Submissions for variant NM_152296.5(ATP1A3):c.1924G>A (p.Val642Ile)

gnomAD frequency: 0.00005  dbSNP: rs201391210

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000358956	SCV000413421	likely benign	Alternating hemiplegia of childhood 2	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV000395872	SCV000413422	likely benign	Dystonia 12	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Invitae	RCV000395872	SCV001376566	uncertain significance	Dystonia 12	2024-01-07	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 642 of the ATP1A3 protein (p.Val642Ile). This variant is present in population databases (rs201391210, gnomAD 0.008%). 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: 329410). 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.
PreventionGenetics, part of Exact Sciences	RCV003409523	SCV004115685	uncertain significance	ATP1A3-related condition	2022-10-19	criteria provided, single submitter	clinical testing	The ATP1A3 c.1963G>A variant is predicted to result in the amino acid substitution p.Val655Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0085% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-42482107-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.