Submissions for variant NM_000702.4(ATP1A2):c.2287C>T (p.Arg763Cys)

dbSNP: rs2101995435

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001756558	SCV001985488	uncertain significance	not provided	2024-11-21	criteria provided, single submitter	clinical testing	Identified in three affected individuals from a single family with familial hemiplegic migraine, however, the variant did not fully segregate with disease as the variant was absent in another affected family member (PMID: 17142831); 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; This variant is associated with the following publications: (PMID: 29343472, 20727009, 24336169, 18294248, 27445835, 17235123, 17142831, 37870493)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002032771	SCV002132076	uncertain significance	Familial hemiplegic migraine	2024-05-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 763 of the ATP1A2 protein (p.Arg763Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial hemiplegic migraine (PMID: 17142831, 29343472). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1303059). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg763 amino acid residue in ATP1A2. Other variant(s) that disrupt this residue have been observed in individuals with ATP1A2-related conditions (PMID: 15159495, 18728015), 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.
PreventionGenetics, part of Exact Sciences	RCV003401671	SCV004120968	uncertain significance	ATP1A2-related disorder	2023-02-14	criteria provided, single submitter	clinical testing	The ATP1A2 c.2287C>T variant is predicted to result in the amino acid substitution p.Arg763Cys. This variant was reported in one family with several members who presented with familial hemiplegic migraine or migraine with aura; however, it did not entirely segregate with disease in the family, as one individual with the variant did not present with the disease (family 6016, Thomsen et al. 2007. PubMed ID: 17142831). This variant was also described as a variant of uncertain significance in a large cohort of patients with hemiplegic migraine; in this study, the variant was present in six patients with hemiplegic migraine (Pelzer et al. 2018. PubMed ID: 29343472, supplementary data). A different amino acid substitution at this position (p.Arg763His) was previously reported in association with hemiplegic migraine (Jurkat-Rott et al. 2004. PubMed ID: 15159495). The c.2287C>T (p.Arg763Cys) variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Although we suspect that this variant may be pathogenic, the clinical significance of this variant is currently classified as uncertain due to the absence of conclusive functional and genetic evidence.