rs80356533

Positions:

• chr19-41985082-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.829G>A​(p.Glu277Lys) 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP1A3 NM_152296.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 7.79

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 topological_domain Cytoplasmic (size 135) in uniprot entity AT1A3_HUMAN there are 4 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, 0.984
• PP5: Variant 19-41985082-C-T is Pathogenic according to our data. Variant chr19-41985082-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-41985082-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP1A3	NM_152296.5	c.829G>A	p.Glu277Lys	missense_variant	8/23	ENST00000648268.1	NP_689509.1
ATP1A3	NM_001256214.2	c.868G>A	p.Glu290Lys	missense_variant	8/23		NP_001243143.1
ATP1A3	NM_001256213.2	c.862G>A	p.Glu288Lys	missense_variant	8/23		NP_001243142.1
ATP1A3	XM_047438862.1	c.739G>A	p.Glu247Lys	missense_variant	8/23		XP_047294818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP1A3	ENST00000648268.1	c.829G>A	p.Glu277Lys	missense_variant	8/23		NM_152296.5	ENSP00000498113

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dystonia 12 Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 24, 2020	For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect ATP1A3 protein function (PMID: 15260953). This variant has been reported in individuals affected with rapid-onset dystonia-parkinsonism (RDP) as well as in an individual with alternating hemiplegia of childhood (AHC) (PMID: 15260953, 17282997, 20558373, 25439493). ClinVar contains an entry for this variant (Variation ID: 12911). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 277 of the ATP1A3 protein (p.Glu277Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 16, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 10, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jul 01, 2022	This ATP1A3 variant (rs80356533) is absent from a large population dataset and has been reported in ClinVar. It has been reported in the literature in at least four unrelated individuals with DYT12. Three bioinformatic tools queried predict that this substitution would be damaging, and the glutamate residue at this position is strongly evolutionarily conserved across the vertebrate species assessed. p.Glu277Lys showed reduced survival in an in vitro cell viability assay (quabain sensitivity) and reduced protein expression in transiently transfected HEK293T cells. Bioinformatic analysis predicts that this missense variant would not affect normal exon 8 splicing, although this has not been confirmed experimentally to our knowledge. This variant is apparently de novo in this individual. We consider c.829G>A to be pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 18, 2024

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30363590, 25447930, 15260953, 25439493, 17282997, 29396171, 27835968, 30550795, 27577505, 24739246, 26417536, 22067897, 27313535, 31361359, 33451880, 26297560) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D;D;D;.;.;.
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	1.0	.;D;D;D;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Benign	1.3	L;L;.;.;.;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.4	.;D;.;D;D;.
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	.;D;.;D;D;.
Sift4G	Pathogenic	0.0010	.;D;D;D;D;.
Polyphen		1.0	D;D;.;.;.;.
Vest4		0.85, 0.85, 0.85
MutPred		0.94		Gain of methylation at E277 (P = 0.0387);Gain of methylation at E277 (P = 0.0387);.;.;.;.;
MVP		0.99
MPC		2.7
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.95
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: rs80356533; hg19: chr19-42489234; COSMIC: COSV57486736; COSMIC: COSV57486736;