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

Total submissions: 17

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	2015-01-06	criteria provided, single submitter	clinical testing	This variant has been previously reported as disease-causing and was found twice in our laboratory as a de novo finding in affected individuals. Once in a 10-month-old female with epilepsy, developmental delay, hypotonia. Once in a 28-year-old femle with hemiplegic cerebral palsy, seizures, scoliosis, GI problems, intellectual disability.
Genetic Services Laboratory,University of Chicago	RCV000030749	SCV000246631	pathogenic	Alternating hemiplegia of childhood 2	2014-10-10	criteria provided, single submitter	clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000413511	SCV000336178	pathogenic	not provided	2015-10-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000413511	SCV000490416	pathogenic	not provided	2018-12-03	criteria provided, single submitter	clinical testing	The D801N variant in the ATP1A3 gene has been reported previously in patients with alternating hemiplegia of childhood (Rosewich et al., 2012; Heinzen et al., 2012; Yang et al., 2014). In all cases in which family studies were performed, the D801N variant was shown to arise de novo. D801N is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D801N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The D801N variant 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). We interpret D801N as a pathogenic variant.
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
Invitae	RCV000644928	SCV000766650	pathogenic	Dystonia 12	2019-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with asparagine at codon 801 of the ATP1A3 protein (p.Asp801Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in multiple individuals affected with alternating hemiplegia of childhood (PMID: 22842232, 22850527, 23409136, 24842602, 24431296). ClinVar contains an entry for this variant (Variation ID: 37107). Experimental studies have shown that this missense change p.Asp801Asn causes reduced ATPase enzyme activity (PMID: 22842232), loss of potassium binding (PMID: 24631656), reduced forward cycling and dominant negativity (PMID: 25681536), and spontaneous recurrent seizures in mice (PMID: 25523819). Multiple missense substitutions at this codon (p.D801E; p.D801V) have been reported in patients with alternating hemiplegia of childhood (PMID: 24100174, PMID: 26410222). This suggests that the aspartic acid residue is critical for ATP1A3 protein function. 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,Klinikum rechts der Isar	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 Praxis fuer Humangenetik Tuebingen	RCV000413511	SCV001247065	pathogenic	not provided	2020-02-01	criteria provided, single submitter	clinical testing
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 Disorders	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.
OMIM	RCV000030749	SCV000053410	pathogenic	Alternating hemiplegia of childhood 2	2014-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000030749	SCV000195709	pathogenic	Alternating hemiplegia of childhood 2	2014-05-04	no assertion criteria provided	literature only
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001004008	SCV001162052	likely pathogenic	Dystonia; Tetraparesis; Oculogyric crisis		no assertion criteria provided	research