19-41967744-C-T

Variant names:

• chr19-41967744-C-T
• rs398122887
• NM_152296.5:c.2839G>A

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_152296.5(ATP1A3):​c.2839G>A​(p.Gly947Arg) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G947W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP1A3 NM_152296.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 7.90
• Publications: 55 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: 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

ENSG00000285505 (HGNC:):

ACMG classification

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

• PS1: Transcript NM_152296.5 (ATP1A3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-41967744-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 689735.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, 0.975
• PP5: Variant 19-41967744-C-T is Pathogenic according to our data. Variant chr19-41967744-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 37110.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
ATP1A3	NM_152296.5	c.2839G>A	p.Gly947Arg	missense_variant	Exon 21 of 23	ENST00000648268.1	NP_689509.1
ATP1A3	NM_001256214.2	c.2878G>A	p.Gly960Arg	missense_variant	Exon 21 of 23		NP_001243143.1
ATP1A3	NM_001256213.2	c.2872G>A	p.Gly958Arg	missense_variant	Exon 21 of 23		NP_001243142.1
ATP1A3	XM_047438862.1	c.2749G>A	p.Gly917Arg	missense_variant	Exon 21 of 23		XP_047294818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP1A3	ENST00000648268.1	c.2839G>A	p.Gly947Arg	missense_variant	Exon 21 of 23		NM_152296.5	ENSP00000498113.1
ENSG00000285505	ENST00000644613.1	n.2839G>A		non_coding_transcript_exon_variant	Exon 21 of 25			ENSP00000494711.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alternating hemiplegia of childhood 2 Pathogenic:5

Jan 03, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant has been observed in multiple (>3) similarly affected unrelated individuals and one of them was confirmed as de novo (PMID: 24842602, PS2_S, PS4_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000280178,VCV000689735, PMID:30283815, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.969, 3CNET: 0.921, PP3_P). A missense variant is a common mechanism associated with Alternating hemiplegia of childhood 2 (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. -

Jan 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 18, 2018

Genetics Laboratory, Instituto de Ciencias en Reproduccion Humana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant c.2839G>A (p.Gly947Arg) has been reported in patients with alternating hemiplegia of childhood: Heizen et al., Nat Genet. 2012;44(9):1030-4. Rosewich H et al. Neurology. 2014;82(11):945-55 and others. The classification according to ACMG 2015 criteria is pathogenic supported by PS1, PM1, PM2, PM6. -

Feb 04, 2020

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant c.2839G>A (p.Gly947Arg)in ATP1A3 gene has been reported in heterozygous state in many individuals affected with alternating hemiplegia of childhood (AHC); in many cases it was shown to arise de novo (Trump, Natalie et al., 2016). Experimental studies have shown that this missense change leads to a reduction in the ATPase activity of the Na+, K+-ATPase α3 subunit encoded by the ATP1A3 gene (Weigand KM et al., 2014). The p.Gly947Arg variant is novel (not in any individuals) in gnomAD exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. The amino acid Gly at position 947 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Gly947Arg in ATP1A3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Dystonia 12 Pathogenic:2 Other:1

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 947 of the ATP1A3 protein (p.Gly947Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with alternating hemiplegia of childhood (AHC) (PMID: 22842232, 24100174, 24523486, 24842602, 24996492, 25447930, 25996915, 26410222, 26993267). In at least one individual the variant was observed to be de novo. It is commonly reported in individuals of European ancestry (PMID: 25447930). ClinVar contains an entry for this variant (Variation ID: 37110). 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%. Experimental studies have shown that this missense change affects ATP1A3 function (PMID: 24631656, 25681536). For these reasons, this variant has been classified as Pathogenic. -

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not provided Pathogenic:1

Feb 26, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect compared to wild-type ATP1A3, the G947R substitution results in absent phosphorylation capacity, ouabain binding and ATPase activity, consistent with complete loss of ATP1A3 function (PMID: 25681536, 32653672); 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; This variant is associated with the following publications: (PMID: 26993267, 28214164, 31164858, 30657467, 30891744, 31061839, 32627437, 33996181, 31069529, 24631656, 25681536, 29567111, 25996915, 24996492, 36484864, 26410222, 32653672, 36192182, 24523486, 24100174, 22842232) -

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

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ATP1A3-related disorder Pathogenic:1

Nov 10, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATP1A3 c.2878G>A variant is predicted to result in the amino acid substitution p.Gly960Arg. This variant, also known as c.2839G>A (p.Gly947Arg) in the literature, has been reported with de novo occurrence in many individuals with alternating hemiplegia of childhood (Heinzen et al. 2012. PubMed ID: 22842232; Delorme et al. 2017. PubMed ID: 28214164; Galaz-Montoya et al. 2019. PubMed ID: 30657467; Demos et al. 2019. PubMed ID: 31164858). This variant is absent from a large population database (https://gnomad.broadinstitute.org/), indicating it is rare. This variant is interpreted as pathogenic. -

Epilepsy;C0018991:Hemiplegia Pathogenic:1

Jun 14, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;D;D;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H;H;.;.;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-4.3	.;D;.;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	.;D;.;D;D
Sift4G	Pathogenic	0.0010	.;D;D;D;D
Polyphen		1.0	D;D;.;.;.
Vest4		0.98, 1.0, 0.98
MutPred		0.87		Gain of helix (P = 0.0496);Gain of helix (P = 0.0496);.;.;.;
MVP		0.98
MPC		2.8
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.95
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs398122887; hg19: chr19-42471896; COSMIC: COSV57484694;