ClinVar Miner

Submissions for variant NM_000702.4(ATP1A2):c.2563G>A (p.Gly855Arg) (rs1553245857)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000516947 SCV000612440 pathogenic not provided 2017-02-07 criteria provided, single submitter clinical testing
Invitae RCV000694302 SCV000822740 pathogenic Familial hemiplegic migraine 2018-09-14 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 855 of the ATP1A2 protein (p.Gly855Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant also falls at the last nucleotide of exon 18 of the ATP1A2 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in an individual affected with familial hemiplegic migraine and was also present in two children who were also affected (PMID: 19874388). ClinVar contains an entry for this variant (Variation ID: 446871). Experimental studies have shown that this missense change results in an ATP1A2 protein with no detectable activity towards establishing and maintaining an electrochemical gradient of Na and K ions across the plasma membrane (PMID: 19874388, 24921013). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. For these reasons, this variant has been classified as Pathogenic.

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