ClinVar Miner

Submissions for variant NM_000702.4(ATP1A2):c.1859C>G (p.Thr620Arg) (rs1057521886)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000434987 SCV000524892 uncertain significance not provided 2018-11-13 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ATP1A2 gene. The T620R variant has not beenpublished as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observedin approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome SequencingProject, indicating it is not a common benign variant in these populations. The T620R variant is a semi-conservativeamino acid substitution, which may impact secondary protein structure as these residues differ in some properties.This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant isprobably damaging to the protein structure/function. Based on the currently available information, it is unclearwhether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000470321 SCV000544731 uncertain significance Familial hemiplegic migraine 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces threonine with arginine at codon 620 of the ATP1A2 protein (p.Thr620Arg). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATP1A2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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