rs387907282

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1PM2PP2PP3_StrongPP5_Moderate

The NM_152296.5(ATP1A3):​c.2431T>C​(p.Ser811Pro) variant causes a missense change. 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

Scores

11
7
1

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 6.06

Publications

16 publications found
Variant links:
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]
ATP1A3 Gene-Disease associations (from GenCC):
  • alternating hemiplegia of childhood 2
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • ATP1A3-associated neurological disorder
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Illumina
  • cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
  • developmental and epileptic encephalopathy 99
    Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
  • dystonia 12
    Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
  • encephalopathy, acute, infection-induced
    Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
  • alternating hemiplegia of childhood
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • complex neurodevelopmental disorder
    Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM1
In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_152296.5
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the ATP1A3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 110 curated pathogenic missense variants (we use a threshold of 10). The gene has 22 curated benign missense variants. Gene score misZ: 6.3327 (above the threshold of 3.09). Trascript score misZ: 9.1232 (above the threshold of 3.09). GenCC associations: The gene is linked to alternating hemiplegia of childhood 2, developmental and epileptic encephalopathy 99, ATP1A3-associated neurological disorder, cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome, dystonia 12, alternating hemiplegia of childhood, encephalopathy, acute, infection-induced, complex neurodevelopmental disorder.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.974
PP5
Variant 19-41970296-A-G is Pathogenic according to our data. Variant chr19-41970296-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 37109.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATP1A3NM_152296.5 linkc.2431T>C p.Ser811Pro missense_variant Exon 18 of 23 ENST00000648268.1 NP_689509.1 P13637-1Q53ES0
ATP1A3NM_001256214.2 linkc.2470T>C p.Ser824Pro missense_variant Exon 18 of 23 NP_001243143.1 P13637-3Q53ES0
ATP1A3NM_001256213.2 linkc.2464T>C p.Ser822Pro missense_variant Exon 18 of 23 NP_001243142.1 P13637-2Q53ES0
ATP1A3XM_047438862.1 linkc.2341T>C p.Ser781Pro missense_variant Exon 18 of 23 XP_047294818.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATP1A3ENST00000648268.1 linkc.2431T>C p.Ser811Pro missense_variant Exon 18 of 23 NM_152296.5 ENSP00000498113.1 P13637-1
ENSG00000285505ENST00000644613.1 linkn.2431T>C non_coding_transcript_exon_variant Exon 18 of 25 ENSP00000494711.1 A0A2R8YEY8

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Alternating hemiplegia of childhood 2 Pathogenic:1
Sep 01, 2012
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Dystonia 12 Pathogenic:1
Oct 03, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 811 of the ATP1A3 protein (p.Ser811Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with alternating hemiplegia of childhood (PMID: 22842232, 26297560, 26410222). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 37109). 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. Experimental studies have shown that this missense change affects ATP1A3 function (PMID: 22842232). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.53
D
BayesDel_noAF
Pathogenic
0.53
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.90
D;D;D;.;.
Eigen
Pathogenic
0.75
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.96
.;D;D;D;D
M_CAP
Pathogenic
0.94
D
MetaRNN
Pathogenic
0.97
D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.3
H;H;.;.;.
PhyloP100
6.1
PrimateAI
Pathogenic
0.89
D
PROVEAN
Uncertain
-3.4
.;D;.;D;D
REVEL
Pathogenic
0.96
Sift
Uncertain
0.0010
.;D;.;D;D
Sift4G
Uncertain
0.0020
.;D;D;D;D
Polyphen
0.99
D;D;.;.;.
Vest4
0.96, 0.98, 0.96
MutPred
0.85
Loss of loop (P = 0.0804);Loss of loop (P = 0.0804);.;.;.;
MVP
1.0
MPC
2.8
ClinPred
1.0
D
GERP RS
3.7
Varity_R
0.94
gMVP
1.0
Mutation Taster
=0/100
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs387907282; hg19: chr19-42474448; API