ClinVar Miner

Submissions for variant NM_152296.5(ATP1A3):c.2417T>G (p.Met806Arg) (rs549006436)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000644929 SCV000766651 likely pathogenic Dystonia 12 2017-11-22 criteria provided, single submitter clinical testing This sequence change replaces methionine with arginine at codon 806 of the ATP1A3 protein (p.Met806Arg). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with alternating hemiplegia of childhood (PMID: 22842232, 26410222). ClinVar contains an entry for this variant (Variation ID: 161142). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This missense change is located in a region of the ATP1A3 protein where a significant number of previously reported ATP1A3 missense mutations are found (PMID: 24523486). These observations suggest that a previously unreported missense substitution within this region may affect protein function, but experiments have not been done to test this possibility. 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.
GeneReviews RCV000148323 SCV000195712 pathogenic Alternating hemiplegia of childhood 2 2014-05-04 no assertion criteria provided literature only

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