Submissions for variant NM_000702.4(ATP1A2):c.1541G>A (p.Arg514Gln)

gnomAD frequency: 0.00003  dbSNP: rs748654627

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000186809	SCV000240379	uncertain significance	not provided	2017-01-27	criteria provided, single submitter	clinical testing	The R514Q variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. A missense substitution in the adjacent residue (C515Y) has been reported previously in two siblings, one reported migraine with aura and the other migraine without aura; the variant was inherited from an unaffected mother (Todt et al., 2005). Further functional studies show that the C515Y substitution results in a complete loss of protein function (Todt et al., 2005). The R514Q variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R514Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. 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. The variant is found in EPILEPSY panel(s).
Invitae	RCV000695539	SCV000824046	uncertain significance	Familial hemiplegic migraine	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 514 of the ATP1A2 protein (p.Arg514Gln). This variant is present in population databases (rs748654627, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of autosomal dominant ATP1A-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 204907). 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. 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000186809	SCV001713906	uncertain significance	not provided	2020-01-08	criteria provided, single submitter	clinical testing