ClinVar

Description

Variant summary: ATP13A2 c.3205G>A (p.Ala1069Thr) results in a non-conservative amino acid change in 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 0.00033 in 249438 control chromosomes, predominantly at a frequency of 0.0026 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 14-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 South Asian origin. c.3205G>A has been reported in the literature as a compound heterozygous genotype in an individual affected with autosomal recessive juvenile-onset Parkinson disease (Suleiman_2018). However, this report does not provide unequivocal conclusions about association of the variant with Neurodegeneration With Brain Iron Accumulation. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29903538). One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.