Submissions for variant NM_004320.6(ATP2A1):c.2322-2A>G

gnomAD frequency: 0.00001  dbSNP: rs1964095605

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001986741	SCV002280002	likely pathogenic	Brody myopathy	2021-05-29	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with ATP2A1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 16 of the ATP2A1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ATP2A1 are known to be pathogenic (PMID: 8841193, 10914677, 23911890).
PreventionGenetics, part of Exact Sciences	RCV003408056	SCV004115748	likely pathogenic	ATP2A1-related disorder	2022-11-15	criteria provided, single submitter	clinical testing	The ATP2A1 c.2322-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice acceptor site in ATP2A1 are expected to be pathogenic, and therefore we interpret c.2322-2A>G as likely pathogenic.