chr19-41970482-G-A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_152296.5(ATP1A3):​c.2324C>T​(p.Pro775Leu) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P775T) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

ATP1A3
NM_152296.5 missense

Scores

12
6
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8U:1

Conservation

PhyloP100: 9.88

Publications

6 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 17 ACMG points.

PM1
In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain 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 chr19-41970483-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 520781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
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, 0.931
PP5
Variant 19-41970482-G-A is Pathogenic according to our data. Variant chr19-41970482-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 280121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATP1A3NM_152296.5 linkc.2324C>T p.Pro775Leu missense_variant Exon 17 of 23 ENST00000648268.1 NP_689509.1 P13637-1Q53ES0
ATP1A3NM_001256214.2 linkc.2363C>T p.Pro788Leu missense_variant Exon 17 of 23 NP_001243143.1 P13637-3Q53ES0
ATP1A3NM_001256213.2 linkc.2357C>T p.Pro786Leu missense_variant Exon 17 of 23 NP_001243142.1 P13637-2Q53ES0
ATP1A3XM_047438862.1 linkc.2234C>T p.Pro745Leu missense_variant Exon 17 of 23 XP_047294818.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATP1A3ENST00000648268.1 linkc.2324C>T p.Pro775Leu missense_variant Exon 17 of 23 NM_152296.5 ENSP00000498113.1 P13637-1
ENSG00000285505ENST00000644613.1 linkn.2324C>T non_coding_transcript_exon_variant Exon 17 of 25 ENSP00000494711.1 A0A2R8YEY8

Frequencies

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

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:3Uncertain:1
May 01, 2017
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance:Uncertain significance
Review Status:flagged submission
Collection Method:clinical testing

- -

Sep 23, 2024
GeneDx
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Not 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; Also known as c.2363C>T (p.Pro788Leu); This variant is associated with the following publications: (PMID: 33057194, 37541188, 35012964, 35982159, 37043503, 32684337) -

Jun 01, 2019
CeGaT Center for Human Genetics Tuebingen
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Sep 01, 2021
Genetic Services Laboratory, University of Chicago
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

DNA sequence analysis of the ATP1A3 gene demonstrated a sequence change, c.2324C>T, in exon 17 that results in an amino acid change, p.Pro775Leu. This sequence change is absent in the gnomAD population database. The p.Pro775Leu change has been previously described as a de novo variant in individuals with ATP1A3-related disorders (PMID: 32684337, https://n.neurology.org/content/94/15_Supplement/1946). The p.Pro775Leu change affects a moderately conserved amino acid residue located in a domain of the ATP1A3 protein that is known to be functional. The p.Pro775Leu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, REVEL, CADD). The vast majority of pathogenic variants in the ATP1A3 gene are missense with many located around the p.Pro775 region. In addition, the ATP1A3 gene appears to be relatively intolerant to missense changes. Collectively this evidence suggests p.Pro775Leu is likely pathogenic, however functional studies have not been performed to prove this conclusively. -

Dystonia 12 Pathogenic:2
Nov 16, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 775 of the ATP1A3 protein (p.Pro775Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of ATP1A3-related conditions (PMID: 32684337; Invitae). This variant is also known as c.2363C>T p.Pro788Leu. ClinVar contains an entry for this variant (Variation ID: 280121). 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%. This variant disrupts the p.Pro775 amino acid residue in ATP1A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 33880529). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Jan 01, 2016
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM2,PP2,PP3,PP5. -

Developmental and epileptic encephalopathy 99 Pathogenic:2
Feb 17, 2023
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

PS2, PM1, PM2, PM5, PP3, PP5 -

Oct 24, 2022
Eurofins-Biomnis
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Inborn genetic diseases Pathogenic:1
Dec 03, 2018
Ambry Genetics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Uncertain
0.16
D
BayesDel_noAF
Uncertain
-0.010
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.74
D;D;T;.;.
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.97
.;D;D;D;D
M_CAP
Pathogenic
0.85
D
MetaRNN
Pathogenic
0.93
D;D;D;D;D
MetaSVM
Pathogenic
0.93
D
MutationAssessor
Uncertain
2.1
M;M;.;.;.
PhyloP100
9.9
PrimateAI
Pathogenic
0.90
D
PROVEAN
Pathogenic
-6.8
.;D;.;D;D
REVEL
Pathogenic
0.77
Sift
Pathogenic
0.0
.;D;.;D;D
Sift4G
Pathogenic
0.0010
.;D;D;D;D
Polyphen
1.0
D;D;.;.;.
Vest4
0.88, 0.88, 0.87
MutPred
0.73
Gain of catalytic residue at P775 (P = 0.0684);Gain of catalytic residue at P775 (P = 0.0684);.;.;.;
MVP
0.88
MPC
2.6
ClinPred
1.0
D
GERP RS
3.8
Varity_R
0.70
gMVP
0.99
Mutation Taster
=1/99
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: rs886041396; hg19: chr19-42474634; API