Submissions for variant NM_000702.4(ATP1A2):c.1643G>A (p.Arg548His)

dbSNP: rs121918616

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000423537	SCV000520966	pathogenic	not provided	2020-08-25	criteria provided, single submitter	clinical testing	Published in vitro functional studies demonstrated that R548H variant results in reduced ATPase activity, alters the affinity for sodium and potassium, and reduces catalytic turnover compared to the wild type protein (Swarts et al., 2013); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 18498390, 23954377, 16088919, 16344534, 27445835)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851832	SCV002237784	pathogenic	Familial hemiplegic migraine	2024-03-12	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 548 of the ATP1A2 protein (p.Arg548His). This variant is present in population databases (rs121918616, gnomAD 0.0009%). This missense change has been observed in individuals with clinical features of autosomal dominant ATP1A2-related conditions (PMID: 16344534; Invitae; Maksemous et al. 2019 Cephalagia Reports Vol. 2). ClinVar contains an entry for this variant (Variation ID: 12926). 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 expected to disrupt ATP1A2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ATP1A2 function (PMID: 23954377). This variant disrupts the p.Arg548 amino acid residue in ATP1A2. Other variant(s) that disrupt this residue have been observed in individuals with ATP1A2-related conditions (PMID: 18498390), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV004555532	SCV004046003	pathogenic	ATP1A2-related disorder		criteria provided, single submitter	clinical testing	This variant has been previously reported as a heterozygous change in patients with Hemiplegic migraine and Basilar migraine (PMID: 16344534, and Maksemous et al., 2019). Additionally, a different variant at the same amino acid position (p.Arg548Cys) has been seen in multiple patients with ATP1A2-Related Disorders (ClinVar Variation ID: 871961). In vitro overexpression studies revealed that the c.1643G>A (p.Arg548His) variant has reduced Na(+) affinity and increased K(+) affinity, leading to reduced catalytic turnover compared to the wild type protein (PMID: 23954377). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0004% (1/251212) and thus is presumed to be rare. The c.1643G>A (p.Arg548His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1643G>A (p.Arg548His) variant is classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV003448245	SCV004175965	pathogenic	Migraine, familial hemiplegic, 2	2024-07-18	criteria provided, single submitter	clinical testing	Criteria applied: PS4_MOD,PM2,PM5,PS3_SUP,PP1,PP2,PP3
Institute of Human Genetics, Heidelberg University	RCV004819208	SCV005440696	pathogenic	Developmental and epileptic encephalopathy 98	2024-04-26	criteria provided, single submitter	clinical testing
OMIM	RCV000013789	SCV000034036	pathogenic	Migraine, familial basilar	2005-12-13	no assertion criteria provided	literature only