ClinVar Genomic variation as it relates to human health

Variant summary: ATP13A2 c.2236G>A (p.Ala746Thr) results in a non-conservative amino acid change located in the P-type ATPase, haloacid dehalogenase domain (IPR044492) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 251344 control chromosomes, predominantly at a frequency of 0.0016 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 8-fold of the estimated maximal expected allele frequency for a pathogenic variant in ATP13A2 causing Neurodegeneration With Brain Iron Accumulation phenotype (0.00019), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.2236G>A has been reported in the literature in the heterozygous state in individuals affected with early onset or familial Parkinson's disease, however it has also been reported in healthy ethnicity-matched control individuals (e.g. Lin_2008, Funayama_2010, Chen_2011). These reports do not provide unequivocal conclusions about association of the variant with disease. Functional experiments have shown that the variant has little to no effect on protein expression and cellular localization, but may mildly increase caspase 3 activity, whereas it was shown to reduce ATPase activity by approximately 40% compared to WT (Chen_2011, Podhajska_2012). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.

BP4_moderate

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 746 of the ATP13A2 protein (p.Ala746Thr). This variant is present in population databases (rs147277743, gnomAD 0.1%). This missense change has been observed in individual(s) with early-onset and late-onset Parkinson disease, as well as unaffected controls (PMID: 19015489, 20227461, 20976737, 21714071, 23522931). This variant is also known as A741T. ClinVar contains an entry for this variant (Variation ID: 465257). 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 ATP13A2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ATP13A2 function (PMID: 21714071, 22768177, 31996848). 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.