19-41986202-C-T

Position:

• chr19-41986202-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_152296.5(ATP1A3):​c.385G>A​(p.Val129Met) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP1A3 NM_152296.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 6.14

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]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity AT1A3_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_152296.5
• PM2: Very rare variant in population databases, with high coverage
• 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). GenCC has associacion of 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, 0.865
• PP5: Variant 19-41986202-C-T is Pathogenic according to our data. Variant chr19-41986202-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 267411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP1A3	NM_152296.5	c.385G>A	p.Val129Met	missense_variant	5/23	ENST00000648268.1	NP_689509.1
ATP1A3	NM_001256214.2	c.424G>A	p.Val142Met	missense_variant	5/23		NP_001243143.1
ATP1A3	NM_001256213.2	c.418G>A	p.Val140Met	missense_variant	5/23		NP_001243142.1
ATP1A3	XM_047438862.1	c.295G>A	p.Val99Met	missense_variant	5/23		XP_047294818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP1A3	ENST00000648268.1	c.385G>A	p.Val129Met	missense_variant	5/23		NM_152296.5	ENSP00000498113

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alternating hemiplegia of childhood 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Dec 20, 2022

PS2, PM2, PP2, PP3 -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 02, 2022

Reported previously as a de novo variant in a patient with neonatal hypotonia, pervasive developmental disorder, episodes of stiffness when sleeping, severe-injurious behaviors, and childhood-onset schizophrenia (Smedemark-Margulies et al., 2016); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27626066) -

ATP1A3-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 25, 2024

The ATP1A3 c.424G>A variant is predicted to result in the amino acid substitution p.Val142Met. This variant is referred to as NM_152296:c.385G>A (p.Val129Met) when reported off of a different transcript. This variant has been reported with de novo occurrence in two individuals, one with childhood-onset schizophrenia (Smedemark-Margulies et al. 2016. PubMed ID: 27626066) and another with an undefined ATP1A3-related phenotype (Vezyroglou et al. 2022. PubMed ID: 36192182). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Juvenile onset psychosis Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Gene Discovery Core-Manton Center, Boston Children's Hospital

Apr 11, 2016

de novo -

Dystonia 12 Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;D;D;.;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Uncertain	2.0	M;M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.4	.;N;.;N;N;.
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	.;D;.;D;D;.
Sift4G	Pathogenic	0.0	.;D;D;D;D;.
Polyphen		1.0	D;D;.;.;.;.
Vest4		0.67, 0.86, 0.67, 0.67
MutPred		0.66		Loss of catalytic residue at V129 (P = 0.0432);Loss of catalytic residue at V129 (P = 0.0432);.;.;.;.;
MVP		0.85
MPC		2.6
ClinPred		0.98	D
GERP RS		3.6
Varity_R		0.79
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs1555865401; hg19: chr19-42490354;