Submissions for variant NM_152296.5(ATP1A3):c.2267G>A (p.Arg756His) (rs606231435)

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489717	SCV000577376	pathogenic	not provided	2017-12-20	criteria provided, single submitter	clinical testing	The R756H variant in the ATP1A3 gene has previously been reported in patients with ataxia, choreoathetosis, hypotonia, seizures, pectus excavatum, functional respiratory abnormality, and abnormalities of hair pigmentation and texture (Brashear et al., 2012; Fitzgerald et al., 2015). This variant has also been observed as a de novo finding in another individual testted at GeneDx with features of an ATP1A3-related disorder. The R756H variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Although this variant is a conservative amino acid substitution, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in the same residue (R756C) has been reported in an individual with alternating hemiplegia of childhood (Kanemasa et al., 2016), supporting the functional importance of this residue of the protein. We interpret R756H as a pathogenic variant.
TIDEX, University of British Columbia	RCV000148315	SCV000586841	pathogenic	Dystonia 12		criteria provided, single submitter	research
Invitae	RCV000148315	SCV000645400	pathogenic	Dystonia 12	2019-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with histidine at codon 756 of the ATP1A3 protein (p.Arg756His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals and families affected with rapid onset dystonia-parkinsonism (PMID: 28441826, 22924536, 28500446) including one de novo observation (PMID: 24793181). It has also been observed to segregate with alternating hemiplegia in a family (PMID: 25996915). ClinVar contains an entry for this variant (Variation ID: 161134). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Arg756Cys) has been determined to be pathogenic (PMID: 27634470, 26400718, 27268479, 29066118, 29397530, 27726050). This suggests that the arginine residue is critical for ATP1A3 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics,Klinikum rechts der Isar	RCV000578251	SCV000680148	pathogenic	Alternating hemiplegia of childhood 2	2017-09-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000624894	SCV000741248	likely pathogenic	Inborn genetic diseases	2016-02-16	criteria provided, single submitter	clinical testing
Undiagnosed Diseases Network,NIH	RCV000791274	SCV000930561	pathogenic	Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome	2019-03-07	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000578251	SCV000996218	pathogenic	Alternating hemiplegia of childhood 2	2018-11-29	criteria provided, single submitter	clinical testing	This variant has been previously reported as a heterozygous change in multiple patients with neurological presentations consistent with an ATP1A3-related disorder (PMID: 22924536, 28382329, 28500446, 28647130). This variant is commonly referred to in the literature as p.Arg756His due to use of a different reference transcript (NM_152296). It has been reported as a likely pathogenic or pathogenic change by multiple clinical diagnostic laboratories in ClinVar (variant ID: 161134). The c.2306G>A (p.Arg769His) variant is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. It affects a highly conserved amino acid and 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.2306G>A (p.Arg769His) variant is classified as pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000489717	SCV001247066	pathogenic	not provided	2016-11-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000148315	SCV001428565	pathogenic	Dystonia 12	2018-01-30	criteria provided, single submitter	clinical testing
GeneReviews	RCV000148315	SCV000195703	pathogenic	Dystonia 12	2014-05-04	no assertion criteria provided	literature only