ClinVar Miner

Submissions for variant NM_000702.4(ATP1A2):c.2273G>C (p.Gly758Ala) (rs147183887)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000715034 SCV000845857 uncertain significance Familial hemiplegic migraine 2018-01-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000186798 SCV000240367 uncertain significance not provided 2016-02-03 criteria provided, single submitter clinical testing The G758A variant has been reported in an individual with sporadic hemiplegic migraine; however, no additional information was provided to unequivocally demonstrate that it was pathogenic (Aceves et al., 2013). The G758A variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, but the 1000 Genomes Project reports it was observed in 1/198 (0.5%) alleles from individuals of Finnish background and in 1/214 (0.5%) alleles from individuals of Spanish background, indicating it may be a rare (benign) variant in these populations. The G758A 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 highly conserved across species. Missense mutations in nearby residues (R763C, R763H, L764P) have been reported in the Human Gene Mutation Database in association with hemiplegic migraine, supporting the functional importance of this region of the protein. Additionally, 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 mutation or a rare benign variant.

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