rs387907281

Variant names:

• chr19-41970284-C-T
• rs387907281
• NM_152296.5:c.2443G>A

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV001711936: Independent functional studies have shown that this missense change leads to a reduction in ATP1A3 Na+/K+ ATPase activity." and additional evidence is available in ClinVar. 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
• Publications: 88 publications found

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, G2P
• ATP1A3-associated neurological disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: Illumina, ClinGen
• cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, Genomics England PanelApp
• developmental and epileptic encephalopathy 99

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• dystonia 12

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, Genomics England PanelApp
• 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

ENSG00000285505 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 21 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001711936: Independent functional studies have shown that this missense change leads to a reduction in ATP1A3 Na+/K+ ATPase activity.; SCV000521282: Functional studies indicate E815K significantly reduces enzyme activity compared to the wild-type (Heinzen et al., 2012; Li et al., 2015); SCV003802799: 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).; SCV000544728: Experimental studies have shown that this missense change affects ATP1A3 function (PMID: 25681536).; SCV001360890: "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)."
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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 cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome, alternating hemiplegia of childhood 2, dystonia 12, alternating hemiplegia of childhood, encephalopathy, acute, infection-induced, complex neurodevelopmental disorder, ATP1A3-associated neurological disorder, developmental and epileptic encephalopathy 99.
• 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 VariationId is 37108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152296.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP1A3	NM_152296.5	MANE Select	c.2443G>A	p.Glu815Lys	missense	Exon 18 of 23	NP_689509.1	P13637-1
	ATP1A3	NM_001256214.2		c.2482G>A	p.Glu828Lys	missense	Exon 18 of 23	NP_001243143.1	P13637-3
	ATP1A3	NM_001256213.2		c.2476G>A	p.Glu826Lys	missense	Exon 18 of 23	NP_001243142.1	P13637-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP1A3	ENST00000648268.1	MANE Select	c.2443G>A	p.Glu815Lys	missense	Exon 18 of 23	ENSP00000498113.1	P13637-1
	ENSG00000285505	ENST00000644613.1		n.2443G>A		non_coding_transcript_exon	Exon 18 of 25	ENSP00000494711.1	A0A2R8YEY8
	ATP1A3	ENST00000545399.6	TSL:2	c.2482G>A	p.Glu828Lys	missense	Exon 18 of 23	ENSP00000444688.1	P13637-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	not provided (6)
5	-	-	Alternating hemiplegia of childhood 2 (5)
2	-	-	Dystonia 12 (3)
1	-	-	Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome;C1868681:Dystonia 12;C3553788:Alternating hemiplegia of childhood 2 (1)
1	-	-	Developmental and epileptic encephalopathy 99 (1)
1	-	-	Dyskinesia;C0013421:Dystonic disorder;C0036572:Seizure;C4022738:Neurodevelopmental delay (1)
1	-	-	Hemiplegia;C0085637:Oculogyric crisis;C0557874:Global developmental delay (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	not specified (1)
1	-	-	Seizure (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		7.8
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.94		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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs387907281; hg19: chr19-42474436; COSMIC: COSV57486474;