Submissions for variant NM_152296.5(ATP1A3):c.2401G>A (p.Asp801Asn)

Total submissions: 30

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Courtagen Diagnostics Laboratory, Courtagen Life Sciences	RCV000030749	SCV000236542	pathogenic	Alternating hemiplegia of childhood 2	2015-03-09	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000030749	SCV000245456	pathogenic	Alternating hemiplegia of childhood 2	2022-05-19	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000030749	SCV000246631	pathogenic	Alternating hemiplegia of childhood 2	2014-10-10	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000413511	SCV000336178	pathogenic	not provided	2015-10-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000413511	SCV000490416	pathogenic	not provided	2021-06-02	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect as D801N is suggested to affect the activity of the Na+/K+ ATPase pump and the substitution of an Aspartic acid for an Asparagine at position 801 is predicted to prevent the normal binding of potassium ions (Heinzen et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25662428, 22850527, 28716275, 32339621, 30891744, 31130284, 24631656, 22842232, 23409136, 25523819, 26417536, 27634470, 27312461, 24842602, 29396171, 29895895, 31061839, 31959558, 32280259, 32653672, 32581362, 33996181, 32005694, 33880529, 32913013, 30755392, 33762331, 33126486, 33098801, 27535533)
Fulgent Genetics, Fulgent Genetics	RCV000515424	SCV000611249	pathogenic	Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome; Dystonia 12; Alternating hemiplegia of childhood 2	2017-05-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000624579	SCV000742201	pathogenic	Inborn genetic diseases	2017-04-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000644928	SCV000766650	pathogenic	Dystonia 12	2023-12-10	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 801 of the ATP1A3 protein (p.Asp801Asn). 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 (PMID: 22842232, 22850527, 23409136, 24431296, 24842602). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 37107). 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: 22842232, 24631656, 25523819, 25681536). This variant disrupts the p.D801 amino acid residue in ATP1A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24100174, 26410222). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
SIB Swiss Institute of Bioinformatics	RCV000030749	SCV000803614	pathogenic	Alternating hemiplegia of childhood 2	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Pathogenic, for Alternating hemiplegia of childhood-2, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (PMID:22842232). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => PS4 downgraded in strength to Moderate (PMID:23409136) (PMID:22842232). PS2 => De novo (paternity and maternity confirmed) (PMID:23409136) (PMID:22842232).
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000030749	SCV001149692	pathogenic	Alternating hemiplegia of childhood 2	2018-04-06	criteria provided, single submitter	clinical testing
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV000030749	SCV001164123	pathogenic	Alternating hemiplegia of childhood 2	2016-08-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000413511	SCV001247065	pathogenic	not provided	2024-08-01	criteria provided, single submitter	clinical testing	ATP1A3: PS2:Very Strong, PM1, PM2, PM5, PS4:Moderate, PP2, PP3, PS3:Supporting
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000644928	SCV001366737	pathogenic	Dystonia 12	2019-01-30	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PM5,PP2,PP3.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001265551	SCV001443703	pathogenic	ATP1A3-related disorder	2019-12-28	criteria provided, single submitter	clinical testing	This variant has been previously reported as a de novo heterozygous change in multiple unrelated individuals with alternating hemiplegia of childhood (PMID: 22850527, 22842232, 23409136). Functional studies indicate that this variant exhibits reduced ATPase activity and phosphorylation in cell culture (PMID: 24631656) and manifests behavioral abnormalities, spontaneous recurrent seizures, and paroxysmal motor abnormalities in mouse models (PMID: 25523819). This variant has been reported in the ClinVar database (Variation ID: 37107). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.2440G>A (p.Asp814Asn) variant is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.2440G>A (p.Asp814Asn) variant is classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000413511	SCV001762184	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000413511	SCV002020881	pathogenic	not provided	2023-10-03	criteria provided, single submitter	clinical testing
3billion	RCV000030749	SCV002058470	pathogenic	Alternating hemiplegia of childhood 2	2022-01-03	criteria provided, single submitter	clinical testing	The variant has been previously reported as de novo in a similarly affected individual (PMID: 24842602, PS2_S). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000037107, PMID:22850527, PS1_S). The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 24842602, PS4_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.905, 3CNET: 0.987, 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). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000210383, PMID: 24100174, 32913013, 26410222, 29915382,15260953, PM5_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000030749	SCV002512691	pathogenic	Alternating hemiplegia of childhood 2	2021-06-16	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PS4 moderate, PM2 moderate, PM5 supporting, PM6 strong, PP3 supporting
Wangler Lab, Baylor College of Medicine	RCV000030749	SCV002577663	pathogenic	Alternating hemiplegia of childhood 2		criteria provided, single submitter	clinical testing	This ATP1A3 missense variant at c.2440G>A (p.D814N) was discovered on exome through the Texome Project (R01HG011795). The variant was de novo in the patient (PS2). It has been previously reported in individuals with Alternating hemiplegia of childhood 2 (PMID: 22842232, 22850527, 23409136). It has not been observed in gnomAD (PM2) and is predicted to be deleterious by multiple computational models (CADD: 29.400)(PP3). The evolutionary conservation of this residue is high. We classify this variant as pathogenic.
