ClinVar Miner

Submissions for variant NM_152296.5(ATP1A3):c.2968G>A (p.Val990Ile)

gnomAD frequency: 0.00001  dbSNP: rs781786336
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000437172 SCV000523475 uncertain significance not provided 2016-02-11 criteria provided, single submitter clinical testing The V990I variant in the ATP1A3 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The V990I variant was not observed in approximately 6500 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 V990I variant is a conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A missense variant in nearby residue (D992Y) has been reported in the Human Gene Mutation Database in association with alternating hemiplegia of childhood (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret V990I as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV001319729 SCV001510487 uncertain significance Dystonia 12 2023-11-09 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 990 of the ATP1A3 protein (p.Val990Ile). This variant is present in population databases (rs781786336, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ATP1A3-related conditions. ClinVar contains an entry for this variant (Variation ID: 383177). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ATP1A3 protein function. 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 RCV002480300 SCV002779330 uncertain significance Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome; Dystonia 12; Alternating hemiplegia of childhood 2; Developmental and epileptic encephalopathy 99 2022-05-12 criteria provided, single submitter clinical testing

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