Submissions for variant NM_152296.5(ATP1A3):c.2116G>A (p.Gly706Arg)

dbSNP: rs782175860

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413243	SCV000491306	pathogenic	not provided	2022-01-11	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24842602, 31785789, 28901192, 33868146, 34356170, 34014491, 27726050, 33177352)
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000853257	SCV000996078	pathogenic	Alternating hemiplegia of childhood 2	2017-10-10	criteria provided, single submitter	clinical testing	This variant was previously identified as pathogenic in two unrelated families with children diagnosed with AHC (PMID: 24842602, 27726050). There is one report of the variant as pathogenic in ClinVar submitted by GeneDx, and the variant is absent from control populations. The ATP1A3 gene is highly intolerant to missense variants and the p.Gly719 residue is highly conserved among eukaryotes. In silico algorithms predict the arginine substitution to have a damaging effect on protein function. No functional characterization of the variant has been performed. Based on the available evidence, the variant is classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001387923	SCV001588680	pathogenic	Dystonia 12	2023-11-11	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 706 of the ATP1A3 protein (p.Gly706Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ATP1A3-related conditions (PMID: 24842602, 27726050, 28901192). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 372799). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.
MGZ Medical Genetics Center	RCV000853257	SCV002581891	likely pathogenic	Alternating hemiplegia of childhood 2	2022-09-05	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV002510573	SCV002820296	likely pathogenic	Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome		criteria provided, single submitter	clinical testing	The missense variant p.G706R in ATP1A3 (NM_152296.5) has been previously reported as a de novo mutation in patient with alternating hemiplegia of childhood (Yang et al, 2014). It has been submitted to the ClinVar database as Pathogenic. The p.G706R variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.G706R missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glycine residue at codon 706 of ATP1A3 is conserved in all mammalian species. The nucleotide c.2116 in ATP1A3 is predicted to be conserved by GERP++ and PhyloP across 100 vertebrates. Hence the above variant is classified as Likely Pathogenic as currently variant is being evaluated by proband solo exome.
Human Genetics Section, Sidra Medicine	RCV000853257	SCV004708156	pathogenic	Alternating hemiplegia of childhood 2	2024-02-28	criteria provided, single submitter	research	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 706 of the ATP1A3 protein (p.Gly706Arg). This variant was previously identified as pathogenic in multiple ClinVar entries. The variant is de novo. We classify this variant as pathogenic.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV004017606	SCV004847196	pathogenic	Developmental and epileptic encephalopathy 99	2023-06-29	criteria provided, single submitter	clinical testing