ClinVar Miner

Submissions for variant NM_000702.4(ATP1A2):c.2288G>A (p.Arg763His)

dbSNP: rs1403515889
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001351840 SCV001546343 uncertain significance Familial hemiplegic migraine 2024-01-10 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 763 of the ATP1A2 protein (p.Arg763His). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with familial hemiplegic migraine (PMID: 15159495). ClinVar contains an entry for this variant (Variation ID: 1047163). 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: 18728015). 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: 17142831), 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.
GeneDx RCV001556171 SCV001777702 likely pathogenic not provided 2024-07-22 criteria provided, single submitter clinical testing Previously reported in one family with familial hemiplegic migraine; variant was present in the affected parent and in one affected and one unaffected child (PMID: 15159495); Published functional studies demonstrate R763H results in altered affinity for extracellular cations and reduced enzyme turnover (PMID: 18728015); Not observed at a 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: 17559350, 24336169, 15907261, 15549578, 22924536, 19455354, 15513297, 16088919, 26167768, 18184292, 37870493, 18728015, 15159495)

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