19-41978041-G-A

Position:

• chr19-41978041-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_152296.5(ATP1A3):​c.1838C>T​(p.Thr613Met) 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. 13/21 in silico tools predict a damaging 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:10 O:1
• Conservation: PhyloP100: 9.97

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 15 ACMG points.

• 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, 0.987
• PP5: Variant 19-41978041-G-A is Pathogenic according to our data. Variant chr19-41978041-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 12909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-41978041-G-A is described in UniProt as null. Variant chr19-41978041-G-A is described in UniProt as null. Variant chr19-41978041-G-A is described in UniProt as null. Variant chr19-41978041-G-A is described in UniProt as null. Variant chr19-41978041-G-A is described in UniProt as null. Variant chr19-41978041-G-A is described in UniProt as null. Variant chr19-41978041-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.1838C>T	p.Thr613Met	missense_variant	14/23	ENST00000648268.1	NP_689509.1
ATP1A3	NM_001256214.2	c.1877C>T	p.Thr626Met	missense_variant	14/23		NP_001243143.1
ATP1A3	NM_001256213.2	c.1871C>T	p.Thr624Met	missense_variant	14/23		NP_001243142.1
ATP1A3	XM_047438862.1	c.1748C>T	p.Thr583Met	missense_variant	14/23		XP_047294818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP1A3	ENST00000648268.1	c.1838C>T	p.Thr613Met	missense_variant	14/23		NM_152296.5	ENSP00000498113.1
ENSG00000285505	ENST00000644613.1	n.1838C>T		non_coding_transcript_exon_variant	14/25			ENSP00000494711.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dystonia 12 Pathogenic:7 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Apr 27, 2018	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Feb 01, 2021	- -
Pathogenic, criteria provided, single submitter	not provided	Institute of Human Genetics, University Hospital of Duesseldorf	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 613 of the ATP1A3 protein (p.Thr613Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with rapid onset dystonia parkinsonism (RDP) (PMID: 15260953, 17282997, 17516473, 22534615, 24523486). 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. ClinVar contains an entry for this variant (Variation ID: 12909). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ATP1A3 function (PMID: 15260953). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Jan 28, 2020	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 03, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2022	Functional studies indicate that T613M interferes with hydrogen bonding near the catalytic site (Rodacker et al., 2006, de Carvalho Aguiar et al., 2004).; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11061257, 17595045, 22850527, 24842602, 15390049, 15260953, 12112218, 29801903, 24523486, 17516473, 30097153, 31061839, 31361359, 33326973, 32653672, Post2009[Article], 17282997, 22534615, 16632466) -

Alternating hemiplegia of childhood 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Génétique des Maladies du Développement, Hospices Civils de Lyon

Aug 10, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D;D;T;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	H;H;.;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.5	.;D;.;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	.;D;.;D;D
Sift4G	Pathogenic	0.0	.;D;D;D;D
Polyphen		1.0	D;D;.;.;.
Vest4		0.97, 0.98, 0.97, 0.97
MutPred		0.93		Loss of catalytic residue at T613 (P = 0.0331);Loss of catalytic residue at T613 (P = 0.0331);.;.;.;
MVP		0.99
MPC		2.6
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.63
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs80356534; hg19: chr19-42482193; COSMIC: COSV57484685;