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

dbSNP: rs587777771

Total submissions: 15

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000234480	SCV000291489	pathogenic	Dystonia 12	2024-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 818 of the ATP1A3 protein (p.Glu818Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome (PMID: 24468074, 25056583, 25895915, 26453127). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 156238). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ATP1A3 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000314245	SCV000329953	pathogenic	not provided	2021-12-24	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 (gnomAD); This variant is associated with the following publications: (PMID: 28483396, 24431296, 24468074, 20301294, 25056583, 26410222, 26400718, 26453127, 25895915, 27091223, 26795593, 29090527, 29184165, 29305691, 30409907, 29397530, 29915382, 30904181, 31410291, 31737037, 31942761, 32907636, 32135597, 28708278, 32576493, 29625811)
CeGaT Center for Human Genetics 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).
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000144250	SCV001976671	pathogenic	Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome	2021-10-01	criteria provided, single submitter	clinical testing	PM1, PM2, PP3, PP5
3billion, Medical Genetics	RCV000144250	SCV002521690	pathogenic	Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome	2022-05-22	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000156238). The variant has been previously reported as de novo or assumed (i.e. paternity and maternity not confirmed) de novo in at least two similarly affected unrelated individuals (PMID: 24468074,25895915, 3billion dataset). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID:24468074, 25056583, 25895915, 26453127) and to co-segregate with the disease in at least 5 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID:24468074). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genetics and Molecular Pathology, SA Pathology	RCV000144250	SCV002556419	pathogenic	Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome	2021-05-20	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000314245	SCV003811145	pathogenic	not provided	2021-11-15	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000144250	SCV003841245	pathogenic	Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome	2023-03-16	criteria provided, single submitter	clinical testing
Department of Human Genetics, Hannover Medical School	RCV000144250	SCV005382646	pathogenic	Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome	2024-10-29	criteria provided, single submitter	clinical testing	ACMG: PS3_Supporting, PS4_Moderate, PM1_Supporting, PM2_Supporting, PP1_Strong, PP2, PP3_Strong
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	RCV000234480	SCV000195717	not provided	Dystonia 12		no assertion 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