glycoprotein subunit (beta). The catalytic subunit of Na+/K+ -ATPase is encoded by multiple genes. This gene encodes an alpha 3 subunit. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 17 ACMG points.
PM1
?
In a topological_domain Cytoplasmic (size 135) in uniprot entity AT1A3_HUMAN there are 10 pathogenic changes around while only 2 benign (83%) in NM_152296.5
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, ATP1A3
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.984
PP5
?
Variant 19-41985082-C-T is Pathogenic according to our data. Variant chr19-41985082-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-41985082-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATP1A3 | NM_152296.5 | c.829G>A | p.Glu277Lys | missense_variant | 8/23 | ENST00000648268.1 | |
ATP1A3 | NM_001256214.2 | c.868G>A | p.Glu290Lys | missense_variant | 8/23 | ||
ATP1A3 | NM_001256213.2 | c.862G>A | p.Glu288Lys | missense_variant | 8/23 | ||
ATP1A3 | XM_047438862.1 | c.739G>A | p.Glu247Lys | missense_variant | 8/23 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATP1A3 | ENST00000648268.1 | c.829G>A | p.Glu277Lys | missense_variant | 8/23 | NM_152296.5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Dystonia 12 Pathogenic:4Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Jul 01, 2022 | This ATP1A3 variant (rs80356533) is absent from a large population dataset and has been reported in ClinVar. It has been reported in the literature in at least four unrelated individuals with DYT12. Three bioinformatic tools queried predict that this substitution would be damaging, and the glutamate residue at this position is strongly evolutionarily conserved across the vertebrate species assessed. p.Glu277Lys showed reduced survival in an in vitro cell viability assay (quabain sensitivity) and reduced protein expression in transiently transfected HEK293T cells. Bioinformatic analysis predicts that this missense variant would not affect normal exon 8 splicing, although this has not been confirmed experimentally to our knowledge. This variant is apparently de novo in this individual. We consider c.829G>A to be pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 24, 2020 | For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect ATP1A3 protein function (PMID: 15260953). This variant has been reported in individuals affected with rapid-onset dystonia-parkinsonism (RDP) as well as in an individual with alternating hemiplegia of childhood (AHC) (PMID: 15260953, 17282997, 20558373, 25439493). ClinVar contains an entry for this variant (Variation ID: 12911). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 277 of the ATP1A3 protein (p.Glu277Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 10, 2010 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 16, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Pathogenic
D;D;D;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L;.;.;.;.
MutationTaster
Benign
A;A;A
PrimateAI
Pathogenic
D
Polyphen
D;D;.;.;.;.
Vest4
0.85, 0.85, 0.85
MutPred
Gain of methylation at E277 (P = 0.0387);Gain of methylation at E277 (P = 0.0387);.;.;.;.;
MVP
0.99
MPC
2.7
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at