ClinVar Miner

Submissions for variant NM_000702.4(ATP1A2):c.1582G>A (p.Asp528Asn) (rs374501280)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000497790 SCV000590133 uncertain significance not provided 2018-01-02 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ATP1A2 gene. The D528N variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to ourknowledge. The D528N variant is observed in 2/10382 (0.02%) alleles from individuals of Africanbackground in large population cohorts (Lek et al., 2016). The D528N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in someproperties. This substitution occurs at a position that is conserved across species, and in-silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense variants in nearby residues have not been reported in Human Gene Mutation Database in association with ATP1A2-related disorders (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000687143 SCV000814695 uncertain significance Familial hemiplegic migraine 2018-04-13 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 528 of the ATP1A2 protein (p.Asp528Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs374501280, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with ATP1A2-related disease. ClinVar contains an entry for this variant (Variation ID: 432411). 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 C15"). 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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