ClinVar Miner

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

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000190725 SCV000244166 pathogenic Inborn genetic diseases 2014-08-29 criteria provided, single submitter clinical testing
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 2020-01-28 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 2020-12-15 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect with reduced pump turnover rate and failure to rapidly regain the resting membrane potential following action potentials (Roenn et al., 2019); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28483396, 24431296, 24468074, 20301294, 25056583, 26410222, 26400718, 26453127, 25895915, 27091223, 26795593, 29090527, 29184165, 28708278, 29305691, 29625811, 30409907, 29397530, 29915382, 30904181, 31410291, 31737037, 31942761, 32907636, 32135597, 32576493)
CeGaT Praxis fuer Humangenetik Tuebingen RCV000314245 SCV001247063 pathogenic not provided 2020-03-01 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000144250 SCV001429018 pathogenic Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome 2019-07-15 criteria provided, single submitter clinical testing This variant was identified as de novo (maternity and paternity confirmed).
OMIM RCV000144250 SCV000189408 pathogenic Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome 2014-08-26 no assertion criteria provided literature only
GeneReviews RCV000144250 SCV000195717 pathogenic Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome 2014-05-04 no assertion criteria provided literature only
Genomics England Pilot Project,Genomics England RCV000144250 SCV001760451 pathogenic Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome no assertion criteria provided clinical testing

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