Submissions for variant NM_000702.4(ATP1A2):c.1283G>A (p.Arg428His)

gnomAD frequency: 0.00001  dbSNP: rs746478136

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000418786	SCV000523605	uncertain significance	not provided	2016-02-04	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the ATP1A2 gene. The R428H variant has not beenpublished as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observedin approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome SequencingProject, indicating it is not a common benign variant in these populations. This substitution occurs at a position thatis conserved across species. In silico analysis predicts this variant is probably damaging to the proteinstructure/function. However, the R428H variant is a conservative amino acid substitution, which is not likely toimpact secondary protein structure as these residues share similar properties. Therefore, based on the currentlyavailable information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
CeGaT Center for Human Genetics Tuebingen	RCV000418786	SCV001248568	uncertain significance	not provided	2019-11-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001865345	SCV002157162	uncertain significance	Familial hemiplegic migraine	2025-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 428 of the ATP1A2 protein (p.Arg428His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with ATP1A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 383264). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ATP1A2 protein function with a negative predictive value of 80%. 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.