ClinVar Miner

Submissions for variant NM_152296.5(ATP1A3):c.2689-1G>T

dbSNP: rs2145944794
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 1
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Kids Neuroscience Centre, Sydney Children's Hospitals Network RCV001726499 SCV001571518 likely pathogenic Dystonia 12 criteria provided, single submitter clinical testing mRNA studies confirm the c.2689-1G>T variant induces abnormal splicing of ATP1A3 transcripts in mRNA derived from blood. Two abnormal splicing events: (1) Intron 19 retention (r.2688_2689ins[2688+1_2689-1;g>u]; p.(Thr897Valfs*119)) (2) Use of a cryptic 3’-splice site (r.2689_2700del; p.(Thr897_Gln900del)). Intron 19 retention encodes 118 missense amino acids and a premature termination codon (p.(Thr897Valfs*119)). These transcripts are predicted to be targeted by nonsense-mediated decay (NMD). Any mis-spliced ATP1A3 transcripts that escape NMD encode ATP1A3 protein lacking 352 amino acids from the C-terminus which encodes the ATPase, P-type cation exchange domain. Use of the cryptic 3’-splice site results in an in -frame deletion of 4 amino acids from the ATPase, P -type cation exchange domain (p.(Thr897_Gln900del)). These transcripts are not predicted to be degraded by NMD. Frameshift, nonsense and missense variants in ATP1A3 are commonly reported in ClinVar as pathogenic variants. Therefore, use of the cryptic 3’-splice site and intron 19 retention induced by the c.2689-1G>T variant are consistent with the known pathogenetic mechanism in ATP1A3 related dystonia (OMIM # 128235). Exon 20 is a canonical exon in the predominant ATP1A3 transcripts expressed in blood and brain, therefore splicing outcomes observed in blood-derived mRNA hold relevance to the manifesting tissue (brain).

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.