ClinVar Miner

Submissions for variant NM_000702.4(ATP1A2):c.1541G>A (p.Arg514Gln) (rs748654627)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000186809 SCV000240379 uncertain significance not provided 2017-01-27 criteria provided, single submitter clinical testing The R514Q variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. A missense substitution in the adjacent residue (C515Y) has been reported previously in two siblings, one reported migraine with aura and the other migraine without aura; the variant was inherited from an unaffected mother (Todt et al., 2005). Further functional studies show that the C515Y substitution results in a complete loss of protein function (Todt et al., 2005). The R514Q variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R514Q variant is a semi-conservative amino 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. The variant is found in EPILEPSY panel(s).
Invitae RCV000695539 SCV000824046 uncertain significance Familial hemiplegic migraine 2018-10-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 514 of the ATP1A2 protein (p.Arg514Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs748654627, ExAC 0.009%). This variant has not been reported in the literature in individuals with ATP1A2-related disease. ClinVar contains an entry for this variant (Variation ID: 204907). 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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