ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Ambry Genetics RCV000715034 SCV000845857 uncertain significance Familial hemiplegic migraine 2018-01-17 criteria provided, single submitter clinical testing The p.G758A variant (also known as c.2273G>C), located in coding exon 16 of the ATP1A2 gene, results from a G to C substitution at nucleotide position 2273. The glycine at codon 758 is replaced by alanine, an amino acid with similar properties. This alteration was detected in a female fulfilling diagnostic criteria for sporadic hemiplegic migraine (Aceves J et al. Case Rep Neurol Med, 2013 Dec;2013:895057). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000715034 SCV001010225 likely benign Familial hemiplegic migraine 2020-12-02 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000186798 SCV001143131 benign not provided 2018-12-06 criteria provided, single submitter clinical testing

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