Submissions for variant NM_000702.4(ATP1A2):c.1318G>A (p.Val440Met)

dbSNP: rs768088341

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000440352	SCV000525316	uncertain significance	not provided	2016-03-15	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the ATP1A2 gene. The V440M variant has not been published as a pathogenic variant, nor has it been reported as a benign variant 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 V440M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. However, in silico analysis predicts this variant is probably 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.
Ambry Genetics	RCV002379337	SCV002692098	uncertain significance	Inborn genetic diseases	2017-08-15	criteria provided, single submitter	clinical testing	The p.V440M variant (also known as c.1318G>A), located in coding exon 10 of the ATP1A2 gene, results from a G to A substitution at nucleotide position 1318. The valine at codon 440 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV003766281	SCV004673622	uncertain significance	Familial hemiplegic migraine	2022-12-20	criteria provided, single submitter	clinical testing	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. 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 ATP1A2 protein function. ClinVar contains an entry for this variant (Variation ID: 384479). This variant has not been reported in the literature in individuals affected with ATP1A2-related conditions. This variant is present in population databases (rs768088341, gnomAD 0.003%). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 440 of the ATP1A2 protein (p.Val440Met).
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000440352	SCV001928521	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000440352	SCV001956468	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000440352	SCV001974815	uncertain significance	not provided		no assertion criteria provided	clinical testing