rs387907281

Positions:

• chr19-41970284-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_152296.5(ATP1A3):​c.2443G>A​(p.Glu815Lys) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. E815E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP1A3 NM_152296.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:20 O:1
• Conservation: PhyloP100: 7.81

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 17 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain 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, 0.992
• PP5: Variant 19-41970284-C-T is Pathogenic according to our data. Variant chr19-41970284-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 37108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-41970284-C-T is described in Lovd as [Pathogenic]. Variant chr19-41970284-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP1A3	NM_152296.5	c.2443G>A	p.Glu815Lys	missense_variant	18/23	ENST00000648268.1
ATP1A3	NM_001256214.2	c.2482G>A	p.Glu828Lys	missense_variant	18/23
ATP1A3	NM_001256213.2	c.2476G>A	p.Glu826Lys	missense_variant	18/23
ATP1A3	XM_047438862.1	c.2353G>A	p.Glu785Lys	missense_variant	18/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP1A3	ENST00000648268.1	c.2443G>A	p.Glu815Lys	missense_variant	18/23		NM_152296.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 07, 2022	The ATP1A3 c.2443G>A (p.Glu815Lys) missense variant results in the substitution of glutamic acid at amino acid position 815 with lysine. Across a selection of the available literature, the c.2443G>A variant has been identified in a de novo state in 15-20% of individuals with ATP1A3-related neurologic disorders (PMID:20301294; PMID: 23409136; PMID: 26410222). Individuals with the c.2443G>A variant tend to have an earlier age of onset of the first paroxysmal manifestation and first hemiplegic event, with frequent neonatal cases, frequent but short duration plegic attacks, less frequent dystonic attacks with a relatively short duration, abnormal ocular movements, severe cognitive disability with moderate to severe intellectual disability, moderate or severe language problems, motor disability, movement disorders, epilepsy and status epilepticus (PMID: 26410222). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. The Glu815 residue is located at the intracellular end between the sixth and the seventh transmembrane domains. A knock-in mouse model expressing the E815K variant of the Atp1a3 gene (Atp1a3 E815K+/-, Matoub, Matb+/-), manifests clinical and neurophysiological features of the most severe form of alternating hemiplegia of childhood (AHC), including poor motor initiative, deeply impaired motor performance, and spontaneous and stress induced hemiplegia and dystonia episodes (PMID: 30071271). Based on the available evidence, the c.2443G>A (p.Glu815Lys) variant is classified as pathogenic for ATP1A3-related neurologic disorders. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jun 28, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 2022	Functional studies indicate E815K significantly reduces enzyme activity compared to the wild-type (Heinzen et al., 2012; Li et al., 2015); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Missense variants in nearby residues reported in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 29396171, 28637637, 24842602, 35253165, 24631656, 22842232, 23409136, 22850527, 25681536, 30071271, 28138908, 31164858, 29895895, 31959558, 33082768, 33619735, 32653672, 33726816, 33126486, 31175295, 33098801, 33287870, 31069529, 35701389, 34231463) -

Alternating hemiplegia of childhood 2 Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Feb 05, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Dec 10, 2021	PS3, PS4, PP2, PP3, PM1, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	May 06, 2021	This variant in the ATP1A3 gene is absent from a large population database and has an entry in ClinVar. It has been reported as a de novo variant in multiple unrelated individuals with alternating hemiplegia of childhood. Individuals with this variant demonstrate an earlier age of onset, more severe motor impairment and a higher prevalence of status epilepticus. Three bioinformatic tools queried predict that this substitution would be damaging, and the glutamate residue at this position is strongly conserved across the vertebrate species assessed. Independent functional studies have shown that this missense change leads to a reduction in ATP1A3 Na+/K+ ATPase activity. We consider this variant to be pathogenic. -

Dystonia 12 Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 28, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ATP1A3 function (PMID: 25681536). 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. ClinVar contains an entry for this variant (Variation ID: 37108). This missense change has been observed in individual(s) with epilepsy, motor function deficits, cognitive impairment, and respiratory failure (PMID: 22842232, 22850527, 23409136, 24631656). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 815 of the ATP1A3 protein (p.Glu815Lys). -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 18, 2018	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Developmental and epileptic encephalopathy 99 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	The variant has been previously reported as de novo in a similarly affected individual (PMID: 24842602, PS2_S). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000037108, PMID:22850527, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.941, 3CNET: 0.982, PP3_P). A missense variant is a common mechanism associated with Developmental and epileptic encephalopathy 99 (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 30, 2023	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 01, 2019

Variant summary: ATP1A3 c.2443G>A (p.Glu815Lys) results in a conservative amino acid change located in the Cation-transporting P-type ATPase, C-terminal domain (IPR006068) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251402 control chromosomes (gnomAD). c.2443G>A has been reported in the literature in multiple individuals affected with alternating hemiplegia of childhood (AHC) (e.g. Heinzen_2012, Ishii_2013, Rosewich_2012). In most of these individuals, this variant was seen as a de novo mutation and was associated with the severe form of the disease. Heinzen et al and Ishii et al suggest that the recurrence of de novo mutation could be due to its location in hypermutable GC-rich sequences of ATP1A3 (Heinzen_2012, Ishii_2013). These data indicate that the variant is very likely to be associated with disease. In functional studies, the variant was found to have reduced Na+/K+ ATPase activity, loss of forward cycling, proton transport and phosphorylation (Heinzen_2012, Li_2015, and Weigand_2014). Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Hemiplegia;C0085637:Oculogyric crisis;C0557874:Global developmental delay Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2018

- -

Dyskinesia;C0013421:Dystonic disorder;C0036572:Seizure;C4022738:Neurodevelopmental delay Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Jun 17, 2021

- -

Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome;C1868681:Dystonia 12;C3553788:Alternating hemiplegia of childhood 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Seizure Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Génétique des Maladies du Développement, Hospices Civils de Lyon

Jan 16, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;D;D;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;D;D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	H;H;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-2.9	.;D;.;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	.;D;.;D;D
Sift4G	Pathogenic	0.0010	.;D;D;D;D
Polyphen		1.0	D;D;.;.;.
Vest4		0.96, 0.98, 0.97
MutPred		0.94		Gain of methylation at E815 (P = 0.0124);Gain of methylation at E815 (P = 0.0124);.;.;.;
MVP		0.99
MPC		2.6
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.92
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs387907281; hg19: chr19-42474436; COSMIC: COSV57486474;