Submissions for variant NM_000702.4(ATP1A2):c.712C>T (p.Arg238Cys)

dbSNP: rs1558004341

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002316178	SCV000847816	uncertain significance	Inborn genetic diseases	2016-09-10	criteria provided, single submitter	clinical testing	The p.R238C variant (also known as c.712C>T), located in coding exon 7 of the ATP1A2 gene, results from a C to T substitution at nucleotide position 712. The arginine at codon 238 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000716971	SCV001407758	uncertain significance	Familial hemiplegic migraine	2022-12-02	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 588262). This variant has not been reported in the literature in individuals affected with ATP1A2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 238 of the ATP1A2 protein (p.Arg238Cys).
GeneDx	RCV003128658	SCV003805019	uncertain significance	not provided	2022-08-22	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
PreventionGenetics, part of Exact Sciences	RCV003411654	SCV004106811	uncertain significance	ATP1A2-related disorder	2023-09-03	criteria provided, single submitter	clinical testing	The ATP1A2 c.712C>T variant is predicted to result in the amino acid substitution p.Arg238Cys. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.