ClinVar Miner

Submissions for variant NM_000702.4(ATP1A2):c.2770G>A (p.Val924Met) (rs373276446)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000440880 SCV000533010 uncertain significance not provided 2016-10-24 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ATP1A2 gene. The V924M variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V924M 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. This substitution occurs at a position that is conserved across species. However, the V924M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. 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 RCV000635217 SCV000756600 uncertain significance Familial hemiplegic migraine 2019-11-08 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 924 of the ATP1A2 protein (p.Val924Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs373276446, ExAC 0.004%). This variant has not been reported in the literature in individuals with ATP1A2-related disease. ClinVar contains an entry for this variant (Variation ID: 390229). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Fulgent Genetics,Fulgent Genetics RCV000763752 SCV000894638 uncertain significance Alternating hemiplegia of childhood 1; Familial hemiplegic migraine type 2 2018-10-31 criteria provided, single submitter clinical testing

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