Submissions for variant NM_000702.4(ATP1A2):c.193C>T (p.Arg65Trp)

gnomAD frequency: 0.00006  dbSNP: rs121918619

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000442150	SCV000518163	uncertain significance	not provided	2024-03-28	criteria provided, single submitter	clinical testing	Reported in several individuals with familial hemiplegic migraine including three siblings; however, variant was not present in another sibling with migraines without aura (PMID: 17877748, 21533730); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34384358, 35257835, 23334666, 26934580, 26147798, 21533730, 17877748, 36044383)
Illumina Laboratory Services, Illumina	RCV000013792	SCV001254125	uncertain significance	Migraine, familial hemiplegic, 2	2017-08-31	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000013792	SCV001367969	uncertain significance	Migraine, familial hemiplegic, 2	2019-05-13	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP2,PP3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001221618	SCV001393674	uncertain significance	Familial hemiplegic migraine	2023-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 65 of the ATP1A2 protein (p.Arg65Trp). This variant is present in population databases (rs121918619, gnomAD 0.01%). This missense change has been observed in individual(s) with familial hemiplegic migraine (PMID: 17877748). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12929). 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) performed at Invitae indicates that this missense variant is not expected to disrupt ATP1A2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect ATP1A2 function (PMID: 34384358). This variant disrupts the p.Arg65 amino acid residue in ATP1A2. Other variant(s) that disrupt this residue have been observed in individuals with ATP1A2-related conditions (PMID: 35257835), which suggests that this may be a clinically significant amino acid residue. 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.
OMIM	RCV000013792	SCV000034039	pathogenic	Migraine, familial hemiplegic, 2	2007-12-01	no assertion criteria provided	literature only
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000442150	SCV001552791	uncertain significance	not provided		no assertion criteria provided	clinical testing	The ATP1A2 p.Arg65Trp variant was identified in the literature in three siblings with hemiplegic migraines but was not identified in the fourth siblings who also suffered from migraines (Tonelli_2007_PMID:17877748). The variant was identified in dbSNP (ID: rs121918619) and ClinVar (classified as a VUS by GeneDx). The variant was also identified in control databases in 17 of 282430 chromosomes at a frequency of 0.00006019 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 13 of 128770 chromosomes (freq: 0.000101), African in 2 of 24964 chromosomes (freq: 0.00008), East Asian in 1 of 19950 chromosomes (freq: 0.00005) and South Asian in 1 of 30616 chromosomes (freq: 0.000033), but was not observed in the Latino, Ashkenazi Jewish, European (Finnish) or Other populations. The p.Arg65 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.