ClinVar Miner

Submissions for variant NM_000702.4(ATP1A2):c.192G>T (p.Gln64His) (rs796052282)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000186812 SCV000240382 uncertain significance not provided 2015-04-10 criteria provided, single submitter clinical testing p.Gln64His (CAG>CAT): c.192 G>T in exon 4 of the ATP1A2 gene (NM_000702.3). The Q64H variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Q64H variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved through mammals. 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 mutation or a rare benign variant. The variant is found in EPILEPSYV2-1 panel(s).
Fulgent Genetics,Fulgent Genetics RCV000764992 SCV000896171 uncertain significance Alternating hemiplegia of childhood 1; Familial hemiplegic migraine type 2 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000815024 SCV000955464 uncertain significance Familial hemiplegic migraine 2019-05-13 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 64 of the ATP1A2 protein (p.Gln64His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATP1A2-related disease. ClinVar contains an entry for this variant (Variation ID: 204910). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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