ClinVar Miner

Submissions for variant NM_022089.4(ATP13A2):c.3057del (p.Tyr1020fs) (rs765632065)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000598921 SCV000709790 pathogenic not provided 2018-01-19 criteria provided, single submitter clinical testing The c.3057delC variant in the ATP13A2 gene has been 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). The c.3057delC variant causes a frameshift starting with codon Tyrosine 1020, changes this amino acid to a Threonine residue, and creates a premature Stop codon at position 3 of the new reading frame, denoted p.Tyr1020ThrfsX3. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Functional studies show that c.3057delC has lower steady-state levels of expression compared with wild-type (Tan et al., 2011). The c.3057delC variant is observed in 36/274698 (0.01%) alleles in large population cohorts and no individuals were reported to be homozygous (Lek et al., 2016). We interpret c.3057delC as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000541447 SCV000915371 likely pathogenic Parkinson disease 9 2017-04-28 criteria provided, single submitter clinical testing 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.
Invitae RCV000541447 SCV000640179 pathogenic Parkinson disease 9 2017-07-27 criteria provided, single submitter clinical testing 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. This variant is present in population databases (rs765632065, ExAC 0.02%). This variant has been reported  in combination with another ATP13A2 variant to segregate with Kufor-Rakeb syndrome (KRS) in a single family (PMID: 16964263). Experimental studies have shown that this deletion results in retention in the ER, accelerated degradation, and reduced mitochondrial membrane potential and ATP synthesis rates in patient-derived fibroblasts (PMID: 21665991, 22296644). Loss-of-function variants in ATP13A2 are known to be pathogenic (PMID: 16964263, 21696388). For these reasons, this variant has been classified as Pathogenic.

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