The ATP1A3 gene is located on chromosome 19 at 19q13.2 and encodes the ATPase Na+/K+ Transporting Subunit Alpha 3. ATP1A3 was first reported in relation to autosomal dominant ATP1A3-related neurologic disorders in 2004 (Carvalho Aguiar et al., PMID:15260953). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s), inheritance pattern, and/or phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity, alternating hemiplegia of childhood 2 (OMIM:614820), CAPOS syndrome (OMIM:601338), developmental and epileptic encephalopathy 99 (OMIM:619606), and dystonia 12 (OMIM: 128235). 8 variants (including 7 missense and 1 in-frame indel) have been reported in 9 probands in 3 publications (Heinzen et al., 2012, PMID: 22842232; Marzin et al., 2018, PMID: 29861155; Miyatake et al., 2021, PMID: 33762331) and are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The genotype-phenotype correlation is not fully understood. Differences in ATPase activity, protein trafficking and interaction with beta subunit are thought to contribute to the wide range of pathogenicity of de novo ATP1A3 variants (PMID: 31425744). This gene-disease relationship is also supported by animal models, expression studies, and functional alteration (Arystarkhova et al., 2019, PMID: 31425744; Battle et al., 2017, PMID: 29022597; Sugimoto et al., 2014, PMID: 24983657; Helseth et al., 2018, PMID: 30071271). In summary, ATP1A3 is definitively associated with autosomal dominant ATP1A3-associated neurological disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date 07.16.2021 (SOP Version 8).
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