Submissions for variant NM_000702.4(ATP1A2):c.1931G>A (p.Arg644Gln)

gnomAD frequency: 0.00001  dbSNP: rs745824475

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001363754	SCV001559879	uncertain significance	Familial hemiplegic migraine	2024-09-10	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 644 of the ATP1A2 protein (p.Arg644Gln). This variant is present in population databases (rs745824475, gnomAD 0.004%). 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: 204894). 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) has been performed 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.
Illumina Laboratory Services, Illumina	RCV001795306	SCV002034847	uncertain significance	Migraine, familial hemiplegic, 2	2021-08-20	criteria provided, single submitter	clinical testing	The ATP1A2 c.1931G>A (p.Arg644Gln) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. The p.Arg644Gln variant is reported at a frequency of 0.000035 in the European (non-Finnish) population of the Genome Aggregation Database (version 2.1.1). Based on the limited evidence, the p.Arg644Gln variant is classified as a variant of uncertain significance for familial hemiplegic migraine.
New York Genome Center	RCV002265673	SCV002548712	uncertain significance	Alternating hemiplegia of childhood 1; Migraine, familial hemiplegic, 2	2021-06-04	criteria provided, single submitter	clinical testing	The inherited c.1931G>A (p.Arg644Gln) variant identified in the ATP1A2 gene substitutes a very well conserved Arginine for Glutamine at amino acid 644/1021 (exon 14/23). This variant is found with low frequency in gnomAD(v3.1.1) (1 heterozygote, 0 homozygotes; allele frequency:6.57e-6) suggesting itis not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Damaging (SIFT; score:0.007) and Pathogenic (REVEL; score:0.6629) to the function of the canonical transcript. This variant is reported as a Variant of Uncertain Significance in ClinVar (VarID:204894)and to our current knowledge has not been reported in affected individuals in the literature. The p.Arg644 residue is within a cytoplasmic domain of the protein(UniProtKB:P50993). Given the lack of compelling evidence for its pathogenicity, the inherited c.1931G>A (p.Arg644Gln) variant identified in the ATP1A2 gene is reported as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV005049464	SCV005681036	uncertain significance	Alternating hemiplegia of childhood 1; Migraine, familial hemiplegic, 2; Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies; Developmental and epileptic encephalopathy 98	2024-03-13	criteria provided, single submitter	clinical testing
GenomeConnect - Brain Gene Registry	RCV002265673	SCV004804610	not provided	Alternating hemiplegia of childhood 1; Migraine, familial hemiplegic, 2		no assertion provided	phenotyping only	Variant classified as Likely pathogenic and reported on 04-01-2021 by New York Genome Center. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.