ClinVar Miner

Submissions for variant NM_152296.5(ATP1A3):c.2452G>A (p.Glu818Lys) (rs587777771)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000190725 SCV000244166 uncertain significance Inborn genetic diseases 2014-08-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Genetic Services Laboratory, University of Chicago RCV000195001 SCV000246633 pathogenic Alternating hemiplegia of childhood 2 2015-07-20 criteria provided, single submitter clinical testing
Invitae RCV000234480 SCV000291489 pathogenic Dystonia 12 2018-08-14 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 818 of the ATP1A3 protein (p.Glu818Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome in 5 families (PMID: 24468074, 25056583, 25895915, 26453127). This variant has also been shown to arise de novo in individuals affected with CAPOS syndrome (PMID: 24468074, 25056583). ClinVar contains an entry for this variant (Variation ID: 156238). 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"). In summary, this is a rare variant that has been reported to segregate with disease in several families and to occur de novo in affected individuals. For these reasons, this change has been classified as Pathogenic.
GeneDx RCV000314245 SCV000329953 pathogenic not provided 2017-11-28 criteria provided, single submitter clinical testing The E818K variant in the ATP1A3 gene has been reported previously in association with CAPOS syndrome in multiple families from different ethnic backgrounds where the variant was found to exclusively co-segregate with the disease in multiple affected individuals (Demos et al., 2014; Rosewich et al., 2014; Potic et al., 2015; Heimer et al., 2015; Maas et al., 2016). The E818K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E818K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other 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. We interpret E818K as a pathogenic variant
OMIM RCV000144250 SCV000189408 pathogenic Cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorinural hearing loss 2014-08-26 no assertion criteria provided literature only
GeneReviews RCV000144250 SCV000195717 pathogenic Cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorinural hearing loss 2014-05-04 no assertion criteria provided literature only

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