MGZ Medical Genetics Center	RCV000030749	SCV002579912	pathogenic	Alternating hemiplegia of childhood 2	2022-04-25	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000030749	SCV004101532	pathogenic	Alternating hemiplegia of childhood 2		criteria provided, single submitter	clinical testing	The ATP1A3 c.2401G>A variant has been reported to be de novo in heterozygous state in multiple individuals affected with alternating hemiplegia of childhood 2 (Heinzen et. al., 2012; Ishii et. al., 2013). Experimental studies have shown that this missense change p.Asp801Asn causes reduced ATPase enzyme activity (Heinzen et. al., 2012), loss of potassium binding (Weigand et. al., 2014), reduced forward cycling and dominant negativity (Ishii et. al., 2013) and spontaneous recurrent seizures in mice (Hunanyan et. al., 2015). Multiple missense substitutions at this codon (p.D801E; p.D801V) have also been reported in patients with the same disorder (Hoei-Hansen CE et. al., 2014, Panagiotakaki et. al., 2015). This suggests that the aspartic acid residue is critical for ATP1A3 protein function. The p.Asp801Asn 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 Asp at position 801 is changed to a Asn changing protein sequence and it might alter its composition and physicochemical properties. The amino acid change p.Asp801Asn in ATP1A3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000644928	SCV005049674	pathogenic	Dystonia 12	2024-02-02	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV002281545	SCV005368383	pathogenic	Developmental and epileptic encephalopathy 99	2024-09-30	criteria provided, single submitter	clinical testing	Criteria applied: PS2_VSTR,PS4,PM5_STR,PS3_MOD,PM2,PP2,PP3
OMIM	RCV000030749	SCV000053410	pathogenic	Alternating hemiplegia of childhood 2	2014-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000644928	SCV000195709	not provided	Dystonia 12		no assertion provided	literature only
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001004008	SCV001162052	likely pathogenic	Dystonic disorder; Tetraparesis; Oculogyric crisis		no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000413511	SCV001958430	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000413511	SCV001967311	pathogenic	not provided		no assertion criteria provided	clinical testing
Center of Excellence for Medical Genomics, Chulalongkorn University	RCV002281545	SCV002570068	pathogenic	Developmental and epileptic encephalopathy 99	2002-09-08	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV001265551	SCV004762795	pathogenic	ATP1A3-related disorder	2023-12-08	no assertion criteria provided	clinical testing	The ATP1A3 c.2440G>A variant is predicted to result in the amino acid substitution p.Asp814Asn. Also known as NM_152296.4:c.2401G (p.Asp801Asn), this variant has been reported to occur de novo in multiple individuals with ATP1A3 diseases including alternating hemiplegia of childhood (AHC) (see for examples at Rosewich et al. 2012 PubMed ID: 22850527; Dong et al. 2020. PubMed: 32005694). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.