ClinVar Miner

Submissions for variant NM_152296.5(ATP1A3):c.2263G>T (p.Gly755Cys) (rs557052809)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneReviews RCV000148314 SCV000195702 pathogenic Alternating hemiplegia of childhood 2 2014-05-04 no assertion criteria provided literature only
Invitae RCV000816262 SCV000956762 pathogenic Dystonia 12 2018-11-21 criteria provided, single submitter clinical testing This sequence change replaces glycine with cysteine at codon 755 of the ATP1A3 protein (p.Gly755Cys). The glycine residue is moderately conserved and there is a large physicochemical difference between glycine and cysteine. This variant also falls at the last nucleotide of exon 16 of the ATP1A3 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 observed in individuals affected with alternating hemiplegia of childhood (PMID: 22850527, 23409136, 24842602). ClinVar contains an entry for this variant (Variation ID: 161133). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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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