ClinVar Miner

Submissions for variant NM_000702.4(ATP1A2):c.889G>A (p.Ala297Thr) (rs181618883)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000678349 SCV000896172 uncertain significance Alternating hemiplegia of childhood 1; Familial hemiplegic migraine type 2 2018-10-31 criteria provided, single submitter clinical testing
Geisinger Autism and Developmental Medicine Institute,Geisinger Health System RCV000678349 SCV000804413 uncertain significance Alternating hemiplegia of childhood 1; Familial hemiplegic migraine type 2 2017-05-26 criteria provided, single submitter provider interpretation This 9 year old female with an intellectual disability was found to carry a missense variant in the ATP1A2 gene. Inheritance is unknown, as is paternal family history. She is non-dysmorphic, normocephalic, and does not have any congenital anomalies. At the date of report, the patient was not presenting with signs of migraines or hemiplegia. The variant is absent from population databases. It is a non-conservative substitution that occurs at a position that is conserved across species. In silico analysis predicts that the variant is probably damaging to protein structure/function.
GeneDx RCV000493825 SCV000583066 uncertain significance not provided 2018-01-26 criteria provided, single submitter clinical testing The A297T variant in the ATP1A2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The A297T 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 A297T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other 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. We interpret A297T as a variant of uncertain significance.
Invitae RCV000533161 SCV000632377 uncertain significance Familial hemiplegic migraine 2018-04-26 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 297 of the ATP1A2 protein (p.Ala297Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs181618883, ExAC 0.01%). This variant has not been reported in the literature in individuals with an ATP1A2-related disease. 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. In summary, this variant has uncertain impact on ATP1A2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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