ClinVar Genomic variation as it relates to human health

The ATP13A2 c.3057delC (p.Tyr1020ThrfsTer3) variant is a frameshift variant and is predicted to result in a premature termination of the protein. The variant has been reported in a compound heterozygous state in four siblings of a large non-consanguineous Chilean family with Kufor-Rakeb syndrome (Ramirez et al. 2006). The variant segregates with disease in this family over two generations, with three unaffected siblings and the mother carrying the p.Tyr1020ThrfsTer3 variant in a heterozygous state. Further evaluation of this same family by Bruggemann et al. (2010) showed that the p.Tyr1020ThrfsTer3 variant in single heterozygous state may be a risk allele for later onset Parkinsonism. Control data are unavailable for this variant, which is reported at a frequency of 0.00021 in the European (non-Finnish) population of the Exome Aggregate Consortium. Functional studies demonstrated that the p.Tyr1020ThrfsTer3 variant protein is mislocalized to the endoplasmic reticulum and is targeted for degradation via the proteasome (Ramirez et al. 2006; Ugolino et al. 2011; Podhajska et al. 2012). Based on the available evidence and the potential impact of frameshift variants, the p.Tyr1020ThrfsTer3 variant is classified as likely pathogenic for Kufor-Rakeb syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

The c.3057delC variant has been previously reported as disease-causing in PMIDs 22296644, 21724849, 29966207, 16964263, 21665991.

Variant summary: ATP13A2 c.3057delC (p.Tyr1020ThrfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00014 in 248620 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATP13A2 causing Neurodegeneration With Brain Iron Accumulation/Kufor-Rakeb syndrome (0.00014 vs 0.00019), allowing no conclusion about variant significance. c.3057delC has been reported in the literature in multiple individuals affected with Neurodegeneration associated with Kufor-Rakeb syndrome (example, Ramirez_2006, Inzelberg_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function demonstrating that this mutant is unstable and localizes in the endoplasmic reticulum (ER), does not reach the lysosome, is cytotoxic and hypersensitizes cells to ER-stress induced cell-death (example, Ugolio_2011). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Reported previously in association with Kufor-Rakeb syndrome in a family where affected individuals were compound heterozygous for the c.3057delC variant and another variant (Ramirez et al., 2006); Published functional studies suggest that c.3057delC has lower steady-state levels of expression compared with wild-type (Tan et al., 2011); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21696388, 21665991, 21724849, 22296644, 16964263, 29966207, 31692161, 31980526, 35180557)

This sequence change creates a premature translational stop signal (p.Tyr1020Thrfs*3) in the ATP13A2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATP13A2 are known to be pathogenic (PMID: 16964263, 21696388). This variant is present in population databases (rs765632065, gnomAD 0.3%). This premature translational stop signal has been observed in individual(s) with Kufor-Rakeb syndrome (KRS) (PMID: 16964263). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 465253). For these reasons, this variant has been classified as Pathogenic.

The c.3057delC (p.Y1020Tfs*3) alteration, located in exon 26 (coding exon 26) of the ATP13A2 gene, consists of a deletion of one nucleotide at position 3057, causing a translational frameshift with a predicted alternate stop codon after 3 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration has been reported in trans with a second ATP13A2 alteration in patients with features of Kufor-Rakeb syndrome, including early-onset Parkinson's disease, and has been shown to segregate with disease in multiple families (Ramirez, 2006; Behrens, 2010; Brüggemann, 2010; Inzelberg, 2018). Functional studies in patient-derived cells suggest this alteration results in loss of function due to impaired localization and degradation in the ER (Ramirez, 2006; Tan, 2011; Ugolino, 2011; Podhajska, 2012). Based on the available evidence, this alteration is classified as pathogenic.

PM2_moderate, PS3, PS4_moderate, PVS1