Submissions for variant NM_000702.4(ATP1A2):c.1148G>A (p.Arg383His)

gnomAD frequency: 0.00001  dbSNP: rs765909830

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000186788	SCV000240357	likely pathogenic	not provided	2017-03-16	criteria provided, single submitter	clinical testing	p.Arg383His (CGC>CAC): c.1148 G>A in exon 9 of the ATP1A2 gene (NM_000702.3). The R383H variant was previously identified in an individual with sporadic hemiplegic migraine; however, parental studies were not performed (Jurkat-Rott et al., 2004). Functional studies suggested that the R383H variant reduces the conformational flexibility of the ATP1A2 protein, resulting in a decrease in enzyme turnover (Tavraz et al., 2008). 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 R383H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution alters a highly conserved position in the cytoplasmic loop between the nucleotide-binding and phosphorylation domains of the ATP1A2 protein (Tavraz et al., 2008), and missense mutations in nearby residues (T376M, T378N) have been reported in association with hemiplegic migraine, supporting the functional importance of this region of the protein. Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in EPILEPSY panel(s).
Mendelics	RCV002247600	SCV002518549	pathogenic	Alternating hemiplegia of childhood 1	2022-05-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003584560	SCV004292940	likely pathogenic	Familial hemiplegic migraine	2024-02-07	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 383 of the ATP1A2 protein (p.Arg383His). This variant is present in population databases (rs765909830, gnomAD 0.03%). This missense change has been observed in individuals with ATP1A2-related conditions and/or hemiplegic migraine (PMID: 15159495, 29486580, 29655203). ClinVar contains an entry for this variant (Variation ID: 204886). 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. Experimental studies have shown that this missense change affects ATP1A2 function (PMID: 18728015). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.