Submissions for variant NM_152296.5(ATP1A3):c.2266C>T (p.Arg756Cys)

dbSNP: rs1064797245

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000488196	SCV000575190	likely pathogenic	not provided	2016-09-30	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000501825	SCV000593519	likely pathogenic	Alternating hemiplegia of childhood 2	2016-06-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000624914	SCV000741354	pathogenic	Inborn genetic diseases	2016-02-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000692668	SCV000820504	pathogenic	Dystonia 12	2023-09-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 756 of the ATP1A3 protein (p.Arg756Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with rapid onset of ataxia, encephalopathy, dystonia, and weakness following a febrile illness (PMID: 26400718, 27268479, 27634470, 27726050, 29066118, 29397530). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 425189). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000850500	SCV000992700	likely pathogenic	Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome; Dystonia 12; Alternating hemiplegia of childhood 2	2018-10-12	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000488196	SCV001446978	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000488196	SCV001793155	pathogenic	not provided	2023-05-25	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29396171, 8496742, 27726050, 22842232, 34765691, 34761051, 34975730, 26400718, 24436111, 19652145, 24123283, 23483595, 27091223, 26297560, 25895915, 26410222, 28293679, 16632466, 22534615, 24739246, 24468074, 29184165, 25656163, 15260953, 24996492, 25359261, 22850527, 29397530, 28647130, 27634470, 27268479, 29346770, 29066118, 30862413, 31269555, 31737037, 32637629, 31216405, 31175295)
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000501825	SCV002512690	pathogenic	Alternating hemiplegia of childhood 2	2021-07-15	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4 moderate, PM2 moderate, PM5, PM6 strong, PP1 moderate, PP3 supporting
Revvity Omics, Revvity	RCV000488196	SCV003811134	pathogenic	not provided	2022-03-29	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000692668	SCV003836469	pathogenic	Dystonia 12	2022-03-25	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital of Duesseldorf	RCV003335375	SCV004046815	pathogenic	Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome		criteria provided, single submitter	not provided
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV004586737	SCV005073728	pathogenic	Seizure	2024-07-01	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004787793	SCV005398258	pathogenic	ATP1A3-associated neurological disorder	2024-10-10	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ATP1A3-associated neurological disorder (MONDO:0700002). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Incomplete penetrance has been observed for the dystonia-12 phenotype, several members of larger families have been reported as having a heterozygous pathogenic variant but no symptoms. (PMID: 20301294). (I) 0115 - Variants in this gene are known to have variable expressivity. ATP1A3-related disorders represent a clinical continuum (PMID: 35945798). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. This variant affects the third nucleotide of exon 17 and is therefore also considered a non-canonical splice site variant. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v4; 1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. This variant is also located in a splice region; however, in silico predictions for abnormal splicing are conflicting. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported nine times as pathogenic and three times as likely pathogenic (ClinVar) and has been reported in thirteen individuals with fever induced paroxysmal encephalopathy and weakness (PMID: 34342181). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000488196	SCV001739883	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000488196	SCV001952062	pathogenic	not provided		no assertion criteria provided	clinical testing
GeneReviews	RCV000692668	SCV002559236	not provided	Dystonia 12		no assertion provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004737556	SCV005361779	pathogenic	ATP1A3-related disorder	2024-03-20	no assertion criteria provided	clinical testing	The ATP1A3 c.2305C>T variant is predicted to result in the amino acid substitution p.Arg769Cys. This variant was reported in several individuals with de novo inheritance with ATP1A3-associated disease (Hully et al 2016. PubMed ID: 27726050; Dard et al 2015. PubMed ID: 26400718; Kanemasa et al 2016. PubMed ID: 27634470). An alternate nucleotide change affecting the same amino acid (p.Arg769His), has been reported to be pathogenic (Rosewich et al 2014. PubMed ID: 24523486; Viollet et al 2015. PubMed ID: 25996915; Brashear et al 2012. PubMed ID: 22924536). A hypothesis that changes at this amino acid residue provide a unique phenotype of fever-induced paroxysmal weakness and encephalopathy (FIPWE) has been postulated (Yano et al 2017. PubMed ID: 28647130). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.