19-41970488-T-C

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_152296.5(ATP1A3):​c.2318A>G​(p.Asn773Ser) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N773I) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

ATP1A3
NM_152296.5 missense

Scores

6
11
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.92
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1
In a transmembrane_region Helical (size 19) in uniprot entity AT1A3_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_152296.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ATP1A3. . Gene score misZ: 6.3327 (greater than the threshold 3.09). Trascript score misZ: 9.1232 (greater than threshold 3.09). The gene has 110 curated pathogenic missense variants (we use a threshold of 10). The gene has 22 curated benign missense variants. GenCC has associacion of the gene with dystonia 12, alternating hemiplegia of childhood 2, ATP1A3-associated neurological disorder, developmental and epileptic encephalopathy 99, alternating hemiplegia of childhood, cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome, alternating hemiplegia of childhood 1, encephalopathy, acute, infection-induced.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.863
PP5
Variant 19-41970488-T-C is Pathogenic according to our data. Variant chr19-41970488-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 161138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-41970488-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ATP1A3NM_152296.5 linkc.2318A>G p.Asn773Ser missense_variant 17/23 ENST00000648268.1 NP_689509.1 P13637-1Q53ES0
ATP1A3NM_001256214.2 linkc.2357A>G p.Asn786Ser missense_variant 17/23 NP_001243143.1 P13637-3Q53ES0
ATP1A3NM_001256213.2 linkc.2351A>G p.Asn784Ser missense_variant 17/23 NP_001243142.1 P13637-2Q53ES0
ATP1A3XM_047438862.1 linkc.2228A>G p.Asn743Ser missense_variant 17/23 XP_047294818.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ATP1A3ENST00000648268.1 linkc.2318A>G p.Asn773Ser missense_variant 17/23 NM_152296.5 ENSP00000498113.1 P13637-1
ENSG00000285505ENST00000644613.1 linkn.2318A>G non_coding_transcript_exon_variant 17/25 ENSP00000494711.1 A0A2R8YEY8

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Alternating hemiplegia of childhood 2 Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterJan 01, 2019- -
Pathogenic, criteria provided, single submitterclinical testing3billion, Medical GeneticsOct 02, 2021Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000161138.2, PS1_S). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Asn773Ile) has been reported as pathogenic (VCV000161139.1, PM5). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.679, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Dystonia 12 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 11, 2024This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 773 of the ATP1A3 protein (p.Asn773Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ATP1A3-related conditions (PMID: 22842232, 32454213). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 161138). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxMay 20, 2024Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32454213, 35177115, 26417536, 27312461, 24739246, 25447930, 26410222, 27577505, 22842232, 31061839, 31942761) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.81
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.050
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.74
D;D;T;.;.
Eigen
Uncertain
0.40
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.99
.;D;D;D;D
M_CAP
Pathogenic
0.46
D
MetaRNN
Pathogenic
0.86
D;D;D;D;D
MetaSVM
Uncertain
0.61
D
MutationAssessor
Uncertain
2.5
M;M;.;.;.
PrimateAI
Pathogenic
0.83
D
PROVEAN
Uncertain
-3.5
.;D;.;D;D
REVEL
Pathogenic
0.68
Sift
Uncertain
0.0010
.;D;.;D;D
Sift4G
Benign
0.13
.;T;T;T;T
Polyphen
0.57
P;P;.;.;.
Vest4
0.90, 0.95, 0.91, 0.90
MutPred
0.69
Loss of catalytic residue at N773 (P = 0.087);Loss of catalytic residue at N773 (P = 0.087);.;.;.;
MVP
0.97
MPC
1.2
ClinPred
0.98
D
GERP RS
3.8
Varity_R
0.53
gMVP
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.11
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs606231437; hg19: chr19-42474640; API