Submissions for variant NM_152296.5(ATP1A3):c.2267G>A (p.Arg756His)

dbSNP: rs606231435

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489717	SCV000577376	pathogenic	not provided	2024-06-08	criteria provided, single submitter	clinical testing	Reported in patients with fever-triggered paroxysmal encephalopathy and weakness (PMID: 22924536, 25533962, 28647130); Published functional studies demonstrate impairment of protein folding and temperature instability (PMID: 36462665); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36703223, 36484864, 33057194, 36339296, 35982159, 24793181, 29396171, 25533962, 28382329, 28500446, 28647130, 30862413, 31269555, 31959558, 28348125, 32637629, 32466254, 34342181, 30542205, 31031587, 35047275, 22924536, 24523486, 28441826, 25996915, 38685976, 36462665)
TIDEX, University of British Columbia	RCV000148315	SCV000586841	pathogenic	Dystonia 12		criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000148315	SCV000645400	pathogenic	Dystonia 12	2023-08-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg756 amino acid residue in ATP1A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26400718, 27268479, 27634470, 27726050, 29066118, 29397530). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 161134). This missense change has been observed in individual(s) with rapid onset dystonia-parkinsonism (PMID: 22924536, 24793181, 25996915, 28441826, 28500446). 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. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 756 of the ATP1A3 protein (p.Arg756His).
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000578251	SCV000680148	pathogenic	Alternating hemiplegia of childhood 2	2017-09-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000624894	SCV000741248	likely pathogenic	Inborn genetic diseases	2016-02-16	criteria provided, single submitter	clinical testing
Undiagnosed Diseases Network, NIH	RCV000791274	SCV000930561	pathogenic	Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome	2019-03-07	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000578251	SCV000996218	pathogenic	Alternating hemiplegia of childhood 2	2018-11-29	criteria provided, single submitter	clinical testing	This variant has been previously reported as a heterozygous change in multiple patients with neurological presentations consistent with an ATP1A3-related disorder (PMID: 22924536, 28382329, 28500446, 28647130). This variant is commonly referred to in the literature as p.Arg756His due to use of a different reference transcript (NM_152296). It has been reported as a likely pathogenic or pathogenic change by multiple clinical diagnostic laboratories in ClinVar (variant ID: 161134). The c.2306G>A (p.Arg769His) variant is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. It affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.2306G>A (p.Arg769His) variant is classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000489717	SCV001247066	pathogenic	not provided	2023-09-01	criteria provided, single submitter	clinical testing	ATP1A3: PS2, PM2, PS4:Moderate, PP2, PP3
Institute of Human Genetics, University of Leipzig Medical Center	RCV000148315	SCV001428565	pathogenic	Dystonia 12	2018-01-30	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001731483	SCV001984656	pathogenic	not specified	2020-07-27	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000489717	SCV002009787	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002272140	SCV002557783	pathogenic	ATP1A3-associated neurological disorder	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, 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) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic and likely pathogenic, and has been commonly observed as de novo in individuals with rapid onset dystonia-parkinsonism, alternating hemiplegia or fever-triggered paroxysmal encephalopathy and weakness (ClinVar, DECIPHER, PMID: 34342181, PMID: 35047275). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Revvity Omics, Revvity	RCV000489717	SCV003826977	likely pathogenic	not provided	2021-11-17	criteria provided, single submitter	clinical testing
3billion	RCV000148315	SCV003841495	pathogenic	Dystonia 12	2023-02-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000161134 / PMID: 22924536) and different missense changes at the same codon (p.Arg756Cys, p.Arg756Leu, p.Arg756Ser / ClinVar ID: VCV000425189, VCV001705555 / PMID: 27634470, 28647130 / 3billion dataset) have been reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000489717	SCV005199635	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
GeneReviews	RCV000148315	SCV000195703	not provided	Dystonia 12		no assertion provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000489717	SCV001744204	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000489717	SCV001956915	pathogenic	not provided		no assertion criteria provided	clinical testing