ClinVar Miner

Submissions for variant NM_000702.4(ATP1A2):c.152G>A (p.Arg51His) (rs144106169)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000475103 SCV000848929 likely benign Familial hemiplegic migraine 2017-05-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Does not segregate with disease in family study (genes with incomplete penetrance)
GeneDx RCV000414480 SCV000491293 uncertain significance not specified 2016-08-03 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ATP1A2 gene. The R51H variant has been reported in association with migraine without aura; however, functional studies showed no significant differences between this variant and the wild type protein (Swarts et al., 2013). The R51H 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 R51H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is 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.
Invitae RCV000475103 SCV000544732 uncertain significance Familial hemiplegic migraine 2018-11-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 51 of the ATP1A2 protein (p.Arg51His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs144106169, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in a family affected with migraine without aura (PMID: 23954377). ClinVar contains an entry for this variant (Variation ID: 372793). Experimental studies have shown that this  this missense change does not affect ATP1A2 protein expression, Na,K-ATPase activity, or ATP affinity and turnover (PMID: 23954377). 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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