rs1064797245

Positions:

• chr19-41970540-G-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_152296.5(ATP1A3):​c.2266C>T​(p.Arg756Cys) variant causes a missense, splice region 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. 13/21 in silico tools predict a damaging outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. R756H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP1A3 NM_152296.5 missense, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16 O:1
• Conservation: PhyloP100: 8.03

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]

ENSG00000285505 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-41970539-C-T is described in Lovd as [Likely_pathogenic].
• 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, 0.988
• PP5: Variant 19-41970540-G-A is Pathogenic according to our data. Variant chr19-41970540-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 425189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-41970540-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP1A3	NM_152296.5	c.2266C>T	p.Arg756Cys	missense_variant, splice_region_variant	17/23	ENST00000648268.1	NP_689509.1
ATP1A3	NM_001256214.2	c.2305C>T	p.Arg769Cys	missense_variant, splice_region_variant	17/23		NP_001243143.1
ATP1A3	NM_001256213.2	c.2299C>T	p.Arg767Cys	missense_variant, splice_region_variant	17/23		NP_001243142.1
ATP1A3	XM_047438862.1	c.2176C>T	p.Arg726Cys	missense_variant, splice_region_variant	17/23		XP_047294818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP1A3	ENST00000648268.1	c.2266C>T	p.Arg756Cys	missense_variant, splice_region_variant	17/23		NM_152296.5	ENSP00000498113.1
ENSG00000285505	ENST00000644613.1	n.2266C>T		splice_region_variant, non_coding_transcript_exon_variant	17/25			ENSP00000494711.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 29, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 30, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 25, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29396171, 8496742, 27726050, 22842232, 34765691, 34761051, 34975730, 26400718, 24436111, 19652145, 24123283, 23483595, 27091223, 26297560, 25895915, 26410222, 28293679, 16632466, 22534615, 24739246, 24468074, 29184165, 25656163, 15260953, 24996492, 25359261, 22850527, 29397530, 28647130, 27634470, 27268479, 29346770, 29066118, 30862413, 31269555, 31737037, 32637629, 31216405, 31175295) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Dystonia 12 Pathogenic:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 24, 2023	ClinVar contains an entry for this variant (Variation ID: 425189). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 756 of the ATP1A3 protein (p.Arg756Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with rapid onset of ataxia, encephalopathy, dystonia, and weakness following a febrile illness (PMID: 26400718, 27268479, 27634470, 27726050, 29066118, 29397530). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 25, 2022	- -

Alternating hemiplegia of childhood 2 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 15, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jul 15, 2021	ACMG classification criteria: PS4 moderate, PM2 moderate, PM5, PM6 strong, PP1 moderate, PP3 supporting -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2016

- -

ATP1A3-associated neurological disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Oct 10, 2024

Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ATP1A3-associated neurological disorder (MONDO:0700002). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Incomplete penetrance has been observed for the dystonia-12 phenotype, several members of larger families have been reported as having a heterozygous pathogenic variant but no symptoms. (PMID: 20301294). (I) 0115 - Variants in this gene are known to have variable expressivity. ATP1A3-related disorders represent a clinical continuum (PMID: 35945798). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. This variant affects the third nucleotide of exon 17 and is therefore also considered a non-canonical splice site variant. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v4; 1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. This variant is also located in a splice region; however, in silico predictions for abnormal splicing are conflicting. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported nine times as pathogenic and three times as likely pathogenic (ClinVar) and has been reported in thirteen individuals with fever induced paroxysmal encephalopathy and weakness (PMID: 34342181). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 12, 2018

- -

ATP1A3-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 20, 2024

The ATP1A3 c.2305C>T variant is predicted to result in the amino acid substitution p.Arg769Cys. This variant was reported in several individuals with de novo inheritance with ATP1A3-associated disease (Hully et al 2016. PubMed ID: 27726050; Dard et al 2015. PubMed ID: 26400718; Kanemasa et al 2016. PubMed ID: 27634470). An alternate nucleotide change affecting the same amino acid (p.Arg769His), has been reported to be pathogenic (Rosewich et al 2014. PubMed ID: 24523486; Viollet et al 2015. PubMed ID: 25996915; Brashear et al 2012. PubMed ID: 22924536). A hypothesis that changes at this amino acid residue provide a unique phenotype of fever-induced paroxysmal weakness and encephalopathy (FIPWE) has been postulated (Yano et al 2017. PubMed ID: 28647130). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

not provided

Institute of Human Genetics, University Hospital of Duesseldorf

-

- -

Seizure Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Génétique des Maladies du Développement, Hospices Civils de Lyon

Jul 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D;D;T;.;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	5.4	H;H;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.9	.;D;.;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	.;D;.;D;D
Sift4G	Pathogenic	0.0	.;D;D;D;D
Polyphen		1.0	D;D;.;.;.
Vest4		0.95, 0.97, 0.95, 0.95
MutPred		0.91		Gain of catalytic residue at L757 (P = 0.0112);Gain of catalytic residue at L757 (P = 0.0112);.;.;.;
MVP		1.0
MPC		2.8
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.72
gMVP		1.0

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: rs1064797245; hg19: chr19-42474692; COSMIC: COSV105875664